Ginkgo biloba L. + (HERBAL MEDICINAL)

HERBAL

M E D I C I N A L

GINKGO, MAIDENHAIR TREE

Ginkgo biloba L. + 

by

RETTODWIKART THENU

GINKGO

(ging’koe)

GINKGO, MAIDENHAIR TREE

SCIENTIFIC NAME

(Ginkgo biloba L.) + (Downgraded for safety)

OTHER COMMON NAMES

Maidenhair tree, rokan, sophium, tanakan, tebofortan, tebonin (Linda, S-R. 2010). Ginkgobaum (Ger.) In England, it is known as ‘Maidenhair tree’ based on its resemblance to the foliage of the ‘Maidenhair fern’ (Adiantum). In Japan, it is known as ‘Ginkyo’ and in France, ‘L’arbre aux Quarante ecus’ and ‘Noyer Du Japon’ (Singh et al., 2008).

SYNONYM(S) (Barnes, J et al., 2007)

Fossil Tree, Kew Tree, Maidenhair Tree, Yin Xing (whole plant), Yin Xing Ye (leaves), Bai Guo (seeds), Salisburia adiantifolia Sm., S. biloba (L.) Hoffmans

HISTORICAL NOTE (Braun, L and Cohen, M. 2010)

Ginkgo biloba is one of the world’s oldest living tree species, earning it the name ‘living fossil’. Its existence can be traced back more than 200 million years and it was commonly found in North America and Europe before the Ice Age. Its place of origin is believed to be remote mountainous valleys of Zhejiang province of eastern China and up to 350 years ago, knowledge about this plant was restricted to China (Singh et al., 2008). Ginkgo was first introduced into Europe in 1690 by the botanist Engelbert Kaempfer, who described it as the ‘tree with duck feet’. Ginkgo has been used medicinally for decades and is now one of the most popular therapeutic agents prescribed in Europe by medical doctors. It has been estimated that in Germany and France, prescriptions for ginkgo make up 1% and 1.3%, respectively, of total prescription sales (Pizzorno & Murray 2006). Also popular in the United States, it was the top-selling herbal medicine in 1999 with sales of US$148 million.

Current estimates indicate that the use of G. Biloba has been growing at a very rapid rate worldwide a 25% per year in the open world commercial market (Singh et al., 2008). Germany, Switzerland and France have respectively 31%, 8% and 5% of the world commercial market. To meet the demand for ginkgo products, 50 million G. biloba trees are grown, especially in China, France and South Carolina, USA, producing 8000 tons of dried leaves each year.

ORIGIN AND DISTRIBUTION

Ginkgo is a tree native to China, Japan and Korea. It is now also found in the United States and Europe.

BOTANICAL DESCRIPTION (Ross, I. A. 2004)

Gingko biloba is a 30 to 40 m high dioecious tree of the CYCADACEAE family, with a girth of about 4 meters. The trees can live for hundreds of years. The bark is light to dark brown with rough grooves and reticulate fissures. The leaves are fan-shaped with bifurcated ribs, fresh green and golden yellow in autumn. The tree flowers for the first time when it is between 20 to 30 years old. The flowers are dioecious. They are in the axils of the lower leaves of the annual growth. The male flowering parts are attached to short catkins. The female flowers have longer pedicles and are at the end of a leafless branch. Fertilization occurs months after pollination by spermatozoids, although usually only one ovule is fully  formed. The seeds later become fleshy and plum-like round and light green or yellow in color. They have a diameter of about 2.5- 3 cm and contain a two-edged edible nut. They smell like butyric, capric or valeric acid when ripe.

        

Figure 1. Ginkgo (Ginkgo biloba)                            Figure 2. Ginkgo – dried drug substance (leaf)

U S E S

USES (Linda, S-R. 2010)

 Gingko is used to decrease disturbances of cerebral functioning and peripheral vascular insuffi ciency in persons with Alzheimer’s disease or other types of agerelated dementia. It is also used as an antioxidant, to improve peripheral artery  disease, and to enhance circulation throughout the body. Other reported uses include the treatment of depressive mood disorders, sexual dysfunction, asthma, glaucoma, menopausal symptoms, multiple sclerosis, headaches, tinnitus, dizziness, arthritis, altitude sickness, and intermittent claudication.

FOOD USE (Barnes, J et al., 2007)

Ginkgo biloba is not used in foods

HERBAL USE (Barnes, J et al., 2007)

Ginkgo has a long history of medicinal use, dating back to 2800 BC. Traditional Chinese medicine used the seeds (kernel/nuts) for therapeutic purposes. The seed is used in China as an antitussive, expectorant and anti-asthmatic, and in bladder inflammation.^{(1, 11,G50)} In China, the leaves of Ginkgo biloba were also used in asthma and in cardiovascular disorders,⁽¹⁾ although the leaves have little history of traditional use in the West. Today, standardised concentrated extracts of G. Biloba leaves are marketed in several European countries, and are used in cognitive deficiency, intermittent claudication (generally resulting from peripheral arterial occlusive disease), and vertigo and tinnitus of vascular origin (see Pharmacological Actions, Clinical studies).^{(G3, G32, G56, G63)}

TRADITIONAL MEDICINAL USES (Ross, I. A. 2004)

China. The fruit pulp is macerated in vegetable oil, and after 100 days it is taken orally for pulmonary tuberculosis ^GCBOM. Hot water extract of the fruit is taken as an anthelmintic^GBOJJ9. Hot water extract of the leaf is taken orally as a vermifuge, and for asthma and senility ^GBOM. The raw seeds are eaten, and the decoction of the seed is taken orally for cancer. The pan-fried seeds are eaten for tuberculosis ^GB0136.

Iran. Hot water extract of the dried leaf is taken orally for vision disturbances associated with blood circulation abnormalities and inflammation, and to improve memory loss associated with blood circulation abnormalities. The ethanol (90% and 95%) extracts are taken orally as an arterial dilator and arterial circulation stimulator ^GBom.

Korea. Hot water extract of the fruit is taken orally for its oxytocic effect ^GB0109.

South Korea. Hot water extract of the seed is taken orally to induce labor ^B0336 and as an abortifacient ^GB0324.

CHEMICAL CONSTITUENTS

CONSTITUENTS (Barnes, J et al., 2007)

LEAF

Amino acids 6-Hydroxykynurenic acid (2-carboxy-4-one-6- hydroxyquinoline), a metabolite of tryptophan.^(3–5) Flavonoids Dimeric flavones (e.g. amentoflavone, bilobetin, ginkgetin, isoginkgetin, sciadopitysin);⁽⁶⁾ flavonols (e.g. quercetin, kaempferol) and their glycosides^{(3, 7)} and coumaroyl esters.

Proanthocyanidins Terpenoids Sesquiterpenes (e.g. bilobalide), diterpenes (e.g. ginkgolides A, B, C, J, M, which are unique cage molecules,^{(8, 9, G48)} and triterpenes (e.g. sterols).

Other constituents Benzoic acid, ginkgolic acids, 2-hexenal, polyprenols (e.g. di-trans-poly-cis-octadecaprenol), sugars, waxes,⁽¹⁾ a peptide.⁽¹⁰⁾

SEEDS

Alkaloids Ginkgotoxin (4-O-methylpyridoxine).⁽¹¹⁾

Amino acids Cyanogenetic glycosides Ginkgolic acids. Ginkbilobin.⁽¹²⁾

CHEMICAL CONSTITUENTS (Ross, I. A. 2004)

(ppm unless otherwise indicated)

Acacetin: Lf ^G80322

Acenaphthene: EO ^G80318

Acetic acid: Pollen ^G80311

Afzelin: Pollen 141 ^G80315

Amentoflavone: Lf 3 .8-5 ^G80263, ^G80295

Anacardic acid: PI ^G80126

Apigenin: Lf ^G80146, Pollen 109 ^G80315

Arabinitol,2-carboxy: Lf 18 nmol/gm ^G80209

Arachidic acid: Pollen ^G80315

Ascorbic acid: Fr 640 ^G80340, Lf ^G80100

Astragalin: Lf 1.8% ^G80261

Atlantone,(E): Heartwood ^G80124

Atlantone,(Z): Heartwood ^G80124

Atlantone, 1 0, 11-dhydro,(Z): Heartwood ^G80124

Atlantone, 1 0, 11-dihydro,(E): Heartwood ^G80124

Atlantone, 1 0, 11-dihydro-6-oxo,(E): Heartwood ^G80124

Auroxanthin: Chloroplast ^G80264

Behenic acid: Pollen ^G80315

Benzene, 1 ,4-dimethyl-2,5-diisopropyl: EQ ^GB0318

Benzoic acid,4-hydroxy: Lf ^GBOM

Betulaprenol 15: Lf ^G80206

Betulaprenol 16: Lf ^G80206

Betulaprenol 17: Lf ^G80206

Betulaprenol 18: Lf ^G80206

Betulaprenol 19: Lf ^G80206

Betulaprenol 20: Lf ^G80206

Betu laprenol 21 : Lf ^G80206

Bilobalide A: Lf ^GBOlOS

Bilobalide: Lf 330 ^GB0169, PI ^GBOLSS

Bilobanone: Lf ^G80242 , Heartwood ^G80124

Bilobetin, 1-5-methoxy: Testa ^G80136

Bilobetin,5-methoxy: Lf 2 ^G80314

Bilobetin: Lf 0.0025%-1.9% ^GBOlOl,^GBOZSS

Bilobol: Fr ^G80154

Campesterol: Kernei ^G80320

Carda no!: Testa ^G80328

Carotene,alpha: Chloroplast ^G80264

Carotene,beta: Lf ^G80189

Carotene,gamma: Chloroplast ^G80264

Catechin,(+): Lf ^GBOLOO, Call Tiss ^GB0243

Catechin,epi,(-): Lf ^G80100

Catechin,epi-gallo,(-): Lf ^G80101

Catechol,(+): Lf ^G80242

Catechol,epi,(-): Lf ^G80242

Catechol,epi-gallo,(-): Lf ^G80242

Catechol,gallo,( + ): Lf ^G80242

Choline: Lf ^G80242

Citric acid: Pollen ^G80311

Cosmosiin: Lf ^G80146

Coumaric acid,para: Pollen 47 ^G80315

Coumarin, iso,8-hydroxy-3-(6-pentadecenyl)-3,4-dihydro: Fr ^G80121

Coumarin, iso,8-hydroxy-3 -heptadecyl-3 ,4-dihydro: Fr ^G80121

Coumarin, iso,8-hydroxy-3-tridecyl-3,4-dihydro: Fr ^GB0121

Cymene,para: EO ^G80318

Cystathionine: Fr 0.16 ^G80343

Daucosterol: Lf ^GBOLOO

Diphenol,4,4-(penta-cis-1-cis-5-diene-1 ,5-diynyl): Lf 22.7 ^GB0117

Docosan-1-ol: Pollen 445 ^G80315

Dolichol: Lf ^G80281

Elemol: Heartwood ^G80124

Ergosterol: Sd ^G80338

Eudesmol,beta: Heartwood ^G80124

Eudesmol,gamma: Heartwood ^G80124

Flavonoids: Lf ^G80308

Flavoxanthin: Chloroplast ^G80264

Formic acid: Pollen ^G80311

Galactocerebroside: Lf ^G80229

Gallocatech in,(+): Lf ^GBOl 01

Gingolide C: Lf ^G80282

Ginkgetin,iso: Lf 21-2900 ^GBOlOl,^GBOZll

Ginkgetin: Lf 42-6530 ^GB0107,^GB0217

Ginkgo biloba polyprenol14: LfG ⁸⁰³²¹

Ginkgo biloba polyprenol 15: LfG ⁸⁰³²¹

Ginkgo biloba polyprenol 16: LfG ⁸⁰³²¹

Ginkgo biloba polyprenol 17: LfG ⁸⁰³²¹

Ginkgo biloba polyprenol 18: Lf ^GB0321

Ginkgo biloba polyprenol19: Lf ^GB0321

Ginkgo biloba polyprenol 20: Lf ^GB0321

Ginkgo biloba polyprenol21: Lf ^GB0321

Ginkgo biloba polyprenol 22: Lf ^GB0321

Ginkgo flavone glycosides: Lf ^GB0199

Ginkgo polyprenol 15: Lf ^GB01&3

Ginkgo polyprenol 16: Lf ^GB0163

Ginkgo polyprenol 17: Lf ^GB01&3

Ginkgo polyprenol 18: Lf ^GB0163

Ginkgo polyprenol 19: Lf ^GB0163

Ginkgo polyprenol 20: Lf ^GB0163

Ginkgo polyprenol21: Lf ^GBo1&3

Ginkgo polyprenol22: Lf ^GB0163

Ginkgo polyprenol 85: Lf ^GBo1&3

Ginkgo polyprenol 90: Lf ^GB0163

Ginkgo polyprenol 95: Lf ^GBO1&3

Ginkgo polyprenol120: Lf ^GB0163

Ginkgo polysaccharide GF-1: Lf ^GB0119

Ginkgo polysaccharide GF-2-A: Lf ^GBOl19

Ginkgo polysaccharide GF-2-B: Lf ^GB0119

Ginkgo polysaccharide GF-3: Lf ^GB0119

Ginkgoic acid,hydro: Endosperm ^GBO13O

Ginkgoic acid: Fr ^GB0154

Ginkgo!: Lf ^GB0317, Endosperm ^GBOBO

Ginkgolic acid,dihydro: Fr ^GB0173

Ginkgolic acid,hydro: Lf ^GB0173

Ginkgolic acid: Fr ^GBOM, Lf <50 ^GB0229

Ginkgolide A: Rt Bk 100 ^GB0114, Lf 4-220 ^GB0111, ^GB01691 Call Tiss ^GB0137, Pi ^GB0185

Ginkgolide B: Rt Bk 100 ^GB0114, Pi ^GB0329, Lf 50-2500 ^GB0111,^GB0176

Ginkgolide C: Pi ^GBOlBS

Ginkgo! ide C: Pi ^GB0329, Lf 0.75-120 ^GB0111,^GB0169, Rt Bk 200 ^GB0114

Ginkgo! ide J: Lf 540 ^GB0164, Call Tiss ^GBOM, Rt ^GB0156

Ginkgolide M: Rt Bk 0.2 ^GB0114

Ginkgotoxin: sd 10 O ^GB011B, Lf ^GB0232

Ginnol: Lf 1260 ^GB+D162, Pollen 463 ^GB0315, Fr ^GBO1S4

Ginnone: Lf ^GBOLOO

Glycerol, OL -th reo-para-hydroxy-phenyl: Lf ^GB0122

Glycerol,threo-guaiacyi,OL: Lf ^GB0122

Heptacosane, N: Lf 3 8.1% ^GB0162

Heptadeca-3,6,9-trien-1-ol: EQ^GB0318

Hexacosan-1-ol: Lf ^GBOLOO

Hexadecanoic acid,14-methyl: Sd OII ^GB0231

Hex-cis-3-en-1-ol: EQ ^GB0318

Hex-cis-4-en-1-ol: EQ ^GBO318

Hexen-1-al: Lf ^GBOlOO

Hex-trans-2-en-1-al: Lf ^GBOlB

Hex-trans-4-en-1-ol: EQ ^GB03lB

lngnoceric acid: Pollen ^GB0315

lonone,beta: EQ ^GB0318

Kaempferol: Lf ^GB0112

Kaempferol-2,6-dirhamnosyl glucoside: Lf ^GB0276

Kaempferol-3 -0-(2,0- [ 6, 0-{para-(beta-0-glucosyl)-oxy-trans-ci n namoyl }-beta-0- glucosyl)-alpha-L-rhamnoside): Lf ^GB014&

Kaempferol-3 -0-(2,6-di -0-rhamnopyranosyl-gl ucopyranos ide): Lf ^GB0202

Kaempferol-3-0-(2,6-dirhamnopyranosylbeta-0-glucopyranoside): Lf ncBozgs

Kaempferol-3-0-(2-0-beta-0-glucopyranosyl)-alpha-Lrhamnopyranoside: Lf 5.3 ^GB0120

Kaempferol-3-0-(6-para-coumaroylglucopyranosyl-

beta-1,4-rhamnopyranoside): Lf ^GBOZBB

Kaempferoi-3-0-(6-para-coumaroylglucosyl(1,2))rhamnoside: Lf ^GB0296

Kaempferol-3 -0- [2, 0-6-0-(para -hydroxytrans-

cinnamoy 1)-beta-0-gl ucosyl) -a 1-

pha-L-rhamnoside: Lf ^GB0146

Kaempfero 1-3-0- [2 -0-(beta -0-gl ucosy I)-alpha-L-rhamnoside): Lf ^GBOl46

Kaempferol-3 -0- [2 -0-6-0-{para-(7 -0-beta-0-

glucopyranosyl)-cou maroyl }-beta-0-

glucopyranosyl)-al pha-L -rhamnopyranoside:Lf 3.1 ^GB0120

Kaempfero 1-3-0- [2 -0-6-0-b is-(a I ph a- Lrhamnosyl)-

beta-0-glucoside]: Lf ^GB0146

Kaempferol-3-0-[3-para-coumaroylglucosyl-beta(1,4)-rhamnoside): Lf2.5% ^GB0261

Kaem pferol-3 -0- [ 6, 0-para-cou maroy l-betaO-

glucopyranosyl(1,2))-alpha-Lrhamnopyranoside: Lf 200 ^GB0295

Kaempferol-3-0- [ 6-0-a I ph a- Lrhamnosyl) beta-0-glucoside): Lf ^GB0146

Kaem pferol-3-0- [ 6-0-para -cou maroy 1-beta-

0-glucosyl-(1,2)-alpha-L-rhamnoside): Lf ^GB0276

Kaempfero 1-3-0- [a I pha-rhamnosy 1-(,2 )alpha-rhamnosyl-(1,6))-beta-0-gl ucoside:Lf 1.2% ^GB0261

Kaempferol-3-0-[alpharhamnosyl(1,2)alpharhamnosyl(1,6))beta-O-glucoside: Lf 700 ^GB0266

Kaempferol-3-0-[beta-Dglucopyranosyl (1,2 )]-alpha-Lrhamnopyranoside: Lf ^GB0122

Kaempferol-3-0-alpha-(6-para-coumaroylglucosyl-

beta-1-4-rhamnoside): Lf ^GB0221

Kaempferol-3-0-alpha-(6-para-coumaroylglucosyl-

beta-1-4-rhamnoside): Lf 47 ^GB0262

Kaempfero 1-3 -0-a I ph a-L- [beta -Dglucopyranosyl(

1,2)rhamnopyranoside]: Lf ^GB0161

Kaempferol-3-0-alpha-L-rhamno-glucoside: Lf 580 ^CSO1O4

Kaempferol-3-0-alpha-L-rhamnoside: Lf ^GB0146

Kaempferol-3-0-beta-D-ruti noside: Lf 0.1 % ^GB0313

Kaempferol-3-0-coumaroylglucorhamnoside: Lf ^GB0174

Kaempferol-3-0-para-coumaroylglucorhamnoside: Lf ^GB0178

Kaempferol-3-0-rhamnosyl (1,2)rhamnosyl(1,6)glucoside: Lf ^GB0296

Kaempferol-3-0-rutinoside: Lf 40-130 ^GB0262,^GB0295

Kaempferol-coumaroyl-glucorhamnoside:Lf ^GB0286

Kynurenic acid,6-hydroxy: Lf 20-966 ^CSO262,^GB024S

Lactic acid: Pollen ^GBO311

Laricitri n-3-0-ruti nos ide: Lf ^GB0295

Lauric acid: Pollen ^GBO315

Legumin-like protein (Ginkgo biloba): Sd ^GB0265

Linalool oxide, trans: EQ ^GB0318

Linoleic acid: Lf, Kernel 44.5% ^GB031O

Linolenic acid, alpha: Lf ^GB012S

Linolenic acid: Fr, Lf ^GBOM

Lutein ester: Lf ^GB0189

Lutein,5-6-epoxy: Chloroplast ^GB0264

Lutein: Lf ^GB0189

Luteolin: Lf ^GB0146

Luteol i n-3-0-beta-D-glucoside: Lf ^GBD146

Malic acid: Pollen ^GB0311

Myriceti n,3-0-methyi-H 3-0-alpha-L -rhamnoside:

Lf 305 ^GBOM

Myriceti n,3-methyl 3-0-(6-0-alpha-Lrhamnosyl)-

beta-D-glucoside: Lf ^GB0146

Myricetin: Lf ^GB0146

Myriceti n-3-0- [ 6-0-(a I pha-L -rham nosy I)beta-

D-gl ucoside]: Lf ^GB0146

Myristic acid: Pollen ^GBO315

Naphthalene,dihydro 2,5,8-trimethyl:

EQ ^GB0318

Neoxanthin,cis: Chloroplast ^GBD264

Neoxanthin,trans: Chloroplast ^GBD264

Neoxanthin: Lf ^GB0189

Octacosan-1-ol: Lf ^GBOLOO

Octadeca-5,9, 12-trienoic acid:

Sd OII ^GB0231

Octadeca-5,9-dienoic acid: Sd OII ^GB0231

Octadecasph i ngadiene, n-alphahydroxypalmitoyl-

glucosyl: Sd ^GB0312

Oleic acid: Kernel 37.5%, Lf ^GB0310

Palmitic acid.alpha-hydroxy: Sd, Kernei ^GB0312

Pentacosane,n: Lf 17.4%, Kernei ^GBD162

Phenol,2 -isopropyl: EQ ^GBD318

Pinitol,(+): Pollen 76 ^GB0315

Pinitol: Lf ^GB0242

Plamitic acid: Lf 25.1 %, Kernei ^GB03 10, Fr^GB01731 Pollen ^GB0315

Populnin: Lf 1.5 ^CBO262, Pollen 119 ^GB0315

Proanthocyanidin: Lf 4.12% ^GB0143

Prodelphinidin: Lf ^GB0242

Propylene,para-tolyl: EQ ^GB03lB

Protein H(Ginkgo biloba): Sd ^GB026S

Protocathechuic acid: Lf ^GB0248

Pyridoxine,4-0-methyl: Sd ^GB017S

Pyridoxine,4-methoxy: Sd 1QO ^GB0116

Pyridoxine,4-methyl: Lf, Sd ^GB0232

Pyruvic acid: Pollen ^GB03LL

Quercetin: Lf 24 ^GB0179

Quercetin-3 -0-(2,6-d i -0-rham nopyranosylglucopyranoside): Lf ^GB0202

Quercetin-3 -0-(2 -0-beta-Dgl ucopyranosyl)-alpha-Lrhamnopyranoside:Lf 2.8 ^GB0120

Quercetin-3 -0-( 6-0-para-cou ma roy l-beta-

D-glucopyranosyl(1,2)alpha-Lrhamnopyranoside): Lf ^GBOZGS

Querceti n-3 -0-(6-paracoumaroyl) glucosyl(1,2)rhamnoside):Lf ^GB0296

Quercetin-3 -0-( 6-para-cou maroy 1-glucopyranosyl-beta-1,4-

rhamnopyranoside): Lf ^GB0288

Quercetin-3 -0-( 6-para-cou ma royl-gl ucosylbeta(

1 ,4)-rhamnoside: Lf 2.1 % ^GB0261

Querceti n-3-0-(al pha-rhamnosyl-(1,2 )alpha-

rhamnosyl-(1,6)-beta-glucoside: Lf 0.8% ^GB0261

Quercetin-3 -0-(a I pharhamnosy I (1,2)a I pharhamnosyl(1,6)beta-glucoside: Lf 700 ^GB0266

Quercetin-3-0- [2 -0-( 6-0-para-hyd roxycinnamoyl)-

beta-D-glucosyl]-alpha-Lrhamnoside:

Lf ^G80146

Quercetin-3-0- [2 -0-( 6-0-parahydroxy-transcin namoyl)-beta-D-glucosyl]-aIpha-Lrhamnoside:

Lf ^G80146

Querceti n-3-0- [2 -0-6-0-{para-(7 -0-beta-Dglucopyra nosy I }-coumaroyl )-beta-D-glucopyranosyl}-coumaroyl)-beta-D-glucopyranosyl]

a I ph a-L -rhamnopyranos ide:Lf 4.4 ^GB0120

Querceti n-3 -0- [2 -0-6-0-bis(al pha-Lrhamnosyl)-

beta-D-gl ucoside]: Lf ^GB0146

Quercetin-3-0- [2 -0-6-0-para-cou maroyl)beta-

D-gl ucopyranosyl]-al pha-Lrhamnopyranosyl-

7 -0-beta-D-gl ucopyranoside:Lf 40 ^G80120

Querceti n-3-0- [2 -0-beta-D-gl ucosyl)-alphaL-rhamnoside: LfG ⁸⁰¹⁴⁶

Quercetin-3-0- [ 6-0-al ph a -L -rhamnosyl]beta-D-glucoside: Lf ^G80146

Querceti n-3 -0- [ 6-0-para-beta-D-gl ucosyl]oxy-trans-c in namoyl-beta-D-gl ucosyalpha-L-rhamnoside: Lf ^GBOl46

Quercetin-3-0- [ 6-0-para-cou maroyl-transcinnamoyl)-

beta-D-glucosyl-alpha-Lrhamnoside: Lf ^GB0276

Quercetin-3 -0-a I pha-( 6-para-cou maroy 1-glucosyl-beta-1 ,2-rhamnoside): Lf ^GB0221

Quercetin-3 -0-a I ph a-( 6-para-cou maroylglucosyl-beta-1 ,4-rhamnoside): Lf 20 ^GB0262

Quercetin-3 -0-al ph a-( 6-para -cou maroylglycosyl-

beta-1 ,4-rhamnoside): Lf 20 ^GB0246

Quercetin-3 -0-al ph a -L -rham no-glucoside: Lf ^GB0100

Querceti n-3 -0-cou maroylglucorhamnoside: Lf ^G80174

Quercetin-3-0-para-coumaroylglucorhamnoside: Lf ^G80178

Quercetin-3-0-rhamnosyl(1,2) rhamnosyl(1,6)glucoside: Lf ^GB0296

Quercitrin,iso: Lf 0.5 ^GB0262

Quercitrin: Lf 0.5 ^GB0262

Quinic acid: Lf ^G80100

Resorcyc I i c ac id,6-(pentadec-8-enyl): Sd ^GB0155

Resorcyclic acid,6-(tridec-8-enyl): Sd ^GB01SS

Rhamneti n, iso 3-0-[2-0-6-0-bis(alpha-Lrhamnosyl)-

beta-D-glucoside]: Lf ^GB0146

Rhamnetin,iso 3-0-[6-0-alpha-Lrhamnosyl)-beta-D-gl ucoside: Lf ^GB0146

Rhamnetin, iso 3-0-beta-D-glucoside: Lf ^GB0146

Rhamnetin,iso 3-0-beta-D-rutinoside: Lf 625 ^GB0313

Rhamnetin,iso 3-0-rutinoside: Lf 2.0% ^GB0261

Rhamnetin,iso: Lf ^G80112

Rhamnetol,iso 3-0-rutinoside: Lf 2 ^G80262

Rutin: Lf 6_940cso262,^GBO179

Salicylic acid,6-heptadeca-cis-9-cis-12-dienyl: Lf soocsono

Salicylic acid,6-heptadecadienyl: Lf ^GBD173

Salicylic acid,6heptadec-cis-8-enyl: Lf 0.44% ^GB0220

Salicylic acid,6-heptadecenyl: Lf, Fr ^GBOM

Sal icy! ic acid,6-heptadecenyl: Lf ^GB0247

Salicylic acid,6-pentadec-cis-8-enyl: Lf 1.2% ^GB0220

Salicylic acid,6-pentadec-cis-enyl: Fr, Lf ^GB0173

Salicylic acid,6-pentadecenyl: Lf ^GB0247

Salicylic acid,6-pentadecyl: Lf ^GB0173

Salicylic acid,6-tridecyl: Fr ^G80173

Salicylic acid,6-tridecyl: Lf 400 ^GB022o

Salicylic acid,6-tridecyl: Lf ^GB0173

Salicylic acid,n-heptadecenyl: Fr, Lf ^GB0151

Salicylic acid,n-heptadecyl: Lf, Fr ^GB0151

Salicylic acid,n-pentadecenyl: Lf, Fr ^GB015 1

Salicylic acid,n-pentadecyl: Lf, Fr ^GB0151

Salicylic acid,n-tridecyl: Lf, Fr ^GB0151

Sciadopitysin: Lf 33-78 ^GBOlO?, ^GBo295

Sequoyitol: Lf ^G80100, Pollen 31 ^GB03l5

Sesamin,(+): Heartwood ^A07572

Shikimic acid: Lf ^G80100

Sitosterol,beta: Lf ^G80102, Pollen ^GB0315,Sd ^GB0338

Stearic acid: Pollen ^G80315

Stogmasterol: Pollen ^GB0315, Lf ^GB0102

Succinic acid: Pollen ^GB0311

Syringetin-3-0-rutinoside: Lf 1.4 ^GB0262

Thymol: EQ ^GB0318

Tocopherol,gamma: Lf 140 ^G80162

Tricosane,n: Lf 12.5% ^G80162

Vanillic acid: Lf ^G80248

Violaxanthin,cis: Chloroplast ^GBOl64

Violaxanth in, trans: Chloroplast ^G80264

Violaxanthin: Lf ^G80189

Zeaxanthin: Chloroplast ^G8D264

ACTIONS (Linda, S-R. 2007)

Much research is available documenting the uses and actions of Ginkgo biloba L. Ginkgo has been used in China since ancient times. Initial research began in Europe in the 1960s.

Cognitive Enhancement Action The cognitive enhancement action of ginkgo is a result of the fl avonoids present in the extract. The pharmacologic actions involve increased release of neurotransmitters, including cat e chol amines, and inhibition of monoamine oxidase. Approximately 50 controlled studies between 1975 and 1997 have demonstrated the positive effects of gingko in the treatment of cerebral insuffi ciency. All studies incorporated various dosages and varying lengths of treatment, and all results were positive. However, newer studies have questioned the benefi t of ginkgo for cognitive function (Carlson et al.,, 2007; Mazza et al.,, 2006).

Vasoprotective and Tissue-Protective Actions The vasoprotective and tissue-protective actions of ginkgo result from several factors: its ability to relax blood vessels, to protect against capillary permeability, to inhibit platelet aggregation, and to decrease ischemia and edema. Studies have confi rmed this effect in rabbits (Monboisse et al.,, 1993).

OTHER ACTIONS(Linda, S-R. 2010)

Gingko has been studied for its antioxidant effects, its relief of altitude sickness, its antiarthritic and analgesic effects, and its relief of ischemia in intermittent claudication.

Antioxidant Action Gingko has been studied for its antioxidant effects. It has been found to eliminate free radicals and is able to inhibit polymorphonuclear neutrophils (Monboisse et al., 1993).

Altitude Sickness Relief Ginkgo can relieve altitude sickness. One study involving two groups of mountain climbers focused on the effects of gingko when traveling to high altitudes. One group took 160 mg of gingko daily while climbing, and the other received a placebo. Both groups ascended to 14,700 feet and made other ascents from that point. None of the gingko group reported full-blown altitude sickness, whereas 82% of the placebo group did (Feng et al.,, 1989). Another study (Gertsch et al., 2002) was designed to identify the time needed to prevent acute mountain sickness. One day of pretreatment with ginkgo 60 mg tid significantly reduced the severity of acute mountain sickness. However, a newer study found no benefit in using ginkgo to prevent altitude sickness (Chow et al., 2005).

Antiarthritic and Analgesic Actions Ginkgetin, a chemical component of gingko, has been studied for its antiarthritic and analgesic effects. Ginkgetin given in dosages of 10-20 mg/kg/day reduced arthritic infl ammation in laboratory animals by 86% at the highest dose given (Kim et al., 1999).

PRODUCT AVAILABILITY (Linda, S-R. 2010)

Capsules, fluid extract, tablets, tincture

PLANT PART USED

Leaves

D O S A G  E

DOSAGES (Linda, S-R. 2010)

Ginkgo may be standardized to 24% ginkgo fl avonglycosides and 6% terpene trilactones.

Alzheimer’s Disease

Ø  Adult PO capsules/extract/tablets: 80 mg tid standardized to 24% fl avonglycosides (Murray, Pizzorno, 1998)

Asthma

Ø  Adult PO extract: 80 mg tid (Murray, Pizzorno, 1998)

Cerebral Vascular Insuffi ciency

Ø  Adult PO extract: 80 mg tid standardized to 24% fl avonglycosides (Murray, Pizzorno, 1998)

General Use

Ø  Adult PO standardized extract: 40 mg tid

Glaucoma

Ø  Extract: 40-80 mg tid standardized to 24% fl avonglycosides (Murray, Pizzorno, 1998)

Impotence from Arterial Insuffi ciency

Ø  Adult PO extract: 80 mg tid standardized to 24% fl avonglycosides (Murray, Pizzorno, 1998)

Menopause

Ø  Adult PO extract: 40 mg tid standardized to 24% fl avonglycosides (Murray, Pizzorno, 1998)

Multiple Sclerosis

Ø  Adult PO extract: 40-80 mg tid standardized to 24% fl avonglycosides (Murray, Pizzorno, 1998)

DOSAGE AND DURATION OF USE (Kraft, K and Hobbs, C. 2004)

– For decreased mental performance: Oral daily dose: 120–240 mg of a specially formulated, standardized Ginkgo biloba extract (GBE; 24 % flavone glycosides, 6 % terpenoids), divided into 2 to 3 portions, to be taken for a period of at least 12 weeks. Thereafter, treatment should be continued after a positive assessment result.

– For peripheral artery occlusion, vertigo, and tinnitus: 120–160 mg GBE per day. Used for 6 to 8 weeks for treatment of vertigo and tinnitus; longer use is only justified if some improvement can be registered. According to some studies use for at least 3 months is necessary for full effect.

DOSAGE (Barnes, J et al., 2007)

Dosages for oral administration (adults) for traditional uses recommended in older and contemporary standard herbal reference texts are given below.

Cognitive deficiency

Leaf extract 120–240 mg dry extract orally in two or three divided doses.^(G3)

Peripheral arterial occlusive disease and vertigo/tinnitus

Leaf extract 120–160 mg dry extract orally in two or three divided doses.^(G3)

Clinical trials of standardised extracts of G. biloba leaves (EGb-761, Willmar Schwabe GmbH and LI-1370, Lichtwer Pharma GmbH) in patients with cognitive deficiency have generally used oral doses ranging from 120–240 mg daily, usually for 8–12 weeks, although some studies have continued treatment for up to 24 or 52 weeks.^(G56) Clinical trials in peripheral arterial occlusive disease used oral doses of 120–160 mg extract daily for 3–6 months.^(G56)

Dosages (Ginkgo) — (Duke 2002)

4.5 g seed (FAY); 4.5 g leaf with 4.5 g root Polygonum multiflorum and 4.5 g bark Uncaria for cardiopathy (FAY); 1–2 tbsp fresh leaf (PED); 2–3 g dry leaf (PED); 2 g dry leaf:10 ml alcohol/10 ml water (PED); 40 mg solid leaf extract 3 ×/day (CAN); 80–120 mg leaf extract/day (CAN); 0.5 ml fluid extract (1:1) 3 ×/day (CAN); 0.5 ml tincture 3 ×/day (SKY); 1 (40 mg extract) tablet 3 ×/day with meals (APA); 1 (385 mg) capsule (StX to contain 40 mg certified potency 50:1 ginkgo leaf extract with at least 24% flavonoid glycosides) 3 ×/day (NH); 40–80 mg StX 3 ×/day; 120–160 mg StX (6% terpene lactones, 24% flavone glycosides) 2–3 ×/day (SKY).

DOSAGE RANGE (Braun, L and Cohen, M. 2004)

The recommended dose varies, depending on indication and condition treated

General Guide

Ø  Dried herb: 9–10 g/day.

Ø  120–240 mg of a 50:1 standardised extract daily in divided doses (40 mg extract is equivalent to 1.4–2.7 g leaves).

Ø  Fluid extract (1:1): 0.5 mL three times daily.

According to Clinical Studies

Ø  Asthma: 40 mg three times daily.

Ø  Dementia and memory impairment: 120–240 mg standardised extract daily in divided doses.

Ø  Intermittent claudication, vertigo: 120–320 mg standardised extract daily in divided doses.

Ø  Normal tension glaucoma: 120 mg standardised extract daily.

Ø  Multiple sclerosis — to improve cognitive function and mood: 120 mg twice daily.

Ø  PMS: 80 mg twice daily, starting on the 16th day of the menstrual cycle until the 5th day of the next cycle.

Ø  Prevention of altitude sickness: 160 mg standardised extract daily, starting 5 days prior to ascent or ginkgo (80 mg per dose) every 12 hours, starting 24 hours before ascending and continuing throughout stay at high altitude.

Ø  Schizophrenia: as an adjunct to clozapine in refractory cases: 120 mg daily.

Ø  Raynaud’s syndrome: 360 mg/day divided into three doses.

Ø  Sexual dysfunction associated with antidepressant drugs: 200 mg standardised extract daily.

Ø  Sexual dysfunction (women): 300 mg daily in conjunction with sex therapy.

Ø  Vitiligo: 120 mg standardised extract daily.

Although some studies report positive effects after 4–6 weeks’ continual use, a trial of at least 12 weeks is recommended in chronic conditions.

INDICATIONS (Kraft, K and Hobbs, C. 2004)

– Several small studies found a moderate benefit when using Ginko for vertigo (dizziness) and tinnitus of vascular and involutional origin.

– Circulatory disorders (peripheral artery occlusion, especially intermittent claudication, for which some controlled studies reported a benefit).

– Memory enhancement in younger people or people with no preexisting memory impairment has been suggested, with both positive and negative recent clinical trials, but this remains controversial.

– For symptomatic treatment of cerebro-organic impairment of mental performance. (Controlled studies showed modest, but statistically significant positive results for cerebral insufficiency. Several reports have indicated modest benefit in controlled studies for Alzheimer’s and non-Alzheimer’s dementia.)

INDICATIONS  (Duke 2002)

Acrocyanosis (1; BGB; WHO); Allergy (1; MAB; PNC; WAM); Alopecia (1; MAB); Altitude Sickness (2; BGB; KOM; MAB; SHT; WAM; WHO); Alzheimer’s (2; COX; KOM; JAM; MAB; PH2; SHT); Anaphylaxis (1; PNC); Angina (f; FAY; PH2); Anxiety (1; MAB); Arrhythmia (1; MAB); Arthrosis (1; COX; FNF; WHO); Asthma (1; AKT; APA; CAN; FAY; MAB; PNC); Atherosclerosis (1; FAY; MAB; SKY); Bacteria (1; DAA); Blennorrhea (f; DAA); Bronchosis (1; APA; FAY; PED; WHO); Cancer (1; COX; DAA; FNF); Capillary Fragility (1; BGB; PH2; SHT; WHO); Cardiopathy (1; APA; MAB; SKY); Caries (f; FAY); Cellulite (1; HFH/JA/’99); Cerebral Insufficiency (2; KOM; PHR; SHT); Chilblain (f; FAY; WHO); Circulosis (1; PHR; SKY); Convulsion (1; MAB); Cough (f; APA; FAD; FAY); Cramp (f; PH2); Cystosis (f; DAA); Deafness (1; APA; MAB); Dementia (2; KOM; SHT; WHO); Depression (1; AKT; KOM; MAB; SKY); Dermatosis (f; FAD); Diabetes (f; SKY); Diarrhea (f; FAD); Dizziness (1; WHO); Dysentery (f; FAY); Dysmenorrhea (2; MAB); Dysuria (f; FAY); Edema (1; KOM; WHO); Emphysema (1; PED); Encephalosis (f; FAY); Enuresis (f; FAY); Fatigue (1; MAB); Filariasis (f; FAY); Freckle (f; FAD); Fungus (f; FAY); Glaucoma (1; AKT); Gonorrhea (f; DAA); Headache (1; KOM; FT69:195; PH2; WHO); Hearing Problem (1; CAN; FT69:195); High Cholesterol (f; FAY); Hypertonia (f; PH2); Impotence (1; APA; BGB; SKY); Inflammation (1; PH2; WHO); Intermittent Claudication (2; KOM; PHR; PH2; SHT; WHO); Ischemia (1; MAB; FNF; WHO); Leukorrhea (f; DAA); Maculosis (2; MAB; SHT); Mastocytosis (1; MAB); Migraine (1; MAB); Multiple Sclerosis (f; SKY); Mycosis (f; FAY); Neuralgia (1; APA); Nystagmus (1; PH2); Obesity (1; MAB); Ophthalmia (1; APA); Pain (1; APA); Parturition (1; WHO); PMS (1; AKT; MAB); Polydipsia (1; MAB); Polyuria (f; FAY; MAB); Post-Phlebitis Syndrome (1; WHO); Pulmonosis (f; FAY); Raynaud’s Syndrome (1; DAA; SKY); Retinosis (1; KOM; MAB; PHR; SHT); Rhinosis (f; DAA; WHO); Ringworm (f; FAY); Scabies (1; APA; FAY); Schizophrenia (1; AKT); Senile Dementia (2; FAY; KOM; SHT); Shock (1; MAB); Sore (1; APA; FAY); Spermatorrhea (f; FAY); Stroke (1; CAN; MAB; SKY); Strangury (f; FAY); Swelling (1; KOM; PHR; WHO); Thrombosis (1; MAB); Tinnitus (2; KOM; PH2; SHT; WHO); Tonsilosis (f; PH2); Tuberculosis (1; APA; DAA; FAY); Vaginosis (f; APA; FAY); Varicosis (1; APA); Vertigo (2; KOM; MAB; PH2; SHT); Worm (1; WHO).

CONTRAINDICATIONS(Linda, S-R. 2010)

Pregnancy category is 2; breastfeeding category is 1A. Ginkgo should not be given to children. It should not be used by persons with coagulation or platelet disorders, hemophilia, seizures, or hypersensitivity to this herb.

CONTRA-INDICATIONS, WARNINGS (Barnes, J et al., 2007)

In view of the intended uses of ginkgo and the documented pharmacological actions of ginkgo, it is not suitable for selftreatment. There are reports of haemorrhagic reactions associated with the use of ginkgo leaf preparations. Until further information is available, it is reasonable to advise that ginkgo should not be used in patients with previous or existing bleeding disorders unless the potential benefits outweigh the potential harms. In view of the lack of conclusive evidence for the efficacy of ginkgo leaf in the various conditions for which it is used, and the serious nature of the potential harm, it is extremely unlikely that the benefit–harm balance would be in favour of such patients using ginkgo leaf preparations. Oestrogenic activity in vitro has been documented for a G. biloba leaf extract.⁽⁴⁴⁾ The clinical relevance of this finding has not been established. The fruit pulp has produced severe allergic reactions and should not be handled or ingested. The seed causes severe adverse effects when ingested. Drug interactions In view of the documented pharmacological actions of ginkgo the potential for preparations of ginkgo leaf to interfere with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered. In particular, ginkgo extract should only be used with caution in patients taking anticoagulant and/or antiplatelet agents. Inhibition of the activity of certain human cytochrome P450 (CYP) drug metabolising enzymes, particularly CYP2C9 and, to a lesser extent CYP1A2, CYP2E1 and CYP3A4, has been described for a standardised extract of ginkgo leaf (EGb-761) in in-vitro studies,⁽¹¹⁶⁾ and other in vitro experiments have reported moderate inhibition of CYP3A4 and CYP2C9 activity by G. biloba and/or its isolated constituents.^{(117, 118)} A flavonoid fraction and most of its subfractions showed strong inhibition of the CYP enzymes CYP2C9, CYP1A2, CYP2E1 and CYP3A4 (IC50 < 40 mg/ mL), whereas a terpenoid fraction inhibited activity of CYP2C9 only.⁽¹¹⁶⁾ The flavonol aglycones kaempferol, quercetin, apigenin and others, but not the terpene lactone and flavonoid glycoside constituents of ginkgo leaf, were found to be potent inhibitors of CYP1A2 and CYP3A.⁽¹¹⁹⁾ An in vivo (rats) study found that a standardised extract of ginkgo leaf (EGb-761) 100 mg/kg body weight administered orally for four days was associated with increased CYP P450 enzymes in the liver and increased the metabolism of endogenous steroids.⁽¹²⁰⁾ The latter finding, however, has not been confirmed in drug interactions studies involving healthy volunteers. A standardised extract of ginkgo leaf (EGb-761) administered orally at a dose of 240 mg daily for 28 days,⁽¹²⁰⁾ and a ginkgo leaf extract 240 mg daily for 14 days,⁽¹²¹⁾ had no statistically significant effects, compared with baseline values, on the profile of endogenous steroids in healthy individuals.^{(120, 121)}

Other drug interaction studies involving healthy individuals report conflicting results with respect to the inhibition or induction of CYP enzymes by ingestion of ginkgo leaf preparations. Studies have found that ginkgo leaf extract was associated with certain changes in the pharmacokinetics of nifedipine,⁽¹²²⁾ and omeprazole,⁽¹²³⁾ but not digoxin,⁽¹²⁴⁾ donepezil,⁽¹²⁵⁾ and warfarin.⁽¹²⁶⁾

In a drug-interaction study involving 12 healthy individuals, administration of a standardised extract of ginkgo leaf (Egb761) administered orally at a dose of 120 mg twice daily for 14 days was not associated with any statistically significant changes, compared with baseline values, in the pharmacokinetics of the probe CYP 2D6 substrate dextromethorphan; ginkgo administration was associated with a statistically significant change, compared with baseline values, in the area under the plasma concentration time curve for the CYP3A4 substrate alprazolam, but as there was no statistically significant change in the elimination half-life of alprazolam, it is unlikely that ginkgo had an inductive effect on CYP3A4.⁽¹²⁷⁾

Pregnancy and lactation No studies appear to have been reported on the effects of G. biloba leaf extracts or ginkgolides in pregnant or lactating women. In view of the many pharmacological actions documented and the lack of toxicity data, use of ginkgo during pregnancy and breastfeeding should be avoided.

SIDE EFFECTS/ADVERSE REACTIONS (Linda, S-R. 2010)

CNS: Transient headache, anxiety, restlessness

GI: Nausea, vomiting, anorexia, diarrhea, flatulence

INTEG: Hypersensitivity reactions, rash

SIDE-EFFECTS, TOXICITY (Barnes, J et al., 2007)

Clinical Data

Clinical data on safety aspects of G. biloba leaf preparations are available from several sources, including clinical trials, postmarketing surveillance-type studies and spontaneous reports of suspected adverse drug reactions. Available data indicate that standardised extracts of ginkgo leaf are well tolerated when used at recommended doses and according to other guidance.^{(52, G21)} However, there are reports of bleeding associated with the use of ginkgo leaf preparations (see Side-effects, Toxicity; Haemorrhage). A Cochrane systematic review of studies assessing G. biloba leaf preparations in cognitive impairment and dementia included 33 randomised, double-blind, controlled trials.⁽⁵⁷⁾ All but one of the included studies investigated the effects of standardised ginkgo leaf extracts EGb-761 and LI-1370 at oral doses ranging from 80– 600 mg daily and typically 200 mg daily. The study that did not use either of these preparations assessed an ethanolic extract of ginkgo leaves (drug-to-extract ratio 4 : 1, standardised for total flavone glycosides 0.20 mg/mL and total ginkgolides 0.34 mg/mL) at doses lower than those used in the other 32 studies. Metaanalyses showed that there were no statistically significant differences between ginkgo (any dose) treatment and placebo in the proportion of trial participants experiencing adverse events, and the numbers of participants withdrawing from the studies.⁽⁵⁷⁾

A systematic review of nine randomised, double-blind, placebocontrolled trials of standardised ginkgo leaf extracts in patients with dementia of the Alzheimer type and/or multi-infarct dementia concluded that, overall, the frequency of adverse effects reported for ginkgo was not markedly different than that for placebo.⁽⁵⁴⁾ The largest trial included in this review involved 327 patients with mild-to-severe dementia related to Alzheimer's disease or multi-infarct dementia who received standardised ginkgo leaf extract (EGb-761) 40 mg orally three times daily (n = 166), or placebo (n = 161), for 52 weeks.⁽⁵⁹⁾ It was reported that there was no statistically significant differences between ginkgo and placebo in the number of participants reporting adverse events, or in the frequency and severity of adverse events. Of 188 adverse events reported during the study, 97 were reported by ginkgo recipients and 91 by placebo recipients. However, clinical trials generally only have the statistical power to detect common, acute adverse effects. Similar findings were reported in another systematic review/ meta-analysis which included eight randomised, double-blind, placebo-controlled trials of ginkgo extract for the treatment of intermittent claudication, involving a total of 415 patients who received standardised extract of ginkgo leaf at doses of 120 or 160 mg daily, or placebo, for up to 24 weeks.⁽⁵⁶⁾ Five of the eight studies included reported (rarely) mild, transient adverse events occurring in ginkgo recipients; the remaining three studies, comprising almost 50% of the total number of patients, did not report any adverse events. A postmarketing surveillance study involving 10 815 patients who received a standardised extract (LI 1370) of ginkgo leaf reported that the frequency of adverse effects was 1.7%.^(G56)

Adverse effects reported with standardised extracts of ginkgo leaf are generally mild, and include nausea, headache, gastrointestinal upset and diarrhoea; allergic skin reactions occur rarely.^{(104, G21,G56)} The World Health Organization's Uppsala Monitoring Centre (WHO-UMC; Collaborating Centre for International Drug Monitoring) receives summary reports of suspected adverse drug reactions from national pharmacovigilance centres of over 70 countries worldwide. To the end of the year 2005, the WHOUMC's Vigisearch database contained a total of 594 reports, describing a total of 1178 adverse reactions, for products reported to contain G. biloba only as the active ingredient (see Table 1).⁽¹⁰⁵⁾ This number may include case reports described below. Reports originated from 23 different countries. The total number of reactions (i.e. not individual cases; one case may describe several reactions) included 58 reactions associated with platelet, bleeding and clotting disorders (see Table 1); other reactions include gastrointestinal haemorrhage, haematemesis and melaena (n = 4 each), bloody diarrhoea ⁽¹⁾, haemorrhagic gastric ulcer ⁽³⁾, epistaxis ⁽⁹⁾, haemoptysis ⁽²⁾, post-operative haemorrhage ⁽³⁾, cerebral, subarachnoid or intracranial haemorrhage ⁽¹³⁾, cerebral infarction or cerebrovascular disorder ⁽⁵⁾ and ocular or retinal haemorrhage ⁽³⁾.

Table 1 Summary of spontaneous reports (n = 594) of suspected adverse drug reactions associated with single-ingredient Ginkgo biloba preparations held in the Vigisearch database of the World Health Organization’s Uppsala Monitoring Centre for the period up to end of 2005.^{(a, b, 105)}

 (These data were obtained from the Vigisearch database held by the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. The information is not homogeneous at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction. Any information included in this report does not represent the opinion of the World Health Organization.) Haemorrhage Reports of bleeding and associated disorders included in the WHO-UMC's Vigisearch database are discussedabove. There are several case reports in the literature of bleeding associated with ingestion of Ginkgo biloba extracts. A systematic review of published case reports describing bleeding associated with ginkgo use identified 15 published case reports (including a new report published in the same paper by the authors of the systematic review). Most of the cases involved serious adverse effects, including intracranial bleeding (n = 8 episodes, two required surgical evacuation, two patients experienced permanent neurologic defects, and one patient died), and ocular bleeding (n =4, all returned to baseline vision although one patient required surgery).⁽¹⁰⁶⁾ Where stated, the duration ginkgo exposure before onset of the adverse event varied from less than two weeks' exposure for the two cases of spontaneous hyphema, less than two months' exposure for two cases of intracranial bleeding, and more than six months' exposure for eight other cases. In most cases, there were other risk factors for bleeding, including clinical risk factors and use of other medicines known to increase the risk of bleeding.⁽¹⁰⁶⁾

In addition, most of the case reports do not adequately describe the ginkgo preparation implicated and, typically, in the rare cases that a sample of the product is available, no chemical analysis of the product is undertaken. Since most of the reports originate from countries where ginkgo products are sold as unlicensed dietary supplements, the possibility that poor or variable pharmaceutical quality of products plays a role in these cases cannot be ruled out. Reports identified by the review include those describing a 70- year-old man who experienced spontaneous bleeding from the iris into the anterior chamber of the eye one week after he began taking standardised ginkgo extract 80 mg daily;⁽¹⁰⁷⁾ a 61-year-old man who had taken ginkgo extract 120 mg or 160 mg daily for six months who experienced a subarachnoid haemorrhage;⁽¹⁰⁸⁾ a 33-year-old woman who began experiencing increasingly severe headaches, as well as double vision and nausea and vomiting, over several months, and who had been consuming standardised ginkgo extract 120 mg daily for two years;⁽¹⁰⁹⁾ a 59-year-old man who experienced vitreous haemorrhage after undergoing a liver transplant and who had been consuming a ginkgo product before and during his operation and subsequent recovery period;⁽¹¹⁰⁾ a 34-year-old man who experienced post-operative bleeding following a laparoscopic cholecystectomy andwho had been taking two ginkgo tablets daily (not further specified);⁽¹¹¹⁾ a 56-year-old man who experienced a cerebral haemorrhage and who had been taking ginkgo leaf extract 40 mg three times daily for 18 months;⁽¹¹²⁾ a 65- year-old woman who experienced retrobulbar haemorrhage and who had been taking ginkgo leaf extract 40 mg three times daily for two years.⁽¹¹³⁾ A causal relationship between ginkgo ingestion and bleeding in these cases has not been definitively established.

A new report published since the systematic review describes a 77-year-old woman who experienced persistent post-operative bleeding from the wound after undergoing a total hip arthroplasty.⁽¹¹⁴⁾ Four weeks post-operatively it was found that the woman had been taking ginkgo leaf extract (not further specified) 120 mg daily. Ginkgo use was stopped and the patient's wound healed within ten weeks. Other effects There is a report of acute myoglobinuria in a 29-year-old man who was a regular weight-trainer and who had been taking a combination preparation containing extracts of ginkgo (200 mg), guarana (Paullinia cupana, 500 mg) and kava (Piper methysticum, 100 mg).⁽¹¹⁵⁾ The man was admitted to an intensive care unit with severe muscle pain and blood creatine kinase and myoglobin concentrations of 100 500 IU/L (normal values: 0–195) and 10 000 ng/mL (normal values: 0–90), respectively. Signs and symptoms subsided within six weeks. The relevance, if any, of ginkgo ingestion to the man's condition, is unclear.

Contact or ingestion of the fruit pulp has produced severe allergic reactions including erythema, oedema, blisters and itching.⁽⁸²⁾ The seed contains the toxin 4-O-methylpyridoxine which is reported to be responsible for 'gin-nan' food poisoning in Japan and China.⁽¹¹⁾ The main symptoms are convulsion and loss of consciousness and lethality is estimated in about 27% of cases in Japan, infants being particularly vulnerable.

INTERACTIONS (Linda, S-R. 2010)

Drug

Anticoagulants (anisindione, dalteparin, dicumerol, heparin, salicylates, warfarin), platelet inhibitor (abciximab), salicylates: Because of the increased risk of bleeding, ginkgo should not be taken concurrently with these products.

Anticonvulsants (carbamazepine, gabapentin, phenobarbital, phenytoin): Ginkgo components may decrease the anticonvulsant effect; avoid concurrent use.

INTERACTIONS—CONT’D (Linda, S-R. 2010)

Buspirone, fl uoxetine: Ginkgo given with these agents may cause hypomania (Jellin et al., 2008).

Cytochrome P450IA2/P4502D6/P4503A4 substrates: Ginkgo may affect drugs metabolized by these agents; use caution if giving concurrently (Jellin et al., 2008).

MAOIs: MAOI action may be increased if taken with ginkgo; do not use concurrently (theoretical).

SSRIs: Ginkgo is often used to reverse the sexual side effects of SSRIs.

Trazadone: Ginkgo with trazadone may cause coma (Jellin et al., 2008).

Herb

Anticoagulant/antiplatelet herbs: Ginkgo may increase the risk of bleeding when used with these herbs (Jellin et al.,2008).

St. John’s wort: Ginkgo with St. John’s wort can lead to hypomania.

Lab Test

Partial thromboplastin time, ASA tolerance test: Ginkgo may cause increased bleeding (partial thromboplastin time, ASA tolerance test).

Platelet activity: Ginkgo may decrease platelet activity.

Prothrombin time, blood salicylate: Ginkgo may increase prothrombin time and blood salicylate.

ADVERSE REACTIONS (Braun, L and Cohen, M. 2010)

In most placebo-controlled studies, there is no difference between the side effect incidence with ginkgo and placebo. Standardised ginkgo leaf extracts have been used safely in trials lasting from several weeks to up to 6 years. In a few cases (less than 0.001%), gastrointestinal upset, headaches and dizziness were reported. It does not appear to alter heart rate and blood pressure, change cholesterol and triglyceride levels or increase intraocular pressure in clinical studies (Chung et al., 1999). At least 10 clinical studies have found no significant effect on bleeding or platelets; however, rare case reports of subarachnoid haemorrhage, subdural haematoma, intracerebral haemorrhage, subphrenic haematoma, vitreous haemorrhage and postoperative bleeding have been reported. Crude ginkgo plant parts that may contain concentrations of 5 ppm of the toxic ginkgolic acid  constituents should be avoided, as they can induce severe allergic reactions.

SIGNIFICANT INTERACTIONS (Braun, L and Cohen, M. 2010)

Adriamycin Studies with an animal model indicate that ginkgo extract EGb 761 reduces the hyperlipidaemia and proteinuria associated with adriamaycin-induced nephropathy, which might be beneficial to enhance the therapeutic index of adriamycin (Abd-Ellah & Mariee 2007). Clinical trials have not been conducted to confirm the activity.

Antidepressant drugs Ginkgo may reduce the sexual dysfunction side effects of these drugs and improve sleep continuity; however, results from clinical studies are mixed —possible beneficial interaction.

Bleomycin Studies with an animal model indicate that ginkgo extract EGb 761 reduces oxidative stress induced by bleomycin. This may improve drug tolerance; however, clinical studies have not yet been conducted to test this further (Erdogan et al., 2006).

Cholinergic drugs Cholinergic activity has been identified for ginkgo; therefore, combined use may theoretically increase drug activity — observe patients using this combination, although the effects may be beneficial when used under supervision.

Cisplatin As a herb with significant antioxidant activity, ginkgo has also been employed as a means of reducing the nephrotoxic effects of cisplatin, a use supported by two in vivo studies (Gulec et al., 2006, Ozturk et al., 2004). Other researchers using animal models have indicated that ginkgo may protect against cisplatin-induced ototoxicity (Huang et al., 2007). Clinical trials are required to confirm significance — adjunctive use may be beneficial when used under professional supervision.

Clozapine Ginkgo may enhance the effects of clozapine on negative affect in refractory schizophrenic patients, according to a placebo-controlled study (Doruk et al., 2008) — beneficial interaction.

Doxorubicin In vivo research suggests that ginkgo can prevent doxorubicin-induced cardiotoxicity suggesting a potentially beneficial interaction, although no human studies are available to confirm clinical significance (Naidu et al., 2002).

Haloperidol In three clinical trials, the effectiveness of haloperidol was enhanced when co-administered with 360 mg of ginkgo daily (Chavez et al., 2006) —beneficial interaction under supervision.

Platelet inhibitor drugs Due to its platelet-activating factor antagonist activity, G. biloba may theoretically enhance the effects of these drugs and increase risk of bruising or bleeding; however, evidence from recent clinical trials have cast doubt on the clinical significance of this activity.

Valproate, dilantin, depakote There is a report of two patients using valproate who experienced seizures with ginkgo use (Chavez et al., 2006). There is also a report of a patient taking Dilantin and Depakote and ginkgo, together with other herbal medicines, who suffered a fatal breakthrough seizure, with no evidence of non-compliance with anticonvulsant medications (Kupiec & Raj 2005). The autopsy report revealed subtherapeutic serum levels for both anticonvulsants, Depakote and Dilantin; however, it is uncertain whether effects can be attributed to ginkgo — observe patient taking ginkgo with these medicines.

Warfarin Theoretically, ginkgo may increase bleeding risk when used together with warfarin; however, evidence from controlled clinical studies do not support this conclusion and have failed to identify any clinically significant pharmacodynamic or pharmacokinetic interaction. This conclusion is supported by a recent systematic review (Bone 2008)— observe.

CONTRAINDICATIONS AND PRECAUTIONS (Braun, L and Cohen, M. 2010)

If unusual bleeding or bruising occurs, stop use immediately. Although new clinical evidence suggests that G. biloba does not affect clotting times, it may be prudent to suspend use for 1 week prior to major surgery in at-risk populations.

Cerebral haemorrhage and epilepsy Rare case reports have suggested that ginkgo should be used with caution in people with known risk factors for cerebral haemorrhage and epilepsy until further investigation can clarify its safety (Benjamin et al., 2001, Granger 2001, Vale 1998).

PREGNANCY USE  Insufficient reliable evidence is available to determine safety.

Clinical note — Does Ginkgo biloba cause significant bleeding and does it interact with warfarin?

(Braun, L and Cohen, M. 2010)

The current body of evidence casts doubt on the clinical significance of the proposed interaction between warfarin and ginkgo, revealing that there is little evidence from controlled studies to demonstrate significant platelet inhibition, bleeding or changes to international normalised ratio (INR) with use of ginkgo (especially EGb 761 or phytochemically similar extracts). To date five clinical trials have been published in peer-reviewed journals which demonstrate that G. biloba does not have a significant effect on platelet function, two studies showing no interaction with warfarin, one study showing no interaction with aspirin and a further study showing no interaction with clopidogrel (Aruna & Naidu 2007, Bal Dit et al., 2003, Beckert et al., 2007, Carlson et al., 2007, Engelsen et al., 2003, Gardner et al., 2007, Jiang et al., 2005, Kohler et al., 2004).

 Studies have included young healthy volunteers and older adults, using doses up to 480 mg/day of ginkgo and time frames up to 4 months. The first controlled study was published in 2003. Bal Dit et al., conducted a double-blind, randomised, placebo-controlled study of 32 young healthy volunteers to evaluate the effect of three doses of G. biloba extract (120, 240 and 480 mg/ day for 14 days) on haemostasis, coagulation and fibrinolysis (Bal Dit et al., 2003). This escalating dose study found no effect on platelet function or coagulation for any dose tested. A year later, results from a larger randomised, placebo-controlled, crossover study that produced similar results was published (Kohler et al., 2004). The study by Kohler, Funk and Keiser investigated the effects of ginkgo (2 × 120 mg/day EGb 761) on 29 different coagulation and bleeding parameters. Once again, no evidence of inhibition of blood coagulation and platelet aggregation was detected. In Australia, Jiang et al., investigated the interaction between warfarin and G. biloba using a randomised, crossover study design (Jiang et al., 2005).

The study of 12 healthy males found no evidence that INR or platelet aggregation was affected by G. biloba. Engelsen, Nielson and Hansen also found no evidence of an interaction between G. biloba and warfarin under double-blind, placebo-controlled trial conditions (Engelsen et al., 2003). The study involved patients stable on long-term warfarin and reported no changes to INR values. In 2007, four more studies were published. Carlson et al., conducted a study of 90 older adults (65–84 years) who were randomly assigned to placebo or a G. biloba-based supplement (160 mg/ day) for 4 months (Carlson et al., 2007). No evidence of alteration to platelet function was seen at this dose. Beckert et al., conducted a smaller trial of 10 volunteers who were administered ginkgo for 2 weeks, after which in vivo platelet function was quantified using the PFA-100 assay (Beckert et al., 2007).

The study used aspirin as a control agent and found that platelet function was not affected by G. biloba, but was markedly inhibited by the administration of aspirin. No clinically or statistically significant differences were seen in a randomised, double-blind, placebo-controlled trial, which investigated the effects of G. biloba (Egb 761, 300 mg/day) on several measures of platelet aggregation among 55 older adults (age 69 ± 10 years) also consuming 325 mg/day aspirin (Gardner et al., 2007). Reports of bleeding or bruising were infrequent and similar for both study groups. Finally, a study of 10 healthy volunteers investigated the effects of two different doses of G. Biloba (120 mg and 240 mg) taken together with clopidogrel (75 mg) (Aruna & Naidu 2007). Platelet inhibition with the combination of G. biloba and clopidogrel was not statistically significant, compared with individual doses of drugs.

PATIENTS’ FAQs

What will this herb do for me? Ginkgo is a very popular herbal treatment that increases peripheral circulation, beneficially influences brain chemicals, protects nerve cells from damage, and may stimulate immune function and reduce inflammation. Scientific evidence has shown that it may improve cognitive function in people with mild-to-moderate cognitive impairment when used long term in sufficient dosage, but it is less successful in people with normal function. It may also improve some aspects of memory in younger people when used short term. Ginkgo may improve symptoms of intermittent claudication and be useful in treating chilblains, PMS, vitiligo, preventing altitude sickness and seasonal affective disorder and possibly sexual dysfunction such as impotence. If taken long term, it does not protect against the development of dementia in the future and it does not effectively treat tinnitus.

When will it start to work? This will depend on the condition treated and the dose used. Generally, G. biloba is a slow-acting herb that can take anywhere from 4 weeks to 3 months to exert maximal effects.

Are there any safety issues?  Ginkgo has been extensively studied and appears to be extremely safe with virtually no side effects in healthy people. Some contraindications and interactions are possible, so it is recommended that it should be taken under professional supervision.

PHARMACOLOGY  

PHARMACOLOGY (Linda, S-R. 2010)

Pharmacokinetics

Excretion _30% of metabolites. Bioavailability is unaffected by food.

PHARMACOLOGY (Kraft, K and Hobbs, C. 2004)

– Herb: Ginkgo leaf (Ginkgo bilobae folium). The herb consists of the dried leaves of Ginkgo biloba L. and preparations of the same.

– Important constituents: Flavonoids (0.5–1.8 %), including quercetin biosides, monosides, and triosides, isorhamnetins, and 3´-O-methyl myristicins as well as biflavonoids (0.4–1.9 %), proanthocyanidins (8–12 %), diterpenes (0.06–0.23 %; ginkgolides A, B, C), and sesquiterpenes (bilobalide, 0.04–0.2 %).

– Pharmacological properties: Ginkgo has antioxidant and membrane-stabilizing activity and improves the circulation. In addition, it increases cerebral tolerance to hypoxia, reduces the age-related reduction of muscarinergic choline receptors and α2-adrenoceptors, and increases the hippocampal absorption of choline. In animals, bilobalide and ginkgolides were found to improve the flow capacity of the blood by lowering viscosity, inactivating toxic oxygen radicals and improving the circulation in cerebral and peripheral arteries. The herb inhibits the development and promotes the elimination of cerebral edema, improves the utilization of ATP and glucose, and stabilizes the cell membranes. Clinical, controlled double-blind studies in humans have confirmed the results of animal experiments (ginkgo was found to improve the memory capacity and microcirculation and reduce the viscosity of plasma).

ACTIVITIES (Duke, 2002)

Antiaggregant (2; BGB; KOM; MAB; PH2; SHT; WHO); Antiallergic (1;PNC); Antialzheimeran (2; COX; JAM); Antianaphylactic (1; PNC); Antiarrhythmic (1; MAB); Antiarthritic (1; COX; FNF); Antiasthmatic (1; AKT; PNC); Anticancer (1; COX; FNF); Anticapillary Fragility (1; BGB; PH2; WHO); Anticonvulsant (1; MAB); Antidementic (1; PH2); Antidepressant (1; AKT); Antiedemic (1; KOM; PHR; WHO); Antiinflammatory (1; PH2; WHO); Antiischemic

(1; FT69:195; FNF; WHO); Antimastocytotic (1; MAB); Antioxidant (2; KOM; MAB; PH2; WAM); Antiseptic (1; MAB); Antispasmodic (f; PH2); Antitussive (f; DAA); Anxiogenic (1; MAB); Anxiolytic (1; MAB); Astringent (1; AKT); Bronchodilator (1; PH2; PNC); Cardioprotective (1; MAB); Cerebrostimulant (1; PNC; SHT; WAM); Cholinergic (1; KOM; SHT); Circulostimulant (1; MAB; PNC; SHT); Convulsant (1; MAB); Hypolipidemic (1; MAB); MAOI (1; MAB); Memorigenic (1; AKT; PAM; PH2; WAM); Neurogenic (f; SKY); Neuroprotective (2; KOM; MAB; SKY); Nootropic (1; BGB; MAB); Peripheral Stimulant (FT69:195); cGMP-Phosphodiesterase Inhibitor (1; WHO); Radioprotective (1; AKT); Thrombolytic (1; MAB); Vasodilator (1; APA; KOM; PED); Vasoprotective (1; BGB); Vermifuge (1; WHO).

PHARMACOLOGICAL ACTIVITIES AND CLINICAL TRIALS (Ross, I. A. 2004)

Acetylglucoseamidase inhibition. The dried leaf extract, administered intravenously to rats at a dose of 2.0 mg/kg, was active on the intestine vs ligation-induced ischemia080272 .

Adaptogenic activity. The flavonoid fraction of the dried leaf, administered intraperitoneally to rats at a dose of 50.0 mg/kg, was active on animals subjected to the stress of being bound in a 5 degrees Celsius and 428 mm Hg environment. The time until colonic temperature had fallen to 23 degrees Celsius and the time to recovery once the animals were removed to normal environment (32 deg. Celsius and 1 ATM) were recorded. When the treatment was given 34 minutes prior to the test, recovery was significantly reduced. When the animals were dosed for 5 days, the time to attain 23 degrees Celsius was increased and the recovery time was decreased significantl ycsoz93.

Adrenergic agonist (beta). Ethanol (95%) extract of the dried leaf, administered intraperitoneally to mice at a dose of 100.0 mg/kg, was active. The extract exerts a specific effect on the noradrenergic system and on Beta-receptors. No variation was found in alpha-2 receptors or serotonin uptake080254.

AIDS therapeutic effect. Ethanol (30%) extract of the leaf, in a mixture containing flavopereirine, dihydro-flavopereirine, naringin and naringenin, taken orally by adults, was effective. The biological activity has been patented080157 .

Allergenic activity. The fruit, taken orally by male adults at a dose of 2 fruits/person, produced erythrema, burning and swelling of the mouth, tenesmus, perirectal burning and pruritis ani 080127.

Analgesic activity. Ethanol (30%) extract of the dried leaf, administered by intravenous infusion to adult patients with dia- betes mellitus who had hyperpathic polyneuropathy syndrome, showed a decrease in symptoms. The biological activity has been patented080297.

Antiaging activity. Ethanol (30%) extract of the dried leaf was effective vs aginginduced changes in mitochondrial morphology and function°8011H.

Antiallergenic activity. Hydro-alcoholic extract of the dried leaf, at a concentration of 0.1 %, was effective in a double-blind, placebo-controlled study of 22 females with contact dermatitis. After pretreatment of the skin with the extract, 68% of the subjects showed significantly reduced skin reactivity as compared with the placeboG80147.

Antiatherosclerotic activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to rabbits receiving a high fat diet at a dose of 10.0 mg/kg daily, was effective080227 .

Antibacterial activity. Hot water extract of the leaf, on agar plate at a concentration of 1.2 mg/disc, was inactive on Streptococcus mutans strains MT5091 and OMZ176. The methanol extract, at a concentration of 0.2 mg/disc, was active on strain MT5091. A concentration of 0.8 mg/disc was active on OMZ176. Methanol/water (1:1) extract, at a dose of 1.2 mg/disc, was active on strains MT5091 and OMZ176c'80331 . Water extract of the leaf, on agar plate, was active on Staphylococcus aureus, MIC 10.5 mg/mlG80219.

Anticerebral edema activity. Ethanol (30%) extract of the dried leaf, administered intraperitoneally to rats at a dose of 5.0 mg/kg daily for 21 days, increased binding density of labeled 8-hydroxy-2(di-n-propylamino) tetralin to 5-HT-1A receptors in aged animals080181 . Ethanol (95%) extract of the dried leaf, at a dose of 0.2 gm/person, was administered either orally or by intravenous infusion to women with idiopathic cyclic edema. Full correction of the biological anomaly resulted in the 5 patients treated by the intravenous infusion, and in  10 patients treated by oral administration. Landis' test was performed before and after the oral treatment080260. The intravenous infusion of the extract, at a dose of 100.0 mg/person, was effective on patients with vasogenic edema observed after irradiation of the brain°80258.

Anticlastogenic activity. Ethanol (30%) extract of the dried leaf, at a concentration of 100.0 mcg/ml, was effective when tested on culture exposed to clastogenic factors from plasma of persons exposed to irradiation080198. A dose of 40.0 mg/day, 3 times daily for 2 months, was effective when taken orally by recovery workers from the Chernobyl accident080219.

Anti cytotoxic activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to mice at a dose of 200.0 mg/ kg, was active on pancreatic beta cells vs alloxan-induced cytotoxicity080180.

Antideafness activity. Ethanol (95%) extract of the dried leaf was taken orally by adults with acute cochlear deafness. At the conclusion of the double-blind therapeutic trial comparing the extract and a standard alpha-blC>cker (nicergoline), a significant recovery was observed in both therapeutic groups. Improvement was distinctly better in the extract-treated group080256.

Antidementia activity. Ethanol (30%) extract of the dried leaf was taken orally by 202 patients with Alzheimer's or multiinfarct dementia. Significant improvement was seen in the Alzheimer's biological activity disease assessment scale and a geriatric evaluation by Relative's rating instrument, but not in clinical global impression of change0801l4• When the extract was taken orally by 12 healthy volunteers, EEG data indicated increased alpha activity080211 . The ethanol (95%) extract, administered intraperitoneally to rats and orally to healthy volunteers at variable dosage levels, was effective in 4 studies using electroencephalograms to measure the effects080267 . The effectiveness of the ethanol (95%) extract of the dried leaf, taken orally by adults of both sexes in the treatment of cerebral disorders due to aging, was evaluated. In the double-blind, drug vs placebo trial involving 166 patients, a specially devised geriatric clinical evaluation scale was used.

The results confirmed that the extract is effective against cerebral disorders due to aging. The difference between control and treatment groups became significant at 3 months and increased during the following months080259. The dried leaf was taken orally by adults at a dose of 150.0 mg/kg, in a study to test the effect on improvement of well being and cerebral functional capacity. The randomized, double-blind, placebo-controlled trial with 50 patients with degenerative and vascular dementia lasted for 13 weeks. Three tablets of 50.0 mg of extract each or 3 placebo tablets were given daily. Adverse side effects were seen under placebo treatment once and under active treatment twice. Significant differences between the groups were seen in 7 of 11 patients after 12 weeks. The active treatment group was significantly faster in carrying out the Figure Connection Test after 6 and 12 weeks. The results indicate a significant improvement in cerebral functional capacity in the patients with degenerative and vascular dementia080289. Ethanol (30%) extract of the leaf, taken orally by adults at a dose of 150.0 mg/day, was effective. Fifty patients aged from 57 to 76 years with cerebra-organic syndrome, participated in a placebo-controlled, double-blind study. After a washout phase of 14 days, the therapy began with the intake of a 50 mg coated tablet 3 times daily. The therapeutic efficacy was tested with the Vienna Determination test, the Figure Connection test, Saccadic eye movement, EEG analysis, and measurement of the evoked potentials. For all5 target criteria, a statistically highly significant superiority of active treatment  was shown in comparison to the placebo group, which appeared after only 3 weeks of treatment and became more obvious after 6 weeks. At the same time the clinical symptoms improved, the results indicated that therapy with the extract in patients with cerebra-organic syndrome contributes to an increased cerebral capacitf80299 • This dose was also active in patients after a subarachnoid hemorrhage and aneurysm operation. Without treatment, even after 7-42 months they had serious cognitive deficits and only 70% of them would have good neuropsychological results. A placebo-controlled, double-blind study was conducted with 50 outpatients after SAH and an aneurysm operation. After 12 weeks of treatment with the extract, significant improvements were shown in the field of attention and verbal short-term memory080304• In a placebo-controlled, double-blind study, the efficacy of the extract on cerebral functional capacity and well-being was studied in 52 ambulant patients with vascular dementia over a period of 3 months. The dose in this case was a drinking solutio  equivalent to 150.0 mg of the leaf extract. A strong placebo effect was observed. At a total study period of 2 years, the stability of the solution was possibly not sufficient. The effectiveness was equivocal080302•

Antiedema activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to rats at a dose of 100.0 mg/kg immediately after the induction of cerebral lipid deoxidation and edema by bromethalin, was effective080307• The extract also decreased the water, sodium and potassium levels vs triethyltin-induced cerebral edema080273• Methanol extract of the fruit, at a dose of 2.0 mg/ear, was effective on the mouse vs 12-0-tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation. The inhibition ratio was 10°80170 •

Antiemetic activity. Ethanol (30%) extract of the dried leaf was administered intragas- trically to rats at a dose of 50.0 mg/kg, in a mixture of 50% ginger, 20% extract and 30% water. The results showed blocked lithium chloride-induced conditioned place aversion, indicating antiemetic activity comparable to metoclopramide080210•

Antifungal activity. Ether extract of the fresh bud, on agar plate, was active on Aspergillus fumigatus 080332 •

Antihyperglycemic activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to male rats at a dose of 50.0 mg/kg, produced weak activity vs streptozotocin- induced non-insulin dependent diabetes mellitus080129• A dose of 80.0 mg/person, taken orally by 7 male volunteers twice daily for 8 weeks, showed no significant change or tendency to change. Differential tests with LHRH and TRH were performed before, and 4 and 8 weeks after the treatment080115•

Antihypoxic effect. Glycoside mixture of the entire plant, taken orally by 8 healthy men in a double-blind, crossover study, demonstrated a hypoxia-protecting effect osoJJo. Water extract of the dried leaf, administered by gastric intubation to rats at a dose of 200.0 mg/kg for 14 days, did not significantly alter brain energy metabolism, although it had a protective effect. A dose of 100.0 mg/kg, administered intraperitoneally to rats, produced an increase in blood glucose level, a slight lowering of lactate and a lowering of the lactate /pyruvate ratio. There was also a less pronounced breakdown of high-energy phosphates in cases of severe hypoxia. Results significant at p <0.001 level080244•

Antiinflammatory activity. Ethanol (30%) extract of the dried leaf, applied externally on mice, was effective vs croton oil-induced edema080186• A dose of 80.0 mg/person, taken orally by adults, was effective vs platelet aggregation factor-induced skin wheal and flare080133 • Ten patients, aged 35-75, participated in a study to determine the effect of  the extract on ulcerative colitis. Of the 10 patients, 3 went into remission, 2 experienced some effects and 5 experienced no effect'l00177 .

Antiischemic effect. Ethanol (30%) extract of the dried leaf, at a concentration of 200.0 mg/kg, improved the mechanical recovery and suppressed the leakage of lactate dehydrogenase during reperfusion. It diminished the decrease of ascorbate content and suppressed the increase of dehydroascorbatea00191. When administered intraarterial to the rabbit at a dose of 10.0 mg/kg, the extract inhibited the increase in lipid peroxidation and superoxide dismutase vs ischemia/reperfusion-injuryG00194. Intragastric administration to rats was effective vs chloroquine-induced increase in amplitude and delay of B wave on electroretinogram, indicative of retinopathyG80195 . A dose of 50.0 mg/kg, administered intragastrically to rats, reduced reperfusioninduced increases in tissue Na• and Cl-, and decreased K• following ischemia injury in streptozotocin-induced diabetic animalsaoozos. A dose of 1.0 mg/kg, administered intravenously to dogs, was effective vs embolic stroke-induced cerebral blood flow decreases and oxygen extraction increasesaoozol. A dose of 100.0 mg/kg, administered intravenously to rats, was not effective vs bilateral carotid obstruction-induced ischemia asoz 1z. A dose of 150.0 mg/person, taken orally by 50 outpatients with degenerative and vascular dementia in a randomized, double-blind, placebo-controlled trial, was found to improve performance on psychometric tests and judgment scales after 6 and 12 weeksa00158. A dose of 10.0 mg/kg, administered subcutaneously to rats, was effective vs middle cerebral artery ligation-induced infarctaoozlz.

Antimutagenic activity. Methanol extract of the dried leaf, on agar plate at a concentration of 50.0 microliters/disc, was inactive on Bacillus subtilis NIG-1125 His Met and Escherichia coli B/R- WP2-TRPaoom.

Antimycobacterial activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to female mice at a dose of 200.0 mg/kg, was inactive on Mycobacterium aviuma80197 • Ethanol (95%) extract of the fresh fruit peel, on agar plate, was active on Mycobacterium smegmatisa 80319 • The fruit, on agar plate, was active on Mycobacterium tuberculosisa80110 • The leaf juice, on agar plate, produced weak activity on Mycobacterium tuberculosis, MIC 1:20a80108 .

Antineurotoxic activity. Ethanol (30%) extract of the dried leaf, in the drinking water of mice at a dose of 50.0 mg/kg for 7 months, increased the projection field of intra- and infra-pyramidal mossy fibers, and reduced the area of stratum radiatumG00187 . The ethanol (95%) extract, administered intragastrically to mice at a dose of 100.0 mg/kg daily for 17 days, prevented a 25% loss of striatal dopaminergic nerve endings seen in control, vs subcutaneously osmopump- released n-methyl-4-phenyl-1 ,2,3,6- tetrahydropyridine (MPTP) at a rate of 100 mg/kg/dayasoz79.

Antioxidant activity. Ethanol (30%) extract of the dried cell free extract, at a concentration of 10.0 mcg/ml, was active on neurons vs oxidative stress induced by hydrogen peroxideG00237 . Ethanol (30%) extract of the dried leaf, at a concentration of 2-16 mcg/ml, reduced the ability of synaptosomes prepared from striata to take up 3H-dopamine rapidly during incubation at 3 7 degrees Celsius, in an oxygenated KrebsRinger medium with 0.1 mM ascorbic acid. Ascorbic acid was responsible for this decrease. Its effectiveness after a 60 minute incubation was concentration-dependent from 1 mM and virtually complete for 0.1 mM. A decrease of synaptosomal membrane fluidity was revealed by measurements of fluorescence polarization. This decrease was potentiated by Fez•. In contrast, it was prevented by the Fez• chelator, deferriozamine (O.lmM), by the extract as well as by the flavonoid quercetin. This preventative effect was shared by trolox (0.1 mM). It is concluded that peroxidation of neuronal membrane lipids induced by ascorbic acid/ Fe 2• is associated with a decrease in membrane fluidity, which in turn reduces the ability of the dopamine transported to take up dopamine080222 . A concentration of 200.0 mg/liter quenches diphenylpicrylhydrazyl in a dose-dependent manner and is able to react with free radicals directly 080191 . A concentration of 25.0 mcg/ml had a time- and dose-dependent effect on the red blood cells. A 14.84% inhibition was produced, results significant at p <0.01 level. A dose of 250.0 mcg/ml produced 56.53% inhibition. Results significant at p <0.001 level080192 ·080193 . The ED50 of the extract was 6.4 mcg/ml vs photo-induced oxidation of low-density lipoprotein cholesterol080238. A concentration of 250.0 meg/ ml was active on human red blood cells vs lipid peroxidation induced by hydrogen peroxide080141 . The IC50 was 150.0 mcg/ml on liver microsomes vs NADPH, ADP and FeCl3-induced lipoperoxidation, results significant at p <0.05 level080204 . A dose of 100.0 mg/day, administered in the drinking water of male rats, was active on the rat brain and liver mitochondria080142 . Intragastric administration to rats, at a dose of 100.0 mg/kg, was effective on bromethalin- induced brain lipid peroxidation and cerebral edema080190 . A dose of 150.0 mg/ kg reduced LDH activity, decreased mitochondrial lipid peroxide content, decreased mitochondrial phospholipid content and increased reduced glutathione content in ischemia-induced rat brain injury080224 . The leaves, administered orally to male rats, inhibited ischemia-induced lipid peroxidation in animals with experimental spinal cord injury080140. The dried leaf, at a concentration of 100.0 mcg/ml, was active vs copper-mediated LDL oxidation°80208 and inhibited LDL-peroxidation, but delta-tocopherol and beta-carotene levels were maintained080200 .

Antiplatelet activity. Ethanol (30%) extract of the dried leaf, at a dose of 60 mg per day for 1.5 years, produced an increase in bleeding time. The dose was taken orally by a 33-year-old woman without significant medical history. She developed bilateral subdural hematomas spontaneously080132 .

Antipolydipsia activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to rats at a dose of 100.0 mg/

kg, was effective vs stress-induced polydipsiaosoln.

Antiproteolytic activity. Ethanol (30%) extract of the dried leaf, at a dose of 40.0 mg/kg in the drinking water of rabbits for 3 weeks, had a protective effect on retinal tissueosolss.

Antishock effect. Ethanol (95%) extract of the dried leaf, administered by intravenous infusion to adults at a dose of 50.0 mg/ person, was effective in a rare but severe case of hypovolemic shock related to monoclonal gammapathy. The treatment resulted in a dramatic recovery, and was followed by oral administration°80251 .

Antistress activity. Ethanol (30%) extract of the dried leaf, administered intragastrically to rats at a dose of 50.0 mg/kg, was effective on the hippocampus vs chronic cold stress-induced desensitization of serotonin-lA receptors at the adenyl cyclase coupling step080144.

Antithrombotic effect. Ethanol (30%) extract of the dried leaf, administered intragastrically to male rats at a dose of 50.0 mg/ kg, was effective vs laser-induced arterial thrombosis. Results significant at p <0.05 level080240. The 95% ethanol extract, administered intravenously to male guinea pigs at variable dosage levels, was active vs PAFacether- induced thrombosis080249·080250 .

Antitinnitus activity. Ethanol (95%) extract of the dried leaf, taken orally by 103 patients in a 13-month treatment period using a double-blind, drug vs placebo method, improved the condition of all the tinnitus patients, irrespective of the prognostic factors. The results were conclusive as regards the effectiveness of the extract, and it was possible to determine the prognostic value of different parameters of special importance080257 •

Antivertigo effect. Ethanol (95%) extract of the dried leaf was used in a study of 70 patients with vertiginous syndrome of recent onset and undetermined origin. In a double-blind trial extending over a 3- month period, the patients were given either the extract or placebo. The effectiveness of the extract on the intensity, frequency and duration of the disorder was statistically significant. At the conclusion of the study, 4 7% of the patients treated had no more symptoms as compared to 18% of those who received the placebo080255 •

Antiviral activity. Hot water extract of the dried fruit, in vera cell cultures at a concentration of 0.5 mg/ml, was inactive on Herpes Simplex 1 virus, measles virus and poliovirus 1° 80183 •

Anxiety induction. Ethanol (30%) extract of the dried leaf, administered intragastrically at a dose of 48.0 mg/kg and intraperitoneally at a dose of 8.0 mg/kg to male rats, decreased the duration of social contact

in social interaction test080241 •

Anxiolytic effect. Acetone/water ( 1:1) extract of the dried leaf, administered intragastrically to female rats at a dose of 1.0 mg/ kg, was active vs elevated plus-maze test. The 30% ethanol extract, in a mixture with Zingiber officinale, was also effective 080218 •

Apoptosis inhibition. Ethanol (30%) extract of the dried leaf, at a concentration of 100.0 mcg/ml assayed in cerebellar cell culture, was active on neurons vs hydroxyl radical-induced apoptosis080230 •

ATP level increased. Ethanol (30%) extract of the dried leaf, at a concentration of 0.5 mcg/ml, was active on the human umbilical vein endothelium vs hypoxiainduced decrease in A TP080214 •

Blood viscosity decreased. The leaf juice, taken orally by 30 artherosclerotic patients 3 times daily for over 3 months, was effective. Two out of 3 patients showed a decrease in blood viscosity 080m.

Blood viscosity increased. Ethanol (95%) extract of the dried latex, taken orally by adults at a dose of 45.0 ml/person, was not effective080275 •

Bradykinin antagonist activity. Flavonoid fraction of the leaf was effective on guinea pig ileum, ED 50 75.0 mcg/ml080103 •

Cardiovascular effect. Ethanol (95%) extract of the dried leaf, administered orally to 36 patients with arteritis for 65 weeks, was active. For the first 6 months of treatment, the patients participated in a double- blind, randomized comparison with 35 well-matched patients taking a placebo. Subsequently, the patients taking the extract were given the option to continue treatment on an open basis with follow-up at regular 3-month intervals. The patients taking the extract had significantly greater pain relief and walking tolerance than the placebo after 6 months of treatment, and the improvement continued throughout the duration of the study 080252 •

Cell membrane stabilization. Ethanol

(30%) extract of the dried leaf, in cell culture at a concentration of 100.0 mcg/ml, was active on pulmonary artery endothelial cells. The extract inhibited LDH release after pre-incubation of the cells with the extractG 80223 • The dried fruit was active on the rabbit RBC, ED50 0.2 mg/ml. A dose of 200.0 mg/kg increased the resistance to hemolysis by 54% after 24 hours080116•

Cerebral arteriosclerotic effect. Ethanol (70%) extract of the dried leaf, taken orally by adults in a chewing gum containing the extract, was effective in treating cerebral apoplexy. The biological activity has been patented080139 •

Cerebral blood flow effect. Ethanol (30%) extract of the dried leaf, administered intragastrically and intraperitoneally to rats of both sexes at a dose of 100.0 mg/kg for 21 days, showed an increase in blood flow, ATP, glucose and lactate levels as compared to controls. When a dose of 200.0 mg/kg was administered to the animals for 14 days, prior to hypobaric hypoxia, the animals survived the hypoxia for a longer time, but the brain metabolism was not affected080139 • The extract was taken orally at a dose of 300.0 mg/kg by 24 hypertensive patients with fundus hypertonicus phase 1 according to Theil. In the randomized, placebo-controlled, double-blind trial, the influence of the extract on retinal blood flow was measured before and on the 14'h and 22nd day of treatment. The daily dose was 3 coated tablets, each containing 100 mg of the extract. In the placebo group, the value did not change considerably. Under Verum treatment, both the blood flow in the quadrant artery and the total blood flow, improved significantly in comparison to the placebo group. The arteriovenous circulation time decreased significantly. Rheological parameters, erythrocyte aggregation and erythrocyte filtration time showed a tendency to decrease, and plasma viscosity demonstrated a significant drop in comparison to placebo080291 • A dose of 150.0 mg/person was tested for the improvement of typical symptoms of cerebral insufficiency in a placebo-controlled, double- blind study. Ninety-nine outpatients with typical symptoms participated in the study that lasted for 12 weeks. The state of health was significantly improved after only 4 weeks. After 12 weeks, 10 of 12 symptoms were clearly improved when compared to the controls080292 •

Cerebral blood flow increase. Ethanol

(30%) extract of the leaf, administered intravenously to rats at a dose of 50.0 mg/kg, was effective on the ante-positioned arteria mesenterica superior. After the induction of lactate acidosis, the effect was measured in 48 single procedures and registered by means of intravital microscopy. Various methods of application and dosages were tested against control solution. However, it was only at 1 minute after local and 15-22 minutes after intravenous application that significant hemorheologic effects could be seen°80305 • A double-blind study of the extract was conducted with 16 volunteers who had signs of cerebral insufficiency in order to prove the pharmacological effects concerning vigilance. An enforced lack of sleep model was used where the topographic aspects of the EEG output could be shown with a special EEG mapping method. After 8 weeks of therapy, the output of the Theta band decreased in the group treated with the extract under enforced lack of sleep, whereas the Alpha slow wave index in the control group increased. The results of the analysis indicated that treatment with the extract influences the EEG frequency spectrum within the sense of increased vigilance080303 • In a placebo-controlled, double-blind study, the efficacy of the extract on cerebral functional capacity and well-being was studied in 52 ambulant patients with vascular dementia over a period of 3 months. The dose in this case was in the drinking solution equivalent to 150.0 mg of the leaf extract. A strong placebo effect was observed. At a total study period of 2 years, the stability of the solution was possibly not sufficient. The effectiveness was equivocal080302 •

Cerebral edema decreased. The dried leaf, administered intragastrically to rats at a dose of 100.0 mg/kg, was effective 080271 •

Cerebral insufficiency improvement. Acetone/water ( 1: 1) extract of the leaf, taken orally by adults at a dose of 160 mg/day, was effective080148 • Ethanol (30%) extract of the dried leaf, taken orally by adults at a dose of 120.0 mg/person daily for 4-6 weeks, was effective080166• The efficacy of the extract, at a dose of 150.0 mg/day, was tested in a double-blind trial of 90 patients with cerebral insufficiency. The average age of the patients was 62.7 years. By the end of the 12 week trial period, there was significant improvement in the patients' performance, observed under Verum, compared to the placebo preparation which was administered to a control group of patients among which the relevant disorders were distributed homogeneously. The effect of the extract was stabilization of a more consistent response behavior with minor intraindividual variations involved. There was improvement in the patients' attention with respect to tasks which required quick orientation and readaptation, or a consistent attentiveness level, to be maintained over a longer period of time (long-term stress). The range of optimum attention with respect to the solution of tasks was enlarged as far as the time was concerned. Improvement in memory performance was experienced, particularly with respect to the visual memory of sensitive parameters of cerebral insufficiency, which may also be due to the improvement in concentration power. Positive changes in subjective performance were also found, which were experienced by the patient and the people in his or her environment. Since improvements of some of the parameters were not observed until the 6'h week of treatment, the test preparation should be used over a minimum period of time080226 •

Chloride channel inhibition. Ethanol (30%) extract of the dried leaf, at a concentration of 50.0 mcg/ml, inhibited isoproterenol-induced chloride current, but no effect was seen on the action potential or associated currents of guinea pig hearfl80182•

Cholesterol level decrease. The dried leaf, taken orally by adults of both sexes at a dose of 120.0 mg/person in combination with garlic, produced improvement in cholesterol with no dietary or exercise changes080196 •

Chronotrophic effect. Ethanol (95%) extract of the dried latex, taken orally by adults at a dose of 45.0 ml/person, was not effective080275 • Ethanol (30%) extract of the dried leaf, taken orally by 10 adult volunteers each with some hemorheological abnormality, was effective. The extract was in combination with Panax ginseng. The

heart rate was measured 1 hour after the treatment080165 •

Circulation stimulation. Ethanol (95%) extract of the dried latex, taken orally by adults at a dose of 45.0 ml/person, was

effective080275 • The influence of the dried leaf, at a dose of 112.5 mg/person on cutaneous microcirculation, was studied in a randomized, placebo-controlled, singleblind crossover study of 2 groups. In the first phase of the study, a liquid preparation was tested against a corresponding placebo. In the second phase, a solid preparation was tested compared with the liquid preparation. Blood pressure, heart rate and capillary diameters stayed constant in both tests. A significant increase of capillary erythrocyte velocity was measured 1 hour after administration of the Ginkgo liquid (57%) followed by the Ginkgo tablet (42%). The peak efficiency of both preparations was reached about 1 hour after administration °80290•

CNS depressant activity. Ethanol (30%) extract of the dried leaf, administered intraperitoneally to male rats at a dose of 16.0 mg/kg, was not effective on locomotor activity080241 •

CNS effects. Ethanol (30%) extract of the dried leaf, administered intragastrically to rats at dose of 10.0 mg/kg, significantly increased the amplitude of spectra analysis of EEG in alloxan-diabetic and extracttreated animals compared to controls 080215• The leaf, taken orally by 36 patients at a dose of 120 mg/day, was effective. The 36 patients with cerebra-organic syndrome (dizziness, memory and concentration loss, and orientation disorders) participated in a double-blind, placebo-controlled study. After 4 to 8 weeks of treatment, the treated group had lower Saccade duration, and better scores on the Wiener determination test and number connection test than the control group. Upon EEG testing, the theta proportion of the theta/alpha ratio was reducedosoJJs.

Corticosteroid synthesis stimulation. Ethanol (30%) extract of the dried leaf, administered intragastrically to male rats at

a dose of 100.0 mg/kg, was active vs ACTHstimulated corticosterone production in adrenocortical cells080145 .

Cytochrome P-450 induction. Ethanol (30%) extract of the dried leaf, taken orally by adults at a dose of 400.0 mg/person, was inactive080203 .

Cytotoxic activity. Acetone, ether and methanol extracts of the dried seed, at a concentration of 5.0% were inactive by the cylinder plate method, and the water extract was equivocal on CA-Ehrlich ascites. The inhibitions were 16 mm, 17 mm, 0 mm and 25 mm, respectively080341 . Chloroform, water and methanol extracts of the leaf, in cell culture, were inactive on LEUK-P388, ED 50 100.0 mcg/ml080228 . Ethanol (30%) extract of the dried leaf, in cell culture at a concentration of 500.0 mcg/ml, was inactive on pulmonary artery endothelial cells 080223 . Ethyl acetate extract of the leaf, in cell culture, produced weak activity on HELA-83 cells, IC50 43.0 mcg/ml080233 .

Desmutagenic activity. The fresh fruit homogenate, on agar plate at a concentration of 100.0 microliters/disc, was active on Salmonella typhimurium TA100 and TA98 vs 1,4-dinitro- 2-methyl pyrrole mutagenesis080327 .

DNA binding inhibition. The dried leaf, in cell culture at a concentration of 10.0 mcg/ml, was active on J urkat cells vs AP -1 binding activity in 12-0-tetradecanoylphorbol 13-acetate-treated cells 080225 .

Dopamine uptake inhibition. Ethanol (30%) extract of the dried leaf, at variable concentrations, was inactive on synaptosomesoso!

Fibrinolytic activity. Ethanol (30%) extract of the dried leaf, administered intraarterially (left coronary artery) to rabbits at a dose of 10.0 mg/kg, was active vs ischemia/ reperfusion-induced decrease in plasminogen activator and increase in plasminogen activator inhibito~80194.

Glucose uptake induction. The dried entire plant, in cell culture at a concentration of 0.25 mcg/ml, was effective on the

smooth muscle cells of pig aorta080269.

Glucose uptake inhibition. Ethanol (30%) extract of the dried leaf, at a dose of 50.0 mg/kg administered 1 hour before the administration of radioactive 2-deoxyglucose, produced a decrease in 21 of 38 brain regions, and whole brain glucose utilization declined by 16.1 %. Glucose utilization was determined autoradiographically in brain slicesoso1s4.

Glucose utilization inhibition. Ethanol (30%) extract of the dried leaf, administered intragastrically to rats at a dose of

50.0 mg/kg, decreased the utilization of glucose in the frontal parietal, somatosensory cortex, nucleus accumbens and ponsoso2o1.

Glutamate receptor blocker. The dried leaf, at a concentration of 2.0 mcg/ml, was active on quisqualate and kainate receptors080213 .

Glutathione formation induction. Ethanol (30%) extract of the dried leaf, in cell culture at a concentration of 200.0 mcg/ml, was active on pulmonary artery endothelial cells vs tert-butylperoxide-induced glutathione depletion°80131 .

Glutathione reductase stimulation. Ethanol (30%) extract of the dried leaf, in cell culture at a concentration of 300.0 mcg/ml, was active on pulmonary artery endothelial cells080131 .

Glycogen content increase. Ethanol (30%) extract of the dried leaf, administered intragastrically to male rats at a dose of 50.0 mg/kg, was effective on the gastrocnemius- soleus muscle vs streptozotocininduced noninsulin dependent diabetes mellitus080129 .

Glycogen synthesis stimulation. The dried entire plant, in cell culture at a concentration of 0.25 mcg/ml, was effective on the smooth muscle cells of pig aortaosoz69.

Hypertensive activity. Ethanol (95%) extract of the dried latex, taken orally by adults at a dose of 45.0 ml/person, was not effec ti ve080275 .

lmmunostimulant activity. Ethanol (95%) extract of the dried latex, taken orally by adults at a dose of 45.0 ml/person, was not effective080275 .

Insecticide activity. Water extract of the dried branches and leaves, at variable concentrations, was inactive on Blatella germanica. When administered intravenously at a dose of 40.0 ml/kg, the extract was inactive on Periplaneta americana 080342 •

Insulin level increase. Ethanol (30%) extract of the dried leaf, administered intragastrically to male mice at a dose of 50.0

mg/kg, was not effective when measured in the plasma080129 .

Insulin release stimulation. Ethanol (30%) extract of the dried leaf, in cell culture at a concentration of 25.0 mg/kg, did not elicit electrical activity and decreased glucose-stimulated spike activity on pancreatic beta cells. A dose of 200.0 mg/kg,

administered intragastrically to mice, increased spike activity on exposure to glucose, an indicator of insulin release080180

Learning enhancement. Acetone/water ( 1:1) extract of the dried leaf, in the ration of male rats at a dose of 50.0 mg/kg, decreased the number of sessions to reach cri- terion performance, as well as the number of errors vs 8-armed radical maze080149 . The 95% ethanol extract, administered intragastrically to mice at a dose of 100.0 mg/kg, improved the acquisition of a 2-response sequence and the retrieval of this response at a later date080280.

Lipid peroxide formation inhibition. Ethanol (30%) extract of the dried leaf, in cell culture at a concentration of 400.0 mcg/ml, was active on pulmonary artery endothelial cells vs tert-butylperoxideinduced peroxidation°80131 . A dose of 100.0 mg/kg daily was administered intragastrically to rats for 10 days. The perfused retina was then isolated and subjected to Fe 2•/Na ascorbate-induced lipid peroxidation. The extract prevented a decrease in the electroretinogram B wave amplitude 080306 . The leaf, in cell culture at a concentration of 50.0 mcg/ml, was effective. Cyclosporin A-induced lipid peroxidation, as assayed by malondialdehyde formation, was entirely inhibited by this dose. The addition of ferric chloride to the incubation medium diminished the effect080284.

Memory enhancement effect. Ethanol (30%) extract of the dried leaf, administered intragastrically to mice at a dose of 100.0 mg/kg, reduced the time to acquisition and enhancement performance in an operant conditioning task, but did not

affect the performance in a passive avoidance test080139 . A dose of 320.0 mg/person was taken orally by 18 elderly patients with age-related memory impairment. In the double-blind, crossover study of the effect on dual-coding abilities, the extract decreased the break point and dual coding from 960 and 1920 msec to 480 and 960 msec080171 . A dose of 600.0 mg/person, taken orally by adults of both sexes, was equivocal. The double-blind, crossover study evaluated the effects of the extract on cognitive functions in healthy humans. The results showed a reduction in reaction time  on the Sternberg memory scanning test 080139. Ethanol (95%) extract of the dried leaf was taken orally by 8 female volunteers at acute and ascending doses of 600.0, 140.0 and 120.0 mg with placebo. One hour after the treatment, the patients were subjected to a battery of tests including critical clicker fusion, choice reaction time, subjective rating scale and Sternberg memory scanning test. In the first 3 tests, no statistically significant differences with the placebo were observed. However, short-term memory, assessed by the Sternberg test, was significantly improved following the 600.0 mg dose, compared to the placebo. These results differentiate the extract from sedative and stimulant drugs, and indicated a specific effect on the memory processes080255. The leaf, taken orally by adults at a dose of 40.0 mg/person, was effective. Thirty-one patients with mild to moderate impairment in memory due to organic causes of at least 3 months duration, participated in a double-blind, placebo-controlled study. The dose was taken 3 times daily for 24 weeks. There was a significant improvement in the digit copying sub-test of the Kendrick battery, and in the median speed of response in a classification taskG80283.

Memory retention impairment. Acetone/ water ( 1:1) extract of the dried leaf, administered intragastrically to rats at a dose of 1.0 mg/kg, was not effective vs inhibitory avoidance conditioning and water maze performanceG80152.

Memory retention improvement. Ethanol (30%) extract of the dried leaf, taken orally by 12 healthy females in a dummy placebo-controlled double-blind study at a dose of 600.0 mg/person, was not effective. The effect on psychomotor and amnesic performances of the acute oral dosing was evaluated. The objective measures of vigilance, choice reaction time, memory tasks and self-rating evaluation tests were performed. The testing sessions took place before and 1 hour after the treatment. No statistically significant changes from placebo were observed on objective measures of vigilance, choice reaction time or subjective rating of drug effects. No differences were seen between treatment on the Sternberg scanning test and picture recognitionG80294. The ethanol (95%) extract was effective when administered intragastrically to mice at a dose of 100.0 mg/kg for 4-8 weeks before operant conditioning and training, and for 10 weeks furtherG80280. The hydro-alcoholic extract, administered intraperitoneally to female mice at a dose of 40.0 mg/kg, enhanced learning and memory

in human adults and aged animals as demonstrated in performance tasksG80150.

Metabolites. Ethanol (30%) extract of the dried leaf, administered intragastrically to mice, produced the following metabolites in the plasma: 3,4-dihydroxyphenylacetic acid, hippuric acid, 3-hydroxyphenylacetic acid, homovanallic acid and benzoic acidGson6.

Microsomal metabolizing system induction. The leaf, taken orally by adults at a dose of 400.0 mg/day for 13 days, did

not affect the elimination half-life of antipyreneGsoJJ4.

Moulting activity. Ethanol (95%) extract of the leaf was inactive on Calliphora erythrocephalaGBoJ37.

Muscarinic receptor increase. Ethanol (30%) extract of the dried leaf was active on the rat hippocampusG80301 . The dried leaf, administered orally to rats at a dose of 100.0 mg/kg daily for 28 days, was active. Receptor population of the 2-year old treated animals was similar to control animals aged 3 months, whereas 2-year old controls showed a significant decrease in receptorsGsozJo.

Neural plasticity enhancement effect. Ethanol (30%) extract of the dried leaf, administered intraperitoneally to unilaterally  vestibular-neurectomized cats at a dose of 50.0 mg/kg daily for 30 days, was effective. The treatment accelerated postural compensation, locomotor balance recovery, spontaneous and evoked neck muscle activity, recovery of spontaneous firing rate of deafferented vestibular nucleus and synaptic reoccupation of the same nucleus in treated animals vs controlsG80287 •

Neuroexcitatory activity. Ethanol (30%) extract of the dried leaf, administered intracerebrally to guinea pigs at a dose of 10.0 mg/ml, was effective. The extract was directly infused into the area of the vestibular nuclei. A stereotyped reversible postural syndrome developed, which was mirror image-related to that induced by unilateral lesion of otolithic receptors, indicating excitation of the lateral vestibular nucleiG80159•

Neuroprotective effect. Ethanol (30%) extract of the dried leaf, administered intragastrically to rats of both sexes at a dose of 100.0 mg/kg, was effective vs neurochemical effects of electroconvulsive shock treatment. The extract reduced free fatty

acid levels in the hippocampus and delayed the increase in diacylglycerol concentration in the hippocampus and cerebral cortex. Intraperitoneal administration reduced behavioral deficits resulting from bilateral frontal cortex lesionsG80139 •

Nitric acid synthase inhibition. Ethanol (30%) extract of the dried leaf, in cell culture, was active on macrophage cell line RAW 264.7 vs lipopolysaccharide plus interferon-gamma-induced nitric acid production, IC50 100.0 mcg/mlGsous. The extract also reduced the rate of production of nitrite from nitroprusside, IC50 20.0 meg/ ml; and scavenges nitric oxide as shown by competition with the oxidation of oxyhemoglobin, IC50 7.5 mcg/mlG80184.

Oxidative burst inhibition. Ethanol (30%) extract of the dried leaf, in cell culture at a concentration of 50.0 mcg/ml, was active on pulmonary artery endothelial cellsGBom.

Peroxide formation inhibition. Ethanol (30%) extract of the dried leaf, at a concentration of 0.1 mcg/ml, was active on cerebellar neurons. Exposure of cultured neurons to the extract for 60 minutes resulted in a decreased intracellular H20 2 when determined by 21,7 –dichlorofluroescin fluorescenceG 80168•

Pharmacokinetics. In a pilot study, two healthy volunteers took 50, 100 and 300 mg of the ethanol (30%) extract of the leaf in the form of coated tablets. Plasma concentrations of the flavonoids were measured over a period of 24 hours. The peak plasma concentrations were reached within 2-3 hours after intake and were proportional to the applied dose. The elimination phase was characterized by a typical exponential function. Twenty-four hours after intake the zero value was reached againG80300 • Ethanol (95%) extract of the dried leaf, administered by gastric intubation to rats, had a half-life of about 4.5 hours. The pharmacokinetics of the extract, based on blood specific activity data vs time course, were characteristic of a 2-compartment model with apparent first order phase. During the first 3 hours, radioactivity was primarily associated with the plasma. Specific activity peaked after 1 and 1.5 hours. Glandular and neuronal tissues and eyes showed a high affinity for the labeled extractG80253 •

Phospholipase A2 activation. Acetone/ water (70:30) extract of the dried leaf, in cell culture at a concentration of 0.3 mg/ ml, was active on endothelial cellsGBol53.

Platelet aggregation inhibition. Ethanol (30%) extract of the dried leaf, taken orally by adults at a dose of 120.0 mg/person, was inactive vs ADP-induced aggregation, and a dose of 80.0 mg/person was active vs platelet aggregating factor-induced aggregationGsom. A dose of 320.0 mg/person, taken orally by 10 volunteers with hemorheological abnormality, was active after 1 hour of administration. The extract taken was a  combination of Ginkgo biloba and Panax ginseng (3:5)osoJ6s.

Platelet aggregation stimulation. Ethanol (95%) extract of the dried latex, taken orally by adults at a dose of 45.0 ml/person, was not effective080275 .

Prolactin inhibition. Ethanol (95%) extract of the dried leaf, in cell culture, was active on the rat pituitary, MIC 1.8 mcg/ml080235.

Protein degradation inhibition. Ethanol (30%) extract of the dried leaf, at a concentration of 500.0 mcg/ml, inhibited protein polymerization on rat liver micro~ somesoso16o.

Protein synthesis stimulation. Ethanol (30%) extract of the dried leaf, administered intragastrically to male rats at a dose of 100.0 mg/kg, was active vs ACTH~stimulated corticosterone production in adrenocortical cells 080145 .

Radical scavenging effect. Ethanol (30%) extract of the dried leaf, at a concentration of 100.0 mcg/ml, was active vs peroxyl induced lipid peroxidation°80200 . The leaf, at a concentration of 100.0 mcg/ml tested in a phenazine methosulfate and NADH system, was effective. A concentration of 125.0 mcg/ml was also effective when determined by low~temperature electron spin resonance080268.

Receptor binding stimulant. Extract of the dried leaf, administered intraperito~ neally to rats at a dose of 5.0 mg/kg daily for 21 days, had no effect on the density of tritiated~rauwolscine, which selectively binds alpha- 2 adrenergic receptors on the hippocampus of young rats ( 4 months of age), but produced an increase in older animals (24 months of age) 080298 .

Serotonin receptor regulation. Ethanol (30%) extract of the dried leaf, administered intraperitoneally to rats at a dose of 5.0 mg/kg daily for 21 days, increased binding density of labeled 8~hydroxy-2-(di~npropylamino) tetralin to 5-HT-1A receptors on the cerebral cortex of aged animals080181 .

Serotonin uptake inhibition. Ethanol (30%) extract of the dried leaf, at concentrations of 32 mcg/ml to 2 mg/ml, was effective on mouse synaptosomes080167.

Serotonin uptake stimulation. Ethanol (30%) extract of the dried leaf, at con~ centrations of 4-16 mcg/ml, was active on mouse synaptosomes. A concentration of 100.0 mg/kg, administered intragastrically to mice twice daily for 4 days preceding the assay, was active on synaptosomes080167 .

Smooth muscle relaxant activity. The nonginkolide-nonflavonoid subfraction of the dried leaf was effective on the corpus cavemosum vs norepinephrine-induced contractions, results significant at p <0.05% level, E050 0.74 mg/ml080234.

Spasmolytic activity. Flower buds, at concentrations of 30-300 mcg/ml, were active on the endothelial lining of a rabbit aorta vs phenylephrine-induced contractions080278 .

Thiobarbiturate reacting substance inhibition.

Ethanol (30%) extract of the dried leaf was taken orally by 15 patients undergoing aortic valve replacement at a dose of 320 mg daily for 5 days prior to surgery. Upon aortic unclamping, the extract inhibited transcardiac release of thiobarbituric acid-reactive species, attenuated free radical levels and reduced delayed leakage of myoglobin and ventricular myosin leakageosolzs.

Tumor promoting inhibition. Methanol extract of the fresh fruit, in cell culture at a concentration of 200.0 mcg/ml, was active on Epstein-Barr virus vs 12-0-hexadecanoylphorbol- 13-acetate~induced EpsteinBarr virus activation°80333 .

Vasoconstrictor activity. The dried entire plant was active on the rabbit vein. The effect was blocked by phenoxybenzamine, E0 50 86.0 mcg/ml080325 .

Vasodilator activity. Ethanol (30%) extract of the leaf, taken orally by adults at a dose of 17.5 mg/person, was effective on a group of 42 patients, normal or with peripheral vascular diseases. The effect of the dose appears similar to that of ergot derivatives, acetylcholine and sodium nicotinate, but is significantly more constant Gsom. Water extract of the leaf, administered by intravenous infusion to a pregnant ewes at a concentration of 1-3.0 mg/kg, increased the fetal arterial pH and P -02 and decreased the base deficit and P-C02 in 45% of the cases. There was also an increase of uterine arterial blood flow. A dose of 140.0 mg/person, given to pregnant women during labor or 12 days before the onset of labor for the treatment of fetal asphyxia caused by impairment of utero-placental circulation unrelated to uterine hyperactivity, was effectiveG80106• The dried leaf was taken orally by 79 patients with peripheral arterial insufficiency, at a dose of 40.0 mg/day for 60 months in a doubleblind randomized clinical trial. The patients had obliterative arterial disease of the lower limbs, Fontaine's stage liB. Painfree walking distance, maximum walking distance and plethysmography recordings were used to assess the efficacy of the treatment. The results indicated that the treatment was active and significantly better than the placeboG80326•

MAIN ACTIONS (Braun, L and Cohen, M. 2010)

The many and varied pharmacological actions of ginkgo preparations are related to the presence of several classes of active constituents.

Antioxidant

G. biloba extract and several of its individual constituents, such as quercetin and kaempferol, have demonstrated significant antioxidant properties in vitro (Hibatallah et al., 1999, Sloley et al., 2000). Antioxidant activity has further been demonstrated in several different animal models. Experimental models investigating the effects of ginkgo on reducing ischaemic injury have shown positive results, indicating that ginkgo reduces the damage caused by oxidative stress during reperfusion. One study using a model of myocardial infarction found that pretreatment with G. biloba extract EGb 761 reduced ischaemic myocardial injury compared to the untreated animals (Schneider et al., 2008). Another in vivo study investigated the effects of G. biloba extract (EGb 761) on lung injury induced by intestinal ischaemia/reperfusion (II/R) (Liu et al., 2007). The treated group received Egb 761 (100 mg/kg/day) via gastric tube for seven consecutive days prior to surgery, whereas the inactive group just received vehicle. Active treatment produced a significant protective effect on lung injury induced by II/R, which may be related to its antioxidant property and suppression of neutrophil accumulation and nitric oxide synthase (iNOS)- induced NO generation. A novel study has investigated the effect of G. biloba on mobile phone-induced oxidative damage in brain tissue of rats (Ilhan et al., 2004). Rats were exposed to the same amount of mobile phone- induced radiation for 7 days with some also pretreated with G. biloba. After exposure, oxidative damage was evident by the: (i) increase in malondialdehyde (MDA) and nitric oxide (NO) levels in brain tissue, (ii) decrease in brain superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) activities and (iii) increase in brain xanthine oxidase (XO) and adenosine deaminase (ADA) activities. Gingko biloba prevented these alterations and the mobile phone-induced cellular injury in brain tissue histopathologically. Topical antioxidant effects have also been investigated. G. biloba has been shown to reduce the effects of UV radiation on skin (Aricioglu et al., 2001, Hibatallah et al., 1999, Kim 2001, Lin & Chang 1997). When applied topically, ginkgo increases the activity of SOD within skin, thereby enhancing the skin’s natural defences.

Vascular Effects

Vasodilation

Ginkgo promotes vasodilation and improves blood flow through arteries, veins and capillaries. Increases in microcirculatory blood flow occur rapidly and have been confirmed under randomised crossover test conditions 1 hour after administration (Jung et al., 1990). Several mechanisms of action are responsible. Currently, these are considered to be: inhibition of NO release, activation of Ca2+-activated K+ (KCa) channels, and increased prostacyclin release (Chen et al., 1997, Koltermann et al., 2007, Nishida & Satoh 2003). In 2008, a clinical study was published which provides further information about the mechanisms involved. Wu et al., investigated the effects of G. biloba extract (GBE) on the distal left anterior descending coronary artery (LAD) blood flow and plasma nitric oxide (NO) and endothelin-1 (ET-1) levels (Wu et al., 2008). The randomised study of 80 volunteers with coronary artery disease (CAD) used Doppler echocardiography to determine blood flow, which was measured at baseline and after 2 weeks of treatment. A significant improvement in maximal diastolic peak velocity, maximal systolic peak velocity and diastolic time velocity integral was observed for the group treated with GBE compared with controls (P < 0.01). Additionally, a significant increase in NO and decrease in ET-1 was observed, suggesting that the observed increase of LAD blood flow might be related to restoration of the delicate equilibrium between NO and ET-1.

Reduces Oedema

Various flavonoids, including anthocyanosides and G. biloba extracts, have been shown to be effective against experimentally induced capillary hyperfiltration (Cohen-Boulakia et al., 2000).

Antiplatelet and anticoagulant

There have been several case reports of G. Biloba causing haemorrhage during or after surgery (Hauser et al., 2002, Schneider et al., 2002) and there is evidence that one of its components, ginkgolide B, is a platelet-activating factor antagonist (Smith et al., 1996). One clinical study demonstrated that EGb 761 (80 mg/day) produced a significant reduction in blood viscosity after 30 days’ treatment (Galduroz et al., 2007). When measured again 90 days after commencement of EGb 761 treatment, a further reduction was observed which appeared to stabilise, as no further reduction was observed after 180 days of use. In contrast, at least 10 clinical studies have found no evidence of significant bleeding or platelet effects due to G. biloba ingestion (Aruna & Naidu 2007, Bal Dit et al., 2003, Beckert et al., 2007, Carlson et al., 2007, Engelsen et al., 2003, Gardner et al., 2007, Jiang et al., 2005, Kohler et al., 2004, Lovera et al., 2007, Wolf 2006). Studies have included young healthy volunteers, older adults, people with multiple sclerosis and people using warfarin or aspirin at the same time as G. biloba. An escalating dose study found that 120 mg, 240 mg or 480 mg given daily for 14 days did not alter platelet function or coagulation (Bal Dit et al., 2003).

Alters Neurotransmitters

Monoamine oxidase (MAO) inhibition

In vitro tests in rat brains suggest that EGb 761 may exert MAO-A and MAO-B inhibitor activity (Wu & Zhu 1999). Tests with isolated constituents, kaempferol, apigenin and chrysin, have demonstrated these to be potent MAO inhibitors, with greater effect on MAO-A than MAO-B (Sloley et al., 2000). Alternatively, one human study using positron emission tomography (PET) found that treatment with G. biloba (EGb 761: 120 mg/day) for 1 month did not produce significant changes in brain MAO-A or MAO-B in the 10 participating volunteers (Fowler et al., 2000).

Serotonin

Another in vitro study found that oral EGb 761 significantly increases the uptake of serotonin, but not dopamine, in cerebral cortex samples from mice (Ramassamy et al., 1992). Another in vivo study identified an antiaggressive effect mediated by 5-HT2A receptors (Shih et al., 2000).

Cholinergic effects

Considering that G. biloba appears to be as effective as anticholinesterase drugs, several researchers have investigated whether it exerts cholinergic effects. Evidence from behavioural, in vitro and ex vivo tests with G. biloba has shown both direct and indirect cholinergic activities (Das et al., 2002, Nathan 2000). The extract appears to increase the rate of acetylcholine turnover and stimulate the binding activity of ligands to muscarinic receptors in the hippocampus (Muller 1989).

Gamma aminobutyric acid (GABA) receptors

Bilobalide in G. biloba is a competitive antagonist for GABA-A receptors according to in vitro tests (Huang et al., 2003). The effect is almost as potent as bicuculline and pictrotoxinin.

Corticosterone

In vivo tests have found that EGb 761 has stressalleviating properties mediated through its moderation of corticosterone levels (Puebla-Perez et al., 2003).

Neuroprotection

G. biloba leaf extract (EGb 761) has demonstrated neuroprotective effects in a variety of studies ranging from molecular and cellular, to animal and human; however, the cellular and molecular mechanisms remain unclear (Ao et al., 2006, Smith et al., 2002). Of the constituents studied, it appears that the bilobalide constituent is chiefly responsible for this activity, although others are also involved (DeFeudis & Drieu 2000). Until recently, it was believed that the antioxidant, membrane-stabilising and platelet-activating factor antagonist effects were chiefly responsible for neuroprotection, but effects at the mitochondria may also be important contributing mechanisms.

Beta-amyloid

G. biloba extract EGb 761 protects cells against toxicity induced by beta-amyloid in a concentration- dependent manner, according to in vitro tests (Bastianetto & Quirion 2002a, 2002b; Bastianetto et al., 2000). In vivo studies have confirmed that ginkgo extract has an antiamyloid aggregation effect (Luo 2006). It appears that ginkgo increases transthyretin RNA levels in mouse hippocampus, which is noteworthy because transthyretin is involved in the transport of beta-amyloid and may provide a mechanism to reduce amyloid deposition in brain (Watanabe et al., 2001). There is also evidence that G. biloba modulates alpha-secretase, the enzyme that cuts the amyloid precursor protein and prevents amyloidogenic fragments from being produced (Colciaghi et al., 2004).

Cerebral ischaemia

There is evidence from experimental and clinical studies that G. biloba extract protects tissues from ischaemia/reperfusion damage (Janssens et al., 2000). According to investigation with an experimental model, EGb 761 could prevent and treat acute cerebral ischaemia, but the effect was most pronounced when administered prophylactically (Peng et al., 2003).

Stabilisation and protection of mitochondrial function

Several in vitro tests have demonstrated that Egb 761 stabilises and protects mitochondrial function (Eckert et al., 2005, Janssens et al., 2000). These observations are gaining the attention of researchers interested in neurodegenerative diseases, as it is suspected that the mitochondria and the phenomenon of mitochondrial permeability transition play a key role in neuronal cell death and the development of such diseases (Beal 2003, Shevtsova et al., 2005).

Immunostimulant

Immunostimulatory activity has been demonstrated in several experimental models (Puebla-Perez et al., 2003, Tian et al., 2003, Villasenor-Garcia et al., 2004). The beneficial effects of EGb 761 on immune function are based on its antioxidant properties, as well as the cell proliferation-stimulating effect.

Anti-inflammatory

The anti-inflammatory activity of ginkgo has been investigated for the whole extract and an isolated biflavonoid component known as ginkgetin, with both forms demonstrating significant anti-inflammatory activity.

Ginkgo extract

Intravenously administered ginkgo extract produced an anti-inflammatory effect that was as strong as the same dose of prednisolone (i.e. 1 mg GBE = 1 mg prednisolone) in an experimental model. Ginkgo extract was also found to significantly reduce the concentration of PGE2, TNF-alpha and NO production in vitro (Ilieva et al., 2004). Studies with subcutaneously administered G. biloba extract in experimental models have also identified significant anti-inflammatory activity, with the addition of antinociceptive effects (Abdel- Salam et al., 2004). Investigation with an animal model of colitis revealed that G. biloba (EGb 761) extract reduces markers of inflammation (iNOS, COX-2 and TNF-alpha) and inflammatory stress (p53 and p53- phospho-serine 15) (Kotakadi et al., 2008).

Ginkgetin

Ginkgetin showed a stronger anti-inflammatory activity than prednisolone when administered by intraperitoneal injection in an animal model of arthritis. Histological examination of the knee joints confirmed the effect (Kim et al., 1999). When used topically in an animal model of chronic skin inflammation and pro-inflammatory gene expression, it was found to inhibit ear oedema by approximately 26% and PGE2 production by 30% (Lim et al., 2006). Histological comparisons revealed that ginkgetin reduced epidermal hyperplasia, inhibited phospholipase A2, and suppressed COX-2 and iNOS expression (Lim et al., 2006).

Anticancer

Studies conducted with various molecular, cellular and whole animal models have revealed that leaf extracts of G. biloba may have anticancer (chemopreventive) properties that are related to its antioxidant, antiangiogenic and gene regulatory actions (DeFeudis et al., 2003). Both the flavonoid and terpenoid constituents are thought to be responsible for many of these mechanisms, meaning that the whole extract is required for activity. Studies in humans have found that ginkgo extracts inhibit the formation of radiationinduced (chromosome-damaging) clastogenic factors and UV-induced oxidative stress, both effects that may contribute to the overall chemopreventive activity. As a result of these observations, there has been a call by some academics for ginkgo to be more widely investigated and used in the prevention and treatment of cancer (Eli & Fasciano 2006).

OTHER ACTIONS

Activity on cytochromes and P-glycoprotein

Several studies have investigated G. biloba for effects on different cytochromes in vitro and with various animal models. Four human studies have also been conducted. Early in vitro tests demonstrated that G. biloba inhibits CYP 3A4; however, clinical studies have found no such effect (Budzinski et al., 2000, Gurley et al., 2002, 2005, Markowitz et al., 2003). In vitro tests have suggested that the effect on cytochromes is biphasic, with low doses of ginkgo extract inducing CYP 1A2 and inhibiting 2D6 and higher doses exhibiting the opposite effect (Hellum et al., 2007). Studies investigating ginkgo extract and its various constituents in animal models have identified induction of CYP 3A1, 1A2, 2E1, 2B½ for ginkgo which appears to be largely mediated by the bilobalide constituent, whereas no effect on CYP 2D6, 2C11 or 2C7 has been demonstrated (Deng et al., 2008, Tang et al., 2007a, Zhao et al., 2006). The question arises of clinical significance and whether the effects observed in animal models also occur in humans to an appreciable degree. To this end, four clinical studies have been conducted clarifying the issue (Duche et al., 1989, Gurley et al., 2002, 2005, Markowitz et al., 2003, Tang et al., 2007a). Tests with human volunteers have found no significant effect on CYP 3A4, 2D6 or 1A2 with G. biloba extract. Little is known about the effects of ginkgo on the drug transporter molecule P-glycoprotein (P-gp). Two in vitro studies have identified induction of P-gp with ginkgo; however, tests with human subjects are required to determine whether the effect occurs in vivo and its clinical significance (Hellum & Nilsen 2008, Yeung et al., 2008).

CLINICAL USE

G. biloba is a complex herb that contains many different active constituents and works by means of multiple mechanisms. In practice, its therapeutic effect is a result of interactions between constituents and mechanisms, giving it applications in many varied conditions. To date, most of the research conducted in Europe has used a standardised preparation known as EGb 761, available commercially as Rokan, Tanakan or Tebonin.

Dementia, memory impairment

G. biloba has been used and studied as a cognitive activator in a variety of populations, such as cognitively intact people, those with cerebral insufficiency, agerelated memory impairment, Alzheimer’s dementia or multi-infarct dementia (Itil et al., 1998, Le Bars et al., 2000, 2002, Oken et al., 1998, Wettstein 1999). It has also been tested in healthy adults with no cognitive deficits to determine whether treatment can further improve memory (Kennedy et al., 2007b). Overall, the evidence suggests that oral ginkgo extract may improve cognitive function in people with mild-to-moderate cognitive impairment, but it is less successful in people with normal cognitive function. Long-term use does not appear to protect against the development of dementia. in healthy subjects aged under 60 years (Canter & Ernst 2007). A number of the acute studies included in the analysis used multiple outcomes and reported positive effects on one or more of these at particular time points with particular doses, but these findings were either not replicated, or contradicted by other studies. The evidence from long-term studies is largely negative. Of those studies that measured subjective effects, only one of five acute studies and one of six long-term studies reported any significant positive results. Since this review, several new studies have been published. Overall, tests with younger subjects taking G. biloba long term have failed to show positive effects on memory; however, short-term benefits after acute dosing may be possible for some aspects of memory. Healthy older adults with poorer cognitive performance appear to experience greater benefit than those with higher cognitive function levels, according to the latest studies, but more research is required to confirm this initial observation. Carlson et al., conducted a 4-month, randomised, double-blind, placebo-controlled study of 90 men and women (age range 65–84 years) (Carlson et al., 2007). Treatment consisted of placebo or a G. Bilobabased supplement containing 160 mg G. biloba, 68 mg gotu kola and 180 mg docosahexaenoic acid per day for 4 months. Of the group, 78 subjects completed the study that found no significant differences in quality of life or adverse events. Researchers commented that high baseline scores for cognitive function may have contributed to the null findings. Tests with younger (18–43 years) and older volunteers (55–79 years) produced different results in a 12-week, double-blind, placebo-controlled study (Burns et al., 2006). The effects of ginkgo (120 mg/ day) were assessed for both groups on a wide range of cognitive abilities, executive function, attention and mood. The older group responded to treatment as long-term memory assessed by associational learning tasks showed significant improvement with ginkgo; however, no other significant differences were found on any other measure. The young adult group (n = 104) failed to respond on any measure, as no significant differences were observed for the treatment or placebo groups. Similarly, no significant effects on mood or any of the cognitive tests employed by Elsabagh et al., were found for ginkgo (120 mg/day) taken over 6 weeks in a placebocontrolled study of 52 young adults (Elsabagh et al., 2005a). In contrast, acute treatment of younger subjects with ginkgo (120 mg) significantly improved performance on the sustained-attention task and pattern-recognition memory task according to a randomised, double-blind study (Elsabagh et al., 2005a). The study of 52 students found no further effects for ginkgo on working memory, planning, mental flexibility or mood. Kennedy et al., reported on a re-analysis of data from three methodologically identical, doubleblind, crossover studies that each included a treatment of 120 mg ginkgo extract and matched placebo (Kennedy et al., 2007b). The analysis found that 120 mg of ginkgo conferred a significant improvement on the ‘quality of memory’ factor and was most evident at 1 and 4 hours after single-dose treatment, but had a negative effect on performance on the ‘speed of attention’ factor, which was most evident at 1 and 6 hours after treatment.

Ginkgo complexed with phospholipids

Some recent data suggest that the complexation of standardised GBE with soy-derived phospholipids may enhance the bioavailability of active components, thereby producing better results. Kennedy et al., tested two different ginkgo products complexed with either phosphatidylserine or phosphatidylcholine in a placebo-controlled study of younger volunteers (Kennedy et al., 2007a). Test subjects were given an acute dose of ginkgo, one of the ginkgo combinations or placebo on separate days (7 days apart). Confirming earlier results, G. biloba (120 mg) as sole treatment was not associated with markedly improved performance on the primary outcomes in this younger population; however, administration of GBE complexed with phosphatidylserine resulted in improved secondary memory performance and significantly increased speed of memory task performance across all of the postdose testing sessions. Interestingly, all three herbal treatments were associated with improved calmness. Whether the superior effect obtained for this combination is due to the complexation of the extracts, their mere combination or the separate psychopharmacological actions of the two extracts remains to be tested.

Cognitive effects in postmenopausal women

One week of treatment with ginkgo (120 mg/day) significantly improved attention, memory and mental flexibility in postmenopausal women according to a double-blind, placebo-controlled study (Elsabagh et al., 2005b). The study tested ginkgo (LI 1370, Lichtwer Pharma, Marlow, UK) over 6 weeks, which significantly improved mental flexibility in women who began the trial with poorer cognitive performance (Elsabagh et al., 2005b). Younger subjects with better cognitive performance at baseline did not experience any significant effects compared to placebo.

Comparisons with anticholinesterase drugs

The type of CNS effects produced by EGb 761 in elderly dementia patients is similar to those induced in tacrine responders and those seen after the administration of other ‘cognitive activators’, according to a small randomised study involving 18 elderly people diagnosed with mild-to-moderate dementia (possible or probable AD) (Itil et al., 1998). The results also demonstrated that 240 mg EGb produced typical cognitive activator ECG profiles (responders) in more subjects (8 of 18) than 40 mg tacrine (3 of 18 subjects). A later review concluded that ginkgo extract and second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) should be considered equally effective in the treatment of mild-to-moderate Alzheimer’s dementia (Wettstein 2000). Commission E approves the use of standardised ginkgo extract in dementia syndromes, including vascular, primary degenerative and mixed types (Blumenthal et al., 2000).

Dementia prevention

The many mechanisms attributed to ginkgo make it an ideal candidate for the long-term prevention of many age-related diseases such as dementia. Two clinical trials were published in 2008, which investigated whether treatment with G. biloba could significantly reduce the incidence of dementia. DeKosky et al., compared the effectiveness of G. biloba to placebo in reducing the incidence of allcause dementia and AD in elderly individuals with normal cognition and those with mild cognitive impairment (MCI) (DeKosky et al., 2008). The large randomised, double-blind, placebo-controlled clinical trial involved 3069 community dwelling subjects aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482). It was conducted at five academic medical centres in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Treatment consisted of a twice-daily dose of 120-mg extract of G. biloba and was not shown to reduce either the overall incidence rate of dementia or AD incidence in elderly individuals. Treatment was well tolerated by this population, as the incidence of side effects was similar for both groups. The same year, Dodge et al., published the results of a double-blind study involving 118 cognitively intact older subjects (85 years or older) (Dodge et al., 2008). In the intention-to-treat analysis, there was no reduced risk of progression to clinical dementia among the GBE group; however, in the secondary analysis, where medication adherence level was controlled, the GBE group had a significantly lower risk of progression and a smaller decline in memory scores. Importantly, more stroke and transient ischaemic attack (TIA) cases were observed among the GBE group, which require further investigation to confirm. Currently, two large double-blind, placebocontrolled studies are underway testing whether G. biloba (120 mg twice daily) is effective in the prevention of dementia in normal elderly people and those with early cognitive decline (Williamson et al., 2008). The complete results from these studies are not expected for another few years.

Acute ischaemic stroke

G. biloba extract is widely used in the treatment of acute ischaemic stroke in China. A Cochrane systematic review identified 14 trials, of which 10 (792 patients) were included (Zeng et al., 2005). In those 10 trials, follow-up was performed at 14–35 days after stroke and in all studies, neurological outcome was assessed, but none of them reported on disability (activities of daily living function) or quality of life (QOL) and only three trials reported adverse events. Nine of the trials were considered to be of inferior quality. Overall results from the 10 studies found that G. biloba extract was associated with a significant increase in the number of improved patients. Of note, one placebo-controlled trial, assessed to be of good quality, failed to show an improvement of neurological deficit at the end of treatment. In view of the shortcomings of many trials and limited evidence, high-quality and largescale randomised controlled trials are still required to determine its efficacy.

Depression

Although studies that have investigated the effects of G. biloba in cerebral insufficiency, a syndrome that is often characterised by depression, have shown positive results, no clinical studies are available that have investigated its use in clinical depression. One randomised, double-blind, placebo-controlled study has investigated its effects in seasonal affective disorder (SAD). G. biloba extract PN246, in tablet form (Bio-Biloba), was tested in 27 patients with SAD over 10 weeks or until they developed symptoms, starting in a symptom-free phase about 1 month before symptoms were expected. In this trial, G. biloba failed to prevent the development of SAD (Lingaerde et al., 1999). Cieza et al., (2003) tested EGb 761 (240 mg/day) on the subjective emotional wellbeing of healthy older subjects (50–65 years) in a randomised, double-blind study. Ginkgo treatment produced a statistically significant difference for the visual analogue scale (VAS) mental health and for QOL, as well as for the Subjective Intensity Score Mood in week 2 compared with placebo. At the end of the study, statistically significant improvement in the EGb 761 group was observed for the variables: depression, fatigue and anger. Several recent studies investigating the effects of ginkgo on memory have also measured effects on mood. The double-blind studies found no significant effects for healthy older or younger volunteers (Burns et al., 2006, Carlson et al., 2007, Elsabagh et al., 2005a). Whether ginkgo may have a mood enhancing effect in a population with diagnosed depression remains to be tested.

Generalised anxiety disorder (GAD)

EGb 761 has demonstrated stress-alleviating and anxiolytic-like activity in preclinical studies, and most recently in a randomised study of 107 patients with GAD (n = 82) or adjustment disorder with anxious mood (n = 25) (Woelk et al., 2006). G. Biloba was tested in two different doses (480 mg and 240 mg/day) against placebo over 4 weeks and found to be significantly superior with a dose-response trend being identified. Beneficial effects were observed after 4 days of treatment. Additionally, ginkgo treatment was safe and well tolerated.

Peripheral vascular diseases

Ginkgo has been used in the treatment of intermittent claudication, Raynaud’s syndrome and chilblains (Mouren et al., 1994, Pittler & Ernst 2000).

Intermittent claudication

In 2000, a meta-analysis of eight clinical trials found a significant difference in the increase in pain-free walking distance in favour of G. biloba over placebo in intermittent claudication (Pittler & Ernst 2000). An earlier randomised study measuring transcutaneous partial pressure of oxygen during exercise showed that a dose of 320 mg/day EGb 761 taken for 4 weeks significantly decreased the amount of ischaemic area by 38%, compared with no change with placebo (Mouren et al., 1994). A more recent 2004 meta-analysis confirmed that ginkgo is more effective than placebo in intermittent claudication (Horsch & Walther 2004). Nine double-blind studies of EGb 761 for intermittent claudication were assessed in a total of 619 patients. A sensitivity analysis of a homogeneous sample in terms of design, treatment duration, inclusion and exclusion criteria and methods of measurement confirms these findings. Most studies have used a dose of 120 mg/day taken in divided doses, although one trial found that 240 mg/day gave better results. It should be recommended as long-term therapy and as an adjunct to exercise for the best results. A year later, Pittler and Ernst conducted a systematic review of all complementary therapies which may be useful as a treatment for intermittent claudication and identified G. biloba as the only effective herbal medicine to show better results than placebo (Pittler & Ernst 2005). Commission E approved the use of standardised ginkgo extract for intermittent claudication (Blumenthal et al., 2000). Two double-blind, placebo-controlled studies found no significant effects for G. biloba on maximal walking time in people with claudication (Gardner et al., 2008, Wang et al., 2007). One study compared the effects of an exercise program with and without the addition of ginkgo treatment in 22 subjects (Wang et al., 2007). Ginkgo was administered for 24 weeks at a dose of 240 mg/day and no differences were seen between the exercise-only phase and the exercise and herbal treatment phase. The other placebo-controlled study used a higher dose of G. biloba (EGb 761; 300 mg/day), which was administered for 4 months (Gardner et al., 2008). Active treatment resulted in a modest but insignificant increase in maximal treadmill walking time and flow-mediated vasodilation in older people with peripheral arterial disease (PAD). The study included 62 adults, aged 70 ± 8 years (mean ± SD).

Raynaud’s syndrome

A standardised G. biloba extract (Seredrin) taken over a 10-week period significantly reduced the number of attacks per week (from 13.2 to 5.8) compared with placebo, according to a randomised study (Muir et al., 2002).

Vertigo, tinnitus and sudden deafness

Ginkgo is used to treat these and other symptoms of vestibule-cochlear disorders. In 1999, a systematic review of five RCTs testing standardised G. biloba extracts in people whose primary complaint was tinnitus concluded that treatment with G. biloba may result in significant improvements in tinnitus (Ernst & Stevinson 1999). Three years later, a review of eight controlled trials in tinnitus confirmed these findings, stating that ginkgo is significantly superior to placebo or reference drugs when used for periods of 1–3 months (Holstein 2001). However, results of two double-blind studies conducted more recently have shifted the evidence against the use of G. biloba in tinnitus. The first was a large, double-blind, placebo-controlled study involving 1121 people aged between 18 and 70 years with tinnitus and 978 matched controls, which found that 12 weeks of treatment with ginkgo extract, LI 1370 (Lichtwer Pharma, Berlin, Germany), 50 mg, three times daily resulted in no significant differences when subjects assessed their tinnitus in terms of loudness and how troublesome it was (Drew & Davies 2001). A more recent doubleblind, placebo-controlled, randomised study of 66 subjects with tinnitus failed to show benefits with active treatment using a dose of 120 mg extract daily over 12 weeks (Rejali et al., 2004). The primary outcome measures used were the Tinnitus Handicap Inventory, The Glasgow Health Status Inventory and the average hearing threshold at 0.5, 1, 2 and 4 kHz. In 2004, Rejali et al., conducted a meta-analysis of clinical trials and found that 21.6% of patients with tinnitus reported benefit from G. biloba versus 18.4% of patients who reported benefit from a placebo. A 2004 Cochrane systematic review came to a similar conclusion, reporting that the limited evidence currently available does not support the use of ginkgo in tinnitus; however, the authors also pointed out that if a greater level of understanding and diagnostic accuracy could be reached about the different aetiologies of tinnitus, this may naturally highlight subgroups of patients in whom further controlled trials of G. biloba are worth considering (Hilton & Stuart 2004).

Salicylate-induced tinnitus

One in vivo study investigating the effects of ginkgo in salicylate-induced tinnitus found a statistically significant decrease in the behavioural manifestation of tinnitus for ginkgo in doses of 25, 50 and 100 mg/kg/day (Jastreboff et al., 1997).

Sudden deafness

Ginkgo extract was as effective as pentoxifylline in the treatment of sudden deafness, according to one randomised, double-blind study (Reisser & Weidauer 2001). Both treatments equally reduced associated symptoms of tinnitus and produced the same effects on the return to normal of speech discrimination. Subjective assessment suggested that G. biloba extract was more beneficial than pentoxifylline. EGb 761 (240 mg/day) has also been shown to accelerate and secure recovery of acute idiopathic sudden sensorineural hearing loss, observable within 1 week of treatment under randomised double-blind test conditions (Burschka et al., 2001). Commission E approves the use of standardised ginkgo extract in these conditions when of vascular origin (Blumenthal et al., 2000).

Macular degeneration, glaucoma and retinopathy

With regard to these ophthalmological conditions, ginkgo has numerous properties that should theoretically make it a useful treatment, such as increasing ocular blood flow, antioxidant and platelet- activating factor inhibitor activity, NO inhibition and neuroprotective abilities.

Macular degeneration

Although some positive evidence exists, a 2000 Cochrane review has suggested that, overall, there is insufficient evidence currently available to conclude that G. biloba treatment is effective in macular degeneration, with further testing required (Evans 2000).

Glaucoma

With regard to glaucoma, the little research conducted so far appears promising. Researchers using colour Doppler imaging have observed significantly increased end-diastolic velocity in the ophthalmic artery after treatment with EGb (120 mg/day) in a placebo-controlled, randomised, crossover study (Chung et al., 1999). A randomised, double-blind, crossover study found that EGb 761 (120 mg/day) taken for 4 weeks produces positive effects in normal tension glaucoma (Quaranta et al., 2003). Furthermore, ginkgo treatment did not significantly alter intraocular pressure, blood pressure or heart rate and was well tolerated.

Chloroquine retinopathy

In vivo tests using electroretinography have identified protective effects against the development of chloroquine-induced retinopathy using G. Biloba (Droy-Lefaix et al., 1992). This has been observed in both acute and chronic chloroquine toxicity of the retina (Droy-Lefaix et al., 1995).

Prevention of altitude sickness

Eight clinical studies have investigated G. biloba as prophylactic treatment against altitude sickness (Chow et al., 2005, Gertsch et al., 2002, 2004, Leadbetter & Hackett 2003, Maakestad et al., 2001, Moraga et al., 2003, 2007, Roncin et al., 1996). The first study was conducted by Roncin et al., (1996). It involved 44 subjects and found that a dose of 160 mg/day taken for 5 days as prophylactic treatment resulted in 0% of subjects developing the cerebral symptoms of acute mountain sickness versus 41% of subjects in the placebo group, whereas only three subjects (13.6%) in the EGb 761 group developed respiratory symptoms of acute mountain sickness (AMS), 18 (81.8%) in the placebo group developed these symptoms. Besides effectively preventing AMS for moderate altitude (5400 m), the treatment also decreased vasomotor disorders of the extremities. In 2001, Maakestad et al., reported on a randomised, double-blind trial of G. biloba (120 mg twice daily starting 5 days before ascent) compared to placebo for the prevention of AMS in 40 college students who underwent rapid ascent from 1400 to 4300 m. Using the Lake Louise Symptoms (LLS) score and Environmental Symptoms Questionnaire as outcomes, G. biloba was shown to significantly reduce the incidence of AMS compared to placebo. A year later, a double-blind study also produced positive results for G. biloba 180 mg/day started 24 hours before rapid ascent from sea level to 4205 m (Gertsch et al., 2002). In subsequent years, some researchers compared ginkgo to acetazolamide. In 2003, two studies, which produced conflicting results, were published. Moraga et al., (2003) compared prophylaxis with G. biloba (80 mg twice daily) versus acetazolamide (250 mg twice daily) versus placebo, which was started 24 hours before rapid ascent to 3700 m. Of 32 subjects enrolled, none of those in the G. biloba group developed AMS compared with 35% of those in the acetazolamide group and 54% of those receiving placebo. Alternately, ginkgo (120 mg twice daily) started 3 days before ascent produced no significant effects when compared to placebo or acetazolamide in a randomised, double-blind study by Leadbetter and Hackett (2003). The study involved 59 subjects who experienced a rapid ascent to 4300 m. Negative results were also obtained by Gertsch et al., (2004) and Chow et al., (2005). The largest negative study involved 487 healthy Western hikers (Gertsch et al., 2004). It compared the effects of ginkgo (60 mg three times daily), acetazolamide (250 mg), combined acetazolamide and ginkgo, and placebo. Participants took at least 3–4 doses before ascent above 4000 m in the Nepal Himalayas. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide, 35% for ginkgo and 14% for combined ginkgo and acetazolamide. Chow et al., conducted a smaller study of 57 healthy unacclimatised subjects using a randomised, placebo-controlled design. Subjects were taken to an elevation of 3800 m within 24 h, with acetazolamide producing significantly better effects than ginkgo or placebo using the Lake Louise Acute Mountain Sickness Scoring System. Subjects receiving ginkgo were as likely as placebo to experience acute mountain sickness, whereas acetazolamide was protective. The most recent study was published in 2007 and tested a different type of treatment regimen that produced significant benefits. The placebocontrolled study of 36 people found that pretreatment followed by continued treatment with G. biloba prevented acute mountain sickness (AMS) and was significantly more effective than acetazolamide (Moraga et al., 2007). Volunteers were given placebo, acetazolamide (250 mg per dose) or ginkgo (80 mg per dose) every 12 hours starting 24 hours before ascending and continued throughout the 3-day stay at high altitude. Not a single person treated with ginkgo experienced AMS, compared with 36% taking acetazolamide and 54% taking placebo. Whilst ginkgo did not alter arterial oxygen saturation compared to acetazolamide, a marked increased saturation in arterial oxygen was seen in comparison with the placebo group.

Premenstrual syndrome (PMS)

A randomised, double-blind study evaluating the effects of EGb 761 in treating congestive symptoms of PMS in a group of 165 women found that treatment over two menstrual cycles (from day 16 until day 5 of the next cycle) was successful. Treatment was particularly effective in reducing breast symptoms, although neuropsychological symptoms were also alleviated (Tamborini & Taurelle 1993).

Vitiligo

A dose of 120 mg/day ginkgo extract significantly stopped active progression of depigmentation in slow-spreading vitiligo and induced repigmentation in some treated patients under double-blind, placebo-controlled study conditions (Parsad et al., 2003). Although the mechanism of action responsible is unknown, antioxidant activity is thought to be important.

Asthma

Ginkgo shows promise as a treatment for asthma, according to studies using a mouse model of asthma and two clinical studies. Ginkgo significantly reduced airway hyperreactivity, improved clinical symptoms and pulmonary function in asthmatic patients in one placebo-controlled study (Li et al., 1997). Platelet-activating factor inhibitor, antioxidant and anti-inflammatory activities are likely to be involved. Reduced airway inflammation was reported in another study of 75 asthma patients, which compared the effects of fluticasone propionate with fluticasone propionate plus ginkgo (Tang et al., 2007b). The addition of ginkgo to treatment resulted in a significant decrease in the infiltration of inflammatory cells such as eosinophils and lymphocytes in the asthmatic airway and relieved airway inflammation. Babayigit et al., used a mouse model of asthma to evaluate the effects of ginkgo on lung histology (Babayigit et al., 2008). Treatment with ginkgo was found to significantly improve the number of goblet cells, mast cells, thicknesses of epithelium, and basement membrane compared to placebo, indicating that active treatment improved all established chronic histological lung changes except smooth muscle thickness.

Sexual dysfunction

Due to its vasodilatory effects, ginkgo has been used in the management of sexual dysfunction in cases where compromised circulation is suspected. One open study has been conducted with subjects experiencing sexual dysfunction associated with antidepressant use (Cohen & Bartlik 1998). Ginkgo extract (average dose 209 mg/day) was found to be 84% effective in treating antidepressantinduced sexual dysfunction, predominantly caused by selective serotonin reuptake inhibitor (SSRI), in a study of 63 subjects (Cohen & Bartlik 1998). A relative success rate of 91% was observed for women, compared with 76% for men, and a positive effect was reported on all four phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm and resolution. Although this was an open trial, the results are encouraging when one considers that the placebo effect is about 25% from past randomised trials of Federal Drug Administration (FDA)-approved medications for erectile dysfunction (Moyad 2002). More recently, a small, triple-blind (investigator, patient, statistician), randomised, placebocontrolled, trial of G. biloba (240 mg/day for 12 weeks) was undertaken with 24 subjects experiencing sexual impairment caused by antidepressant drugs (Wheatley 2004). The authors report some spectacular individual responses in both groups, but no statistically significant differences, and no differences in side effects. Meston et al., (2008) conducted two studies of women with sexual dysfunction (Meston et al., 2008). The first was a single-dose, placebo-controlled study using 300 mg ginkgo extract, which produced a small but significant facilitatory effect on physiological, but not subjective, sexual arousal in 99 sexually dysfunctional women. The second study investigated long-term use of ginkgo (300 mg/day) over 8 weeks, which found that herbal treatment combined with sex therapy significantly increased sexual desire and contentment compared to placebo or ginkgo as sole treatment.

Parkinson’s disease

There is great interest in the application of safe substances, such as G. biloba, in neurodegenerative diseases such as Parkinson’s disease because of their neuroprotective and mitochondrial protective effects. Currently, investigation with ginkgo is limited to animal studies of experimentally induced Parkinson’s disease, which have shown it to afford some protection against neuronal loss (Ahmad et al., 2005, Kim et al., 2004).

OTHER USES

G. biloba is used for many other indications, including improving connective tissue conditions such as haemorrhoids, common allergies, reducing the effects of exposure to radiation and to prevent some of the complications associated with diabetes. In the UK and other European countries, the cardioprotective effects of EGb 761 in myocardial ischaemia and reperfusion are currently being investigated in preclinical studies.

Adjunct in cancer treatment

As a herb with significant antioxidant and neuroprotective activities, ginkgo has been used to reduce the toxic side effects of some chemotherapeutic drugs. Evidence from in vivo studies demonstrates protective effects against nephrotoxicity induced by cisplatin and cardiotoxicity induced by doxorubicin (Naidu et al., 2002, Ozturk et al., 2004). More recently, G. biloba extract (EGb 761) given intraperitoneally as 200 mg/kg, was found to protect against cisplatin-induced ototoxicity in an animal model (Huang et al., 2007). Another in vivo study showed that G. biloba extract prevented adriamycin-induced hyperlipidaemic nephrotoxicity and was associated with a decrease in oxidative stress and total NO levels of renal tissues (Abd-Ellah & Mariee 2007). Clinical trials are not yet available to determine its effectiveness in practice.

Cancer prevention

A 2006 review puts forward the case that G. Biloba should be more widely used as a safe preventative agent for reducing cancer incidence. This recommendation is based on results from numerous in vitro and experimental studies showing that ginkgo affects many factors associated with the incidence and mortality of cancer (Eli & Fasciano 2006).

Multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middleaged adults, resulting in problems with coordination, strength, cognition, affect and sensation. Two clinical studies have investigated whether ginkgo treatment may help reduce some of these impairments. Johnson et al., (2006) conducted a randomised, double-blind study which compared the effects of ginkgo (EGb 761; 240 mg/day) to placebo on depression, anxiety, fatigue, symptom severity and functional performance using validated measures for each outcome (Johnson et al., 2006). Twentytwo people with MS were enrolled in the study. Significantly, more people administered ginkgo showed improvement on four or more measures with improvements associated with significantly larger effect sizes on measures of fatigue, symptom severity and functionality. The ginkgo group also exhibited less fatigue at follow-up compared with the placebo group and treatment was well tolerated with no side effects or adverse effects reported. The cognitive function of people with multiple sclerosis significantly improved after 12 weeks of treatment with G. biloba extract (120 mg twice a day), according to a randomised, double-blind, placebo-controlled trial (Lovera et al., 2007). A treatment effect trend, limited to the Stroop test, indicated that ginkgo treatment may have an effect on cognitive domains assessed by this test, such as susceptibility to interference and mental flexibility. People with greater cognitive impairment at the start of the study experienced more improvement with treatment than higher functioning people. No serious drug-related side effects occurred.

Schizophrenia — adjunctive treatment

G. biloba given as an adjunct to the atypical antipsychotic medicine, clozapine, in the treatment of refractory schizophrenia was shown to enhance drug effects on negative symptoms according to a placebo-controlled study involving 42 patients with chronic, treatment-resistant schizophrenia (Doruk et al., 2008). Ginkgo was used at a dose of 120 mg/ day for 12 weeks.

CLIENT CONSIDERATIONS (Linda, S-R. 2010)

Assess

Ø Assess the reason the client is using ginkgo.

Ø Assess for hypersensitivity reactions. If present, discontinue the use of this herb and administer an antihistamine or other appropriate therapy.

Ø Assess for the use of anticoagulants, platelet inhibitors, or MAOIs (see Interactions).

Administer

Ø Inform the client that ginkgo takes 1 to 6 months before it becomes effective.

Teach Client/Family

Ø Inform the client that pregnancy category is 2 and breastfeeding category is 1A.

Ø Caution the client not to give ginkgo to children.

Ø Caution the client not to use ginkgo with anticoagulants, platelet inhibitors, trazadone, or MAOIs.