192

101.Krishnaraju AV, Sundararaju D, Sengupta K, Venkateswarlu S, Trimurtulu G. Safety and toxicological evaluation of demethylated curcuminoids; a novel standardized curcumin product. Toxicol Mech Methods 2009; 19: 447-460.

102.NTP (1993). NTP Toxicology and carcinogenesis studies to turmeric oleoresin (CAS No. 8024-37-1)(Major Component 79-85% curcumin, CAS No. 458-37-7) in F344/N rats and B6C3F1 mice (free Studies). Natl Toxicol Program Tech Rep Ser 427, 1-275.

Ginkgo biloba extract

Robert Ritch

Ginkgo biloba extract (GBE) contains over 60 known bioactive compounds, about 30 of which are found nowhere else in nature. The standardized extract used most widely in clinical research, EGb 761 (Dr Willmar Schwabe GmbH & Co, Karlsruhe, Germany), contains 24% ginkgo flavone glycosides (flavonoids), 6% terpene lactones (ginkgolides and bilobalide), approximately 7% proanthocyanidines, and other, uncharacterized compounds.1

GBE has been claimed effective in a variety of disorders associated with aging, including cerebrovascular disease, peripheral vascular disease, dementia, tinnitus, bronchoconstriction, and sexual dysfunction. GBE appears to have many properties applicable to the treatment of non-IOP-dependent risk factors for glaucomatous damage.2 GBE exerts significant protective effects against free radical damage and lipid peroxidation in various tissues and experimental systems. Its antioxidant potential is comparable to water soluble antioxidants such as ascorbic acid and glutathione and lipid soluble ones such as alpha-tocopherol and retinol acetate.3 The antioxidant properties of are due to its direct free radical scavenging activity. Proteasome inhibitory properties of anthocyanins may contribute to their antioxidative, anti-inflammatory and neuroprotective activities, rationalizing their use in neurodegenerative disorders.4

GBE preserves mitochondrial metabolism and ATP production in various tissues and partially prevents morphologic changes and indices of oxidative damage associated with mitochondrial aging.5-9 In contrast to other antioxidants, gingko has the capacity to enter the inner mitochondrial membrane, thus making it an effective antioxidant at the mitochondrial level.10 It can scavenge nitric oxide11 and possibly inhibit its production.12

Substantial experimental evidence exists to support the view that GBE has neuroprotective properties in conditions such as hypoxia/ischemia, seizure activity, cerebral edema, and peripheral nerve damage.13,14 GBE protects against glutamate toxicity.15,16 It can reduce glutamate-induced elevation of calcium concentrations17 and can reduce oxidative metabolism in both resting and calciumloaded neurons.18 Neurons in tissue culture are protected from a variety of toxic insults by GBE, which inhibits apoptosis.

GBE improves both peripheral and cerebral blood flow. It is effective in treating Raynaud’s disease, which is strongly associated with normal-tension glaucoma.23,24 It has been reported to protect myocardium against hypoxia and ischemia-reperfusion injury25,26 and to relax blood vessel walls.27 GBE is a strong

inhibitor of platelet activating factor.28 There is mixed evidence for functional improvement in patients with Alzheimer’s-type and multi-infarct dementias. Preliminary data suggest that GBE may increase the probability of survival in the elderly population.29

It has been suggested that alterations in systemic NO and ET-1 activity (endothelial dysfunction) are involved in vascular dysregulation in glaucoma.30-33 GBE reportedly attenuates endothelial dysfunction34 and improvement of peripheral circulation by GBE is at least partly attributable to its effects on the NO-pathway or endothelium-dependent vasodilation.35,36 Further studies of GBE on the ocular circulation and progression of normal-tension glaucoma are warranted.

In the eye, GBE may have a protective effect against the progression of diabetic retinopathy37 and reduces ischemia-reperfusion injury in rat retina.38 GBE protects retinal photoreceptors against light-induced damage by preventing oxidative stress in the retina.39,40 Chloroquine-induced ERG changes were prevented by simultaneous treatment with GBE.41 In a rat model of central retinal artery occlusion, GBE reduced edema and necrosis and blocked the reduction in b-wave amplitude.42

Jia et al. found that GBE suppressed dexamethasone-induced IOP elevation in rabbits.43 It reduced the dexamethasone-associated accumulation of extracellular materials within the cribriform layers of the trabecular meshwork and achieved better meshwork cellularity. In cultured human trabecular cells, GBE substantially reduced dexamethasone-induced myocilin expression.43,44 investigated the dosage dependence of intragastral GBE versus saline on RGC survival in the rat optic nerve crush model. The mean survival rate increased significantly (P < 0.001) from 58.4 ± 9.0% in the saline group to 74.2 ± 6.8% in the highdosage GBE group. The same group found that intraperitoneal administration gave similar results.45

GBE has been reported to improve automated visual field indices.46,47 In one clinical cross-over study of low-dose, short-term treatment in normal volunteers, GBE increased ophthalmic artery blood flow by a mean of 24%.48 A more recent study, however, failed to confirm these results.49

A systematic review of case reports concluded that ‘the causality between ginkgo intake and bleeding is unlikely.’50 A systematic review of eight randomized controlled trials concluded that the ‘available evidence does not demonstrate that GBE causes significant changes in blood coagulation parameters.’51 The idea that the combination of ginkgo and anticoagulant or antiplatelet drugs might represent a serious health risk is based on several case reports but not supported by clinical trials.52

References

1.De Feudis FV. Ginkgo biloba Extract (EGb 761): Pharmacological activities and clinical applications. Paris: Elsevier 1991.

2.Ritch R. A potential role for Ginkgo biloba extract in the treatment of glaucoma. Medical Hypotheses 2000; 54: 221-235.

194

3.Köse K, Dogan P. Lipoperoxidation induced by hydrogen peroxide in human erythrocyte membranes. 2. Comparison of the antioxidant effect of Ginkgo biloba extract (EGb 761) with those of water-soluble and lipid-soluble antioxidants. J Int Med Res 1995; 23: 9-18.

4.Dreiseitel A, Schreier P, Oehme A, et al. Inhibition of proteasome activity by anthocyanins and anthocyanidins. Biochem Biophys Res Comm 2008; 372: 57-61.

5.Pierre S, Jamme I, Droy-Lefaix MT, et al. Ginkgo biloba extract (EGb 761) protects NaKATPase activity during cerebral ischemia in mice. NeuroReport 1999; 10: 47-51.

6.Janssens D, Delaive E, Remacle J, Michiels C. Protection by bilobalide of the ischaemiainduced alterations of the mitochondrial respiratory activity. Fundam Clin Pharmacol 2000; 14: 193-201.

7.Sastre J, Lloret A, Borras C, et al. GBE EGb 761 protects against mitochondrial aging in the brain and in the liver. Cell Mol Biol 2002; 48: 685-692.

8.Eckert A, Keil U, Kressmann S, et al. Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress. Pharmacopsychiatry 2003; 36 Suppl 1: S15-23.

9.Eckert A, Keil U, Scherping I, et al. Stabilization of mitochondrial membrane potential and improvement of neuronal energy metabolism by Ginkgo biloba extract EGb 761. Ann NY Acad Sci 2005; 1056: 474485.

10.Hirooka K, Tokuda M, Miyamoto O, et al. The Ginkgo biloba extract (EGb 761) provides neuroprotective effect on retinal ganglion cells in a rat model of chronic glaucoma. Curr Eye Res 2004; 28: 153-157.

11.Marcocci L, Maguire JJ, Droy-Lefaix MT, Packer L. The nitric oxide-scavenging properties of Ginkgo biloba extract (EGb 761). Biochem Biophys Res Commun 1994; 201: 748-755.

12.Kobuchi H, Droy-Lefaix MT, Christen Y, Packer L. Ginkgo biloba extract (EGb 761): Inhibitory effect on nitric oxide production in the macrophage cell line RAW 264.7. Biochem Pharmacol 1997; 53: 897-904.

13.Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationshiop to platelet-activating factor (PAF). J Ethnopharmacol 1996; 50: 131-139.

14.Ahlemeyer B, Krieglstein J. Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer’s disease. Pharmacopsychiatry 2003; 36 Suppl 1: S8-14.

15.Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Bilobalide, a component of the Ginkgo biloba extract (EGb 761), protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. Cell Mol Biol 2002; 48: 663-670.

16.Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicityinduced neuronal death. Pharmacopsychiatry 2003; 36 Suppl 1: S89-94.

17.Zhu L, Wu J, Liao H, Gao J, Zhao XN, Zhang ZX. Antagonistic effects of extract from leaves of Ginkgo biloba on glutamate neurotoxicity. Acta Pharmacol Sinica 1997; 18: 344-347.

18.Oyama Y, Fuchs PA, Katayama N, Noda K. Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca(2+)-loaded brain neurons. Brain Res 1994; 635: 125-129.

19.Ahlemeyer B, Mowes A, Krieglstein J. Inhibition of serum deprivationand staurosporineinduced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur J Pharmacol 1999; 367: 423-430.

20.Zhou LJ, Zhu XZ. Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. J Pharmacol Exp Ther 2000; 293: 982-988.

21.Guidetti C, Paracchini S, Lucchini S, et al. Prevention of neuronal cell damage induced by oxidative stress in vitro: effect of different Ginkgo biloba extracts. J Pharmacy Pharmacol 2001; 53: 387-392.

22.Lu G, Wu Y, Mak YT, et al. Molecular evidence of the neuroprotective effect of Ginkgo biloba (EGb761) using bax/bcl-2 ratio after brain ischemia in senescence-accelerated mice, strain-prone 8. Brain Res 2006; 1090: 23-28.

23.Muir AH, Robb R, McLaren M, Daly F, Belch JJ. The use of Ginkgo biloba in Raynaud’s disease: a double-blind placebo-controlled trial. Vasc Med 2002; 7: 265-267.

24.Choi WS, Choi CJ, Kim KS, et al. To compare the efficacy and safety of nifedipine sustained release with Ginkgo biloba extract to treat patients with primary Raynaud’s phenomenon in South Korea; Korean Raynaud study (KOARA study). Clin Rheumatol 2009; 28: 553-559.

25.Haramaki N, Aggarwal S, Kawabata T, Droy-Lefaix MT, Packer L. Effects of natural antioxidant Ginkgo biloba extract (EGb 761). on myocardial ischemia-reperfusion injury. Free Radic Biol Med 1994; 16: 789-794.

26.Punkt K, Welt K, Schaffranietz L. Changes of enzyme activities in the rat myocardium caused by experimental hypoxia with and without ginkgo biloba extract EGb 761 pretreatment. A cytophotometrical study. Acta Histochem 1995; 97: 67-79.

27.Satoh H, Nishida S. Electropharmacological actions of Ginkgo biloba extract on vascular smooth and heart muscles. Clin Chim Acta 2004; 342: 13-22.

28.Koch E. Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications after oral intake of Ginkgo biloba extracts. Phytomedicine 2005; 12: 10-16.

29.Dartigues JF, Carcaillon L, Helmer C, et al. Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort. J Am Geriatr Soc 2007; 55: 395-399.

30.Nicolela MT, Ferrier SN, Morrison CA, et al. Effects of cold-induced vasospasm in glaucoma: the role of endothelin-1. Invest Ophthalmol Vis Sci 2003; 44: 2565-2572.

31.Grieshaber MC, Flammer J. Blood flow in glaucoma. Curr Opin Ophthalmol 2005; 16: 79-83.

32.Henry E, Newby DE, Webb DJ, Hadoke PW, O’Brien CJ. Altered endothelin-1 vasoreactivity in patients with untreated normal-pressure glaucoma. Invest Ophthalmol Vis Sci 2006; 47: 2528-2532.

33.Su WW, Cheng ST, Hsu TS, Ho WJ. Abnormal flow-mediated vasodilation in normal-tension glaucoma using a noninvasive determination for peripheral endothelial dysfunction. Invest Ophthalmol Vis Sci 2006; 47: 3390-3394.

34.Zhou W, Chai H, Courson A, et al. Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries. J Vasc Surg 2006; 44: 853-862.

35.Chen X, Salwinski S, Lee TJF. Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway. Clin Exp Pharmacol Physiol 1997; 24: 958-959.

36.Wu WR, Zhu XZ. Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against MPTP-induced nigrostriatal dopaminergic toxicity in C57 mice. Life Sci 1999; 65: 157-164.

37.Droy-Lefaix MT, Szabo-Tosaki ME, Doly MN. Free radical scavenger properties of EGb 761 on functional disorders induced by experimental diabetic retinopathy. In: Cutler RG, Packe L, Bertram J, Mori A (Eds.). Oxidative stress and aging. Basel: Birkhäuser Verlag 1996; 277-286.

38.Szabo ME, Droy-Lefaix MT, Doly M, Braquet P. Modification of ischemia/reperfusioninduced ion shifts (Na+, K+, Ca2+ and Mg2+ by free radical scavengers in the rat retina. Ophthalmic Res 1993; 25: 1.

39.Ranchon I, Gorrand JM, Cluzel J, Droy-Lefaix MT, Doly M. Functional protection of photoreceptors from light-induced damage by dimethylthiourea and Ginkgo biloba extract. Invest Ophthalmol Vis Sci 1999; 40: 1191-1199.

40.Xie Z, Wu X, Gong Y, et al. Intraperitoneal injection of Ginkgo biloba extract enhances antioxidation ability of retina and protects photoreceptors after light-induced retinal damage in rats. Curr Eye Res 2007; 32: 471-479.

41.Meyniel G, Doly M, Millerin M, Braquet P. Involvement of PAF (Platelet-Activating Factor) in chloroquine-induced retinopathy. C R Acad Sci III 1992; 314: 61-65.

42.Droy-Lefaix MT, Szabo ME, Doly M. Ischaemia and reperfusion-induced injury in the retina obtained form normotensive and spontaneously hypertensive rats: effects of free radical scavengers. Int J Tissue React 1993; 15: 85-91.

43.Jia LY, Sun L, Fan DS, et al. Effect of topical Ginkgo biloba extract on steroid-induced changes in the trabecular meshwork and intraocular pressure. Arch Ophthalmol 2008; 126: 1700-1706.