Non-pharma therapy for glaucoma and other
al. 1996; Ahlemeyer & Krieglstein 2003) GBE
ocular diseases (Consensus document 2010)
protects against glutamate toxicity. (Chandrasekaran et al. 2002; Chandrasekaran et
Ginkgo biloba extract (GBE)
al. 2003) It can reduce glutamate-inducedelevation of calcium concentrations (Zhu et al.
Ginkgo biloba extract contains over 60 known
1997) and can reduce oxidative metabolism in
bioactive compounds, about 30 of which are
both resting and calcium-loaded neurons. (Oyama
found nowhere else in nature. The standardized
et al. 1994) Neurons in tissue culture are protected
extract used most widely in clinical research,
from a variety of toxic insults by GBE, which
EGb 761 (Dr Willmar Schwabe GmbH & Co,
inhibits apoptosis. (Ahlemeyer et al. 1999; Zhou &
Zhu 2000; Guidetti et al. 2001; Lu et al. 2006)
flavone glycosides (flavonoids), 6% terpenelactones (ginkgolides and bilobalide),
GBE improves both peripheral and cerebral blood
flow. It is effective in treating Raynaud’s disease,
other, uncharacterized compounds. (De Feudis
which is strongly associated with normal-tension
glaucoma. (Muir et al. 2002; Choi et al. 2009) Ithas been reported to protect myocardium against
GBE has been claimed effective in a variety of
hypoxia and ischemia-reperfusion injury (Haramaki
disorders associated with aging, including
et al. 1994; Punkt et al. 1995) and to relax blood
cerebrovascular disease, peripheral vascular
vessel walls. (Satoh & Nishida 2004) GBE is a
disease, dementia, tinnitus, bronchoconstriction,
strong inhibitor of platelet activating factor. (Koch
and sexual dysfunction. GBE appears to have
2005) There is mixed evidence for functional
many properties applicable to the treatment of
improvement in patients with Alzheimer’s-type and
non-IOP-dependent risk factors for glaucomatous
multi-infarct dementias. Preliminary data suggest
damage. (Ritch 2000) GBE exerts significant
that GBE may increase the probability of survival
protective effects against free radical damage
in the elderly population. (Dartigues et al. 2007)
and lipid peroxidation in various tissues andexperimental systems. Its antioxidant potential is
It has been suggested that alterations in systemic
comparable to water soluble antioxidants such as
NO and ET-1 activity (endothelial dysfunction) are
ascorbic acid and glutathione and lipid soluble
involved in vascular dysregulation in glaucoma.
ones such as alpha-tocopherol and retinol
(Nicolela et al. 2003; Grieshaber & Flammer 2005;
acetate. (Köse & Dogan 1995) The antioxidant
Henry et al. 2006; Su et al. 2006) Ginkgo biloba
properties of are due to its direct free radical
extract reportedly attenuates endothelial
scavenging activity. Proteasome inhibitory
dysfunction (Zhou et al. 2006) and improvement of
properties of anthocyanins may contribute to their
peripheral circulation by GBE is at least partly
attributable to its effects on the NO-pathway or
neuroprotective activities, rationalizing their use
endothelium-dependent vasodilation. (Chen et al.
in neurodegenerative disorders. (Dreiseitel et al.
1997; Wu & Zhu 1999) Further studies of GBE on
the ocular circulation and progression of normal-tension glaucoma are warranted.
GBE preserves mitochondrial metabolism andATP production in various tissues and partially
In the eye, GBE may have a protective effect
prevents morphologic changes and indices of
against the progression of diabetic retinopathy
oxidative damage associated with mitochondrial
(Droy-Lefaix et al. 1996) and reduces ischemia-
aging. (Pierre et al. 1999; Janssens et al. 2000;
reperfusion injury in rat retina. (Szabo et al. 1993)
Sastre et al. 2002; Eckert et al. 2003; Eckert et
GBE protects retinal photoreceptors against light-
al. 2005) In contrast to other antioxidants, gingko
induced damage by preventing oxidative stress in
has the capacity to enter the inner mitochondrial
the retina. (Ranchon et al. 1999; Xie et al. 2007)
antioxidant at the mitochondrial level. (Hirooka et
prevented by simultaneous treatment with GBE.
al. 2004) It can scavenge nitric oxide (Marcocci
(Meyniel et al. 1992) In a rat model of central
et al. 1994) and possibly inhibit its production.
retinal artery occlusion, GBE reduced edema and
necrosis and blocked the reduction in b-waveamplitude. (Droy-Lefaix et al. 1993)
Substantial experimental evidence exists tosupport the view that GBE has neuroprotective
dexamethasone-induced IOP elevation in rabbits.
hypoxia/ischemia, seizure activity, cerebral
(Jia et al. 2008) It reduced the dexamethasone-
edema, and peripheral nerve damage. (Smith et
associated accumulation of extracellular materials
within the cribriform layers of the trabecular
(EGb 761) in global brain ischemia and in
excitotoxicity-induced neuronal death.
cellularity. In cultured human trabecular cells,
Pharmacopsychiatry 36 Suppl 1: S89-94.
GBE substantially reduced dexamethasone-induced myocilin expression. (Jia et al. 2008) Ma
Chen X, S Salwinski & TJF Lee (1997): Extracts
et al investigated the dosage dependence of
of Ginkgo biloba and ginsenosides exert cerebral
intragastral GBE versus saline on RGC survival
vasorelaxation via a nitric oxide pathway. Clin Exp
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%
Choi WS, CJ Choi, KS Kim & et al (2009): To
in the high-dosage GBE group. The same group
compare the efficacy and safety of nifedipine
found that intraperitoneal administration gave
sustained release with Ginkgo biloba extract to
treat patients with primary Raynaud's phenomenonin South Korea; Korean Raynaud study (KOARA
GBE has been reported to improve automated
visual field indices. (Raabe et al. 1991; Quarantaet al. 2003) In one clinical cross-over study of
Chung HS, A Harris, JK Kristinsson, T Ciulla, C
Kagemann & R Ritch (1999): Ginkgo biloba
volunteers, GBE increased ophthalmic artery
extract increases ocular blood flow velocity. J
blood flow by a mean of 24%. (Chung et al.
Ocular Pharmacol Therap 15: 233-240.
1999) A more recent study, however, failed toconfirm these results. (Wimpissinger et al. 2007)
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A systematic review of case reports concluded
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that the causality between ginkgo intake and
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De Feudis FV (1991): Ginkgo biloba Extract (EGb
trials concluded that the available evidence does
761): Pharmacological activities and clinical
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changes in blood coagulation parameters’’. (Savovic´ et al. 2005) The idea that the
Dreiseitel A, P Schreier, A Oehme & et al (2008):
combination of ginkgo and anticoagulant or
Inhibition of proteasome activity by anthocyanins
antiplatelet drugs might represent a serious
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Oyama Y, PA Fuchs, N Katayama & K Noda
(1994): Myricetin and quercetin, the flavonoidconstituents of Ginkgo biloba extract, greatly
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Smith PF, K Maclennan & CL Darlington (1996):
improvement in myocardial ischemia-reperfusion
The neuroprotective properties of the Ginkgo
injury in vitro has been reported. (Pataki et al.
biloba leaf: a review of the possible relationshiop
2002; Bagchi et al. 2003; Shao et al. 2003) Activin,
a new generation antioxidant derived from grape
seed proanthocyanidins, reduces plasma levels ofoxidative stress and adhesion molecules (ICAM-1,
Su WW, ST Cheng, TS Hsu & WJ Ho (2006):
VCAM-1 and E-selectin) in patients with systemic
Abnormal flow-mediated vasodilation in normal-
sclerosis. (Kalin et al. 2002) Supplementation of a
meal with GSE minimizes postprandial oxidative
stress by increasing the antioxidant levels in
dysfunction. Invest Ophthalmol Vis Sci 47: 3390-
plasma, and, as a consequence, enhancing the
resistance to oxidative modification of low densitylipoproteins. (Natella et al. 2002) Grape seed
Szabo ME, MT Droy-Lefaix, M Doly & P Braquet
proanthocyanidins have also been reported to
(1993): Modification of ischemia/reperfusion-
have activity against HIV-1 entry into cells. (Nair et
al. 2002) Grape seed extract has recently been
Shigematsu et al. 2003) It inhibits lipid
shown to inhibit the growth of prostate cancer
peroxidation of low-density lipoprotein (LDL),
cells in mice. (Raina et al. 2007) In the eye, GSE
prevents the cytotoxicity ofoxidized LDL, and
inhibits key components of cataractogenesis by
protects cells against lipid peroxidation.
reducing oxidative stress within lens epithelial
(Chanvitayapongs et al. 1997) Resveratrol
cells. (Barden et al. 2008) and significantly
protects against the degeneration of neurons
prevents and postpones development of cataract
afteraxotomy. (Araki et al. 2004) A single infusion
formation in rats with hereditary cataracts.
of resveratrol can elicit neuroprotective effects on
cerebral ischemia-induced neuron damagethrough free radical scavenging and cerebral blood
elevation due to nitric oxide release. (Lu et al. 2006) Its antiapoptotic activity has led to the
Resveratrol (3,5,40-trihydroxystilbene), a
suggestion that resveratrol may make a useful
powerful polyphenolic antioxidant, is found
dietary supplement for minimizing oxidative injury
largely in the skins of red grapes and berries and
in immune-perturbed states and human chronic
came to scientific attention as a possible
explanation for the low incidence of heart diseaseamong the French, who eat a relatively high-fat
Levels of intracellular heme (iron-protoporphyrin
diet (the French paradox). Many studies suggest
IX), a pro-oxidant, increase after stroke. In
that consuming alcohol (especially red wine)
neuronal cell cultures, resveratrol induces heme
may reduce the incidence of coronary heart
oxygenase 1, suggesting that increased heme
disease (CHD). Grape juice, which is not a
oxygenase activity is a unique pathway by which
fermented beverage, is not a significant source of
resveratrol can exert its neuroprotective actions.
resveratrol. A large number of studies in the past
few years suggests its benefit in vitro and in vivoin a variety of human disease models, including
Resveratrol directly inhibits CYP1B1. The
cardioprotection, neuroprotection, immune
versatility of RSV lies in its diverse targeting of
regulation, and cancer chemoprevention. For an
membrane and intracellular receptors, signaling
extensive review, see (Pervaiz & Holme 2009).
Substantial data show that actions of resveratrol
include inhibition of lipid peroxidation and platelet
transcription factors, and it can activate or repress
aggregation, metal chelating (primarilycopper),
a number of signal-transducing pathways found
free radical’scavenging activity, antiinflammatory
throughout the cell (Pervaiz & Holme 2009)
activity, modulation of lipid metabolism,antifungal properties, and anticancer and
There appears to be an association between aging
estrogen-like activity. (Pervaiz & Holme 2009)
and neurodegenerative diseases, such asAlzheimer’s, and that modulation by both caloric
Resveratrol increases the lifespan of the yeast,
restriction and drugs which mimic caloric
restriction, such as resveratrol, can ameliorate
Caenorhabditis elegans, and the fruitfly,
these diseases. (Liu et al. 2007) Resveratrol
Drosophila melanogaster. It was later shown to
reduces the levels of secreted and intracellular
extend the lifespan of the short-lived fish,
amyloid-ß peptides by proteosomal degradation.
Nothobranchius furzeri, (Valenzano & Cellerino
2006) and has now been shown to significantlyincrease the health and survival of mice on a
In the eye, resveratrol suppresses selenite-
high-calorie diet, pointing to a new approach to
induced oxidative stress and cataract formation in
treating diseases of aging. (Baur et al. 2006)
rats. (Doganay et al. 2006) The authors suggested
Among its multiple functions, resveratrol
that the presence of oxidative stress in selenite
activates sirtuins (silent information regulator
cataract development and its prevention by
proteins), a family of proteins that play an
resveratrol support the possibility that high natural
important role in DNA repair, gene silencing,
consumption of resveratrol in food can help
chromosomal stability and longevity. (Michan &
prevent human senile cataract. Resveratrol also
induces dilation of retinal arterioles, suggesting apotential benefit for this compound in the treatment
The physiologic effects of resveratrol appear to
of retinal vascular disease. (Nagaoka et al. 2007)
be related to its ability to regulate nutrition and
Sirtuin-1 activators (such as resveratrol)
longevity genes. (Pervaiz & Holme 2009)
demonstrate neuroprotective properties in mouse
Resveratrol is an effective antioxidant. (Frankel
models of optic neuritis and multiple sclerosis.
et al. 1993; Chanvitayapongs et al. 1997;
radical scavenging and cerebral blood flow
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Increased nuclear NAD biosynthesis and SIRT1activation prevent axonal degeneration. Science
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Bagchi D, CK Sen, SD Ray & et al (2003):Molecular mechanisms of cardioprotection by a
Nagaoka T, TW Hein, A Yoshida & et al (2007):
novel grape seed proanthocyanidin extract. Mutat
Resveratrol, a component of red wine, elicits
dilation of isolated porcine retinal arterioles: role ofnitric oxide and potassium channels. Invest
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Effect of grape polyphenols on oxidative stress incanine lens epithelial cells. Am J Vet Res 69: 94-
Nair MP, C Kandaswami, S Mahajan & et al
(2002): Grape seed extract proanthocyanidinsdownregulate HIV-1 entry coreceptors, CCR2b,
Baur JA, KJ Pearson, NL Price & et al (2006):
Resveratrol improves health and survival of mice
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Chanvitayapongs S, B Draczynska-Lusiak & AY
Natella F, F Belelli, V Gentili & et al (2002): Grape
Sun (1997): Amelioration of oxidative stress by
antioxidants and resveratrol in PC12 cells.
postprandial oxidative stress in humans. J Agric
Doganay S, M Borazan, M Iraz & Y Cigremis
Pataki T, I Bak, P Kovacs & et al (2002): Grape
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Kalin R, A Righi, A Del Rosso & et al (2002):Activin, a grape seed-derived proanthocyanidin
Raina K, RP Singh, R Agarwal & C Agarwal
extract, reduces plasma levels of oxidative stress
(2007): Oral grape seed extract inhibits prostate
and adhesion molecules (ICAM-1, VCAM-1 and
tumor growth and progression in TRAMP mice.
E-selectin) in systemic sclerosis. Free Radical
Shao ZH, LB Becker, TL Vanden Hoek & et al
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Prevention and treatment of Alzheimer disease
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Resveratrol, a red wine constituent polyphenol,
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responses induced by ischemia/reperfusion,platelet-activating factor, or oxidants. Free Radic
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Neuroprotective effects of resveratrol on cerebralischemia-induced neuron loss mediated by free
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experimental optic neuritis. Invest Ophthalmol Vis
attention deficit hyperactivity disorder in children.
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After oral administration of pycnogenol, plasma
and the pharmacology of aging: a new vertebrate
samples significantly inhibited NFkB activation and
model to validate an old molecule. Cell Cycle 5:
MMP-9 release from human monocytes, indicating
that it exerts anti-inflammatory effects by inhibitingproinflammatory gene expression. (Grimm et al.
Yamakoshi J, M Saito, S Kataoka & S Tokutake
2006) Glutamate inhibits cyclo-oxygenases 1 and
(2002): Procyanidin-rich extract from grape
2. (Schafer et al. 2006) This cytotoxicity was
seeds prevents cataract formation in hereditary
inhibited by both GBE and pycnogenol.
cataractous (ICR/f) rats. J Agric Food Chem 50:
(Kobayashi et al. 2000) Pycnogenol not only
suppresses the generation of reactive oxygenspecies, but also attenuates caspase-3 activation
Zhuang H, YS Kim, RC Koehler & S Dore
and DNA fragmentation, suggesting protection
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resveratrol, a red wine constituent, protectsneurons. Ann N Y Acad Sci 993: 276-286.
Pycnogenol has also been reported to inhibitangiotensin-converting enzyme and to enhance
the microcirculation by increasing capillarypermeability. (Packer et al. 1999) It inhibits
Pycnogenol, an extract of French maritime pine
progression of preproliferative diabetic retinopathy
bark (Pinus pinaster), is primarily composed of
(Schonlau & Rohdewald 2001) and may reduce
procyanidins and phenolic acids and is a potent
the risk of formation of both diabetic retinopathy
antioxidant with strong free radical-scavenging
and cataract. (Kamuren et al. 2006) More recently,
activity against reactive oxygen and nitrogen
in patients with mild to moderate retinal edema,
pycnogenol treatment significantly improved both
catechin and epicatechin subunits, which are
the edema and retinal thickness as measured by
important in human nutrition. (Rohdewald 2002)
high resolution ultrasound. (Steigerwalt et al. 2009) Laser Doppler flow velocity measurements
Pycnogenol is effective in patients with venous
at the central retinal artery showed a statistically
microangiopathy (Cesarone et al. 2006)and
significant increase from 34 to 44 cm/s in the
accelerates healing in leg ulcerations from
chronic venous insufficiency (Belcaro et al. 2005)
effects in the control group. (Steigerwalt et al.
and diabetes. (Belcaro et al. 2006) In chronic
venous insufficiency, pycnogenol reduced lowerleg circumference and symptoms of pain,
Steigerwalt et al (Steigerwalt et al. 2008)
evaluated the effects of the food supplement
‘heaviness", and reddening of the skin. (Koch
Mirtogenol (Mirtoselect and Pycnogenol) on IOP
and ocular blood flow in 20 subjects versus 18
endothelial cells from Aß-induced injury. (Liu et
controls. After three months of treatment, the IOP
was lowered compared to that of untreated
creatinine, BUN, LDH, IL-1beta, IL-6, and TNF-
controls from a baseline of 25.2 mmHg to 22.0
alpha levels in ischemia reperfusion injury in
mmHg (p<0.05). Ocular blood flow (central
unilaterally nephrectomized rats. (Ozer Sehirli et
retinal, ophthalmic, and posterior ciliary arteries)
improved both in the systolic and diastoliccomponents as measured by Color Doppler
Pretreatment with pycnogenol reduces smoke-
induced platelet aggregation. (Araghi-Niknam etal. 2000) Pycnogenol significantly reduces LDL-
cholesterol levels. (Devaraj et al. 2002; Koch
Rohdewald & RR Watson (2000): Pine bark
2002) A randomized controlled trial reported it
extract reduces platelet aggregation. Integrative
effective for erectile dysfunction. (Stanislavov et
al. 2007) It has also been reported to improvesymptoms of jetlag. (Belcaro et al. 2008) It
Belcaro G, MR Cesarone, BM Errichi & et al
inhibits not only HIV-1 binding to host cells, but
also its replication after entry in susceptible cells
improvement and faster healing with local use of
in vitro. (Feng et al. 2008) It has been reported to
increase urinary catecholamines and ameliorate
Belcaro G, MR Cesarone, BM Errichi & et al
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PUBLISHED No. 12-2188 E.D., a minor by and through her mother and next friend; DENISE DARCY, PFIZER, INC.; ROERIG, a division of Pfizer, Inc.; GREENSTONE, LLC, f/k/a Greenstone Ltd., No. 12-2189 J.C., a minor by and through his mother and next friend; MICHELLE COOK, PFIZER, INC.; ROERIG, a division of Pfizer, Inc.; GREENSTONE, LLC, f/k/a Greenstone Ltd., No. 12-2190 D.B.,
MINISTRY OF AGRICULTURE AND RURAL DEVELOPMENT NATIONAL AGRO-FORESTRY-FISHERIES QUALITY ASSURANCE DEPARTMENT The Residues Monitoring Program for Certain Harmful Substances in aquaculture fish and products thereof in 2009 and Implementation Plan in 2010 RESULTS OF THE MONITORING PROGRAM FOR CERTAIN HARMFUL 1. General The Program for control of residues in farmed fish has