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Grape Seed Extract

Plant Part Used

Seed/Skin

Active Constituents

Polyphenols, including proanthocyanidins also known as procyanidins or oligomeric proanthocyanidin (OPCs); gallic acid.(1),(40)

[span class=alert]This section is a list of chemical entities identified in this dietary supplement to possess pharmacological activity. This list does not imply that other, yet unidentified, constituents do not influence the pharmacological activity of this dietary supplement nor does it imply that any one constituent possesses greater influence on the overall pharmacological effect of this dietary supplement.[/span]

Introduction

Condensed tannins termed oligomeric proanthocyanidins (OPCs), or procyanidolic oligomers (PCOs), are the main active constituents found in grape seed and are possibly some of the most important natural products to be discovered in the last several years. They are flavonoid-rich compounds, which are being heavily regarded as some of the most potent antioxidants found in nature. An in vitro study reported that OPCs contained in grape seed are approximately 2 times more powerful than vitamin E and as much as 4 times stronger than vitamin C.(2) They may enhance absorption of and work synergistically with vitamin C, and have been reported to actually spare vitamin E from oxidation in vitro.(3) Activity of these OPCs include antibacterial, antiviral, anticarcinogenic, anti-inflammatory, anti-allergic, and vasodilatory.(4) In addition, they have been found to inhibit lipid peroxidation, platelet aggregation, capillary permeability and fragility, and to affect enzyme systems including phospholipase A2, xanthine oxidase, cyclooxygenase, and lipoxygenase. Proanthocyanidins have been associated with the term "French Paradox," or the observation that a high dietary intake of fats in France is not associated with an increase in atherosclerosis and other cardiovascular diseases.(5)

Interactions and Depletions

Interactions

Dosage Info

Dosage Range

25-100mg (standardized extract), 1-3 times a day.

Most Common Dosage

50mg (standardized extract), 2 times a day.

Standardization

[span class=doc]Standardization represents the complete body of information and controls that serve to enhance the batch to batch consistency of a botanical product, including but not limited to the presence of a marker compound at a defined level or within a defined range.[/span]

The most current available medical and scientific literature indicates that the dietary supplement should be standardized to a procyanidolic value of greater than 95 and 90% total polyphenols OR at least 80% proanthocyanidins.

Uses

Frequently Reported Uses

  • Antioxidant
  • Cardiovascular health, including blood pressure, vascular health and lipid balance
  • Improves Capillary Fragility And Permeability
  • Improves Elastic Fibers Of Collagen And Elastin Of Capillaries
  • Improves Microcirculation To The Brain, Heart, Periphery

Other Reported Uses

  • Allergies
  • Anticancer
  • Asthma
  • Decreases Platelet Aggregation, Improves Blood Flow
  • Arterial Or Venous Insufficiency, Intermittent Claudication
  • Dental Health
  • Anti-Aging Effects

Toxicities & Precautions

General

No known toxicity or adverse effects even under high doses.(6)

Health Conditions

Based on pharmacology, use with caution in individuals with bleeding disorders.

Pregnancy/ Breast Feeding

If pregnant or nursing, consult a physician before use.

Age Limitations

Do not use in children under 2 years of age unless recommended by a physician.

Pharmacology

Antioxidant/Antiinflammatory

OPCs found in grape seed are antioxidants, or free radical scavengers.(7) Free radical damage has been associated with nearly every chronic degenerative disease, including cardiovascular diseases, arthritis, hypercholesterolemia and cancer.(4) Proanthocyanidins contained in grape seed are reported to neutralize lipid peroxidation damage to cell membranes through their free radical scavenging activity, including hydroxyl, lipid peroxides and iron-induced lipid peroxidation.(20),(21),(22),(23),(24),(25)

The antioxidant capacity of procyanidins found in grape seed extract are reported in laboratory studies to modulate inflammatory processes, including reducing the expression of IL-6 and MCP-1 and enhancing the production of the anti-inflammatory adipokine adiponectin suggesting that may have a beneficial effect on low-grade inflammatory diseases.(41) Inflammatory up-regulation is strongly associated with chronic diseases such as inflammatory bowel diseases, thyroid and other hormonal imbalances, obesity, type 2 diabetes, insulin resistance, sleep disturbances, cardiovascular diseases and cancer.  Laboratory studies have reported that the antioxidant polyphenols found in grape seed extract help attenuate inflammatory processes seen in an Alzheimer’s brain model, reducing amyloid-beta deposition and microglia activation.(42)

Laboratory studies have reported grape seed extract may inhibit vascular cell adhesion molecule (VCAM)-1 induction by advanced glycation end products (AGE) by activating PPAR gamma expression.(43)  A human study looked at the plasma level of free radical-induced 8-isoprostane formation in healthy human subjects after grape seed administration.(44) A significant reduction in 8-isoprostane levels was found, supporting grape seed’s antioxidant benefits in humans.

Cardiovascular Health

Grape polyphenols have been reported in laboratory and human studies to have antioxidant properties that are beneficial to cardiovascular health, including decreasing low-density lipoprotein-cholesterol oxidation and platelet aggregation, vasoprotection and antiatherosclerotic properties.(45),(46) Proanthocyanidins are claimed to support collagen structures and inhibit the destruction of collagen, strengthening capillary walls and other vessels.(2),(8) Collagen protection is claimed to be very important for health because it allows red blood cells to penetrate into the microcapillary system and prevent fluids from leaking out of the microvasculature.(9),(10) OPCs reportedly protect 1-antitripsin, a chemical that keeps enzymes from breaking down collagen, elastin and hyaluronic acid(11),(12) and directly inhibits these substances from damaging enzymes. OPCs have also been reported to decrease edema, based upon the stabilization of the capillary wall and prevention of the increase in capillary permeability.(13),(14),(15) In one double-blind, placebo controlled study, 71 patients with peripheral venous insufficiency received grape seed extract (300mg OPCs) or placebo daily.(16) The individuals receiving the grape seed extract reported a 75% reduction in the symptoms associated with venous insufficiency. Another report of a single administration of OPCs (150mg) resulted in an increase in venous tone in patients with varicosities.(17) Similarly, a double blind, placebo controlled study of elderly individuals with either spontaneous or drug-induced low capillary resistance were treated with OPCs from grape seed (100-150mg) or placebo.(18) The study results reported a noticeable improvement (53% of treated individuals) in capillary resistance after two weeks of therapy.

The OPCs of grape seed have also been reported to have PAF inhibiting ability in laboratory studies, with potency comparable to that of aspirin.(19) The inhibitory effect of OPCs on thromboxane biosynthesis may explain the platelet aggregation inhibiting activity.

The antioxidant effect may be useful in protection from unhealthy cholesterol levels. A laboratory animal study reported that a single dose proanthocyanidins from grape seeds increased the resistance of blood plasma against oxidative stress.(26) Several clinical studies have reported administration of grape seed extract decreases levels of oxidized LDL cholesterol.(27),(28),(47)

A small clinical study found that grape seed extract was beneficial in lowering systolic and diastolic blood pressures in patients with metabolic syndrome.(48) There were no significant changes in lipids or blood glucose values.

Cancer Support

Grape seed proanthocyanidins were recently reported to be cytotoxic in vitro against some cancer cell lines, including human breast, lung, colon, gastric, prostate and others.(33),(49),(50),(51) Grape seed extract has been reported in laboratory studies to be a potential agent in breast cancer support through suppression of aromatase expression,(52),(53) Also, the grape seed extract enhanced the growth and viability of the normal human gastric mucosal cells and murine macrophage cells. Grape seed proanthocyanidins were also reported to have radioprotective activity, decreasing the damaging effects of radiation in an in vitro study.(34) Another in vitro study reported that OPCs from grape seed were effective in reducing the damaging effects of chemotherapeutic agents (idarubicin, doxorubicin and cyclophosphamide) on Chang liver cells, and may be useful in preventing the toxic effects of these agents in individuals undergoing cancer treatment.(35),(54) Grape seed OPCs were also reported in a laboratory animal study to be hepatoprotective against acetaminophen, decreasing the damaging effects on hepatocytes and reducing liver injury.(36) Grape seed extract’s mechanism in cancer includes inhibition of angiogenesis via suppression of vascular endothelial growth factor (VEGF) signaling and inducing apoptosis via activation of c-Jun NH2-terminal kinase.(55),(56)

A double-blind, placebo controlled, randomized phase II trial did not find any benefit when using grape seed extract to improve breast tissue induration after high dose radiation therapy.(57)

Allergic Conditions

OPCs have been reported to inhibit the degradation of mast cells and the subsequent release of mediators of inflammation, such as histamine and prostaglandins, and therefore may be useful in allergies and sinus problems.(8),(37) OPCs have also been reported to inhibit the enzyme xanthine oxidase, a major producer of free radicals.(38) OPCs have been used in allergies because of their reported ability to inhibit degradation of mast cells and the subsequent release of histamine and other mediators of inflammation. In contrast, a study involving forty-nine seasonal allergic rhinitis sufferers compared the effects of 100mg grape seed extract twice a day against placebo. The evaluation of multiple endpoints demonstrated no significant differences between the treatment and placebo groups.(39)

 

Visual Health

OPCs have been reported effective in improving the visual performances after glare as well as the visual adaptation.(29) An open trial of 147 individuals with retinopathy were administered OPCs from grape seed (100mg) daily.(30) The authors reported successful treatment of exudations secondary to hypoxia. The matrix metalloproteinases (MMP's), a protein which plays a key role in the extracellular matrix turnover, is thought to be involved in ocular pathologies such as glaucoma, diabetic retinopathy, macular degeneration, vitreous degeneration and corneal stroma ulceration.(31) An in vitro study using OPCs from grape seed was reported to inhibit this type III collagenase activity and may be beneficial in reducing the damaging effects on ocular structures.(32)

Other Uses

Laboratory studies have found that grape seed extract may be beneficial in oral health, positively affected the in vitro demineralization and/or remineralization processes of artificial root caries lesions and also inhibiting matrix metalloproeinases (MMPs) produced by inflammatory cells in response to gram (-) periodontopathogens.(58),(59)

References

  1. Leung A, et al. Encylopedia of Common Natural Ingredients Used in Foods, Drugs, and Cosmetics. New York: Wiley-Interscience Publication; 1996:288-89.
  2. View Abstract: Bagchi D, et al. Oxygen Free Radical Scavenging Abilities of Vitamins C and E, and a Grape Seed Proanthocyanidin Extract in Vitro. Res Commun Mol Pathol Pharmacol. 1997;95(2):179-89.
  3. Maffei Facino R, et al. Regeneration of Endogenous Antioxidants, Ascorbic Acid, Alpha Tocopherol, by the Oligomeric Procyanide Fraction of Vitus vinifera L:ESR Study. Boll Chim Farm. 1997;136(4):340-44.
  4. View Abstract: Fine AM. Oligomeric Proanthocyanidin Complexes: History, Structure, and Phytopharmaceutical Applications. Altern Med Rev. Apr2000;5(2):144-51.
  5. View Abstract: Das DK, Sato M, Ray PS, et al. Cardioprotection of Red Wine: Role of Polyphenolic Antioxidants. Drugs Exp Clin Res. 1999;25(2-3):115-20.
  6. View Abstract: Boss PK, et al. Expression of Anthocyanin Biosynthesis Pathway Genes in Red and White Grapes. Plant Mol Biol. 1996;32(3):565-69.
  7. Bombardelli E, Morazzoni P. Vitis vinifera, L. Fitoterapia. 1995;66(4):291-317.
  8. View Abstract: Maffei Facino R, et al. Free Radicals Scavenging Action and Anti-enzyme Activities of Procyanidines from Vitis vinifera. A Mechanism for Their Capillary Protective Action. Arzneim-Forsch/Drug Res. 1994;44(5):592-601.
  9. View Abstract: Fauconneau B, et al. Comparative Study of Radical Scavenger and Antioxidant Properties of Phenolic Compounds from Vitis vinifera Cell Cultures Using in Vitro Tests. Life Sci. 1997;61(21):103-10.
  10. View Abstract: Frankel EN, et al. Inhibition of Oxidation of Human Low-density Lipoprotein by Phenolic Substances in Red Wine. Lancet. 1993;341(8843):454-57.
  11. View Abstract: Robert AM, et al. The Effect of Procyanidolic Oligomers on Mesenchymal Cells in Culture. II --Attachment of Elastic Fibers to the Cells. Pathol Biol. (Paris). 1990;38(6):601-07.
  12. Jonadet M, et al. Anthocyanosides Extracted from Vitis vinifera, Vaccinium myrtillus and Pinus maritimus. I. Elastase-inhibiting Activities in Vitro. II. Compared Angioprotective Activities in Vivo. J Pharm Belg. 1983;38(1):41-46.
  13. Baruch J. Effect of Endotelon in Postoperative Edema. Results of a Double-blind Study Versus Placebo in 32 Female Patients. Ann Chir Plast Esthet. 1984;29(4):393-5.
  14. View Abstract: Zafirov D, Bredy-Dobreva G, Litchev V, et al. Antiexudative and Capillaritonic Effects of Procyanidines Isolated from Grape Seeds (V. Vinifera). Acta Physiol Pharmacol Bulg. 1990;16(3):50-4.
  15. View Abstract: Blazso G, Gabor M. Oedema-inhibiting Effect of Procyanidin. Acta Physiol Acad Sci Hung. 1980;56(2):235-40.
  16. Thebaut JF, Thebaut P, Vin F. Study of Endotelon in Functional Manifestations of Peripheral Venous Insufficiency. Gaz Med France. 1985;92:96-100.
  17. View Abstract: Royer RJ, Schmidt CL. Evaluation of Venotropic Drugs by Venous Gas Plethsymograhy. A Study of Proanthocyanidolic Oligomers. Sem Hop. 1981;l57:2009-2013.
  18. Dartenuc JY, Marache P, Choussat H. Capillary Resistance in Geriatry. A Study of a Microangioprotector - Endotelon. Bord Med. 1980;13:903-907.
  19. View Abstract: Chang WC, et al. Inhibition of Platelet Aggregation and Arachidonate Metabolism in Platelets by Procyanidins. Prostaglandins Leukot Essent Fatty Acids. Dec1989;38(3):181-88.
  20. View Abstract: Robert L, et al. The Effect of Procyanidolic Oligomers on Vascular Permeability. A Study Using Quantitative Morphology. Pathol Biol. (Paris). 1990;38(6):608-16.
  21. View Abstract: Bagchi D, Garg A, Krohn RL, et al. Protective Effects of Grape Seed Proanthocyanidins and Selected Antioxidants Against TPA-induced Hepatic and Brain Lipid Peroxidation and DNA Fragmentation, and Peritoneal Macrophage Activation in Mice. Gen Pharmacol. May1998;30(5):771-6.
  22. View Abstract: Lagrue G, et al. A Study of the Effects of Procyanidol Oligomers on Capillary Resistance in Hypertension and in Certain Nephropathies. Sem Hop. 1981;57(33-36):1399-1401.
  23. View Abstract: Fitzpatrick DF, et al. Endothelium-dependent Vasorelaxing Activity of Wine and Other Grape Products. Am J Physiol. 1993;265(2 Pt 2):H774-H778.
  24. Uchida S, et al. Active Oxygen Free Radicals Are Scavenged by Condensed Tannins. Prog Clin Biol Res. 1988;280:135-38.
  25. View Abstract: Koga T, Moro K, Nakamori K, et al. Increase of Antioxidative Potential of Rat Plasma by Oral Administration of Proanthocyanidin-rich Extract from Grape Seeds. J Agric Food Chem. May1999;47(5):1892-7.
  26. View Abstract: Natella F, Belelli F, Gentili V, Ursini F, Scaccini C. Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. J Agric Food Chem. Dec2002;50(26):7720-5.
  27. View Abstract: Vigna GB, et al. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism. 2003 Oct;52(10):1250-7.
  28. View Abstract: Corbe C, Boissin JP, Siou A. Light Vision and Chorioretinal Circulation. Study of the Effect of Procyanidolic Oligomers (Endotelon). J Fr Ophtalmol. 1988;11(5):453-60.
  29. Verin MMP, Vilda A, Maurin JF. Therapeutic Essay. Retinopathy and OPC. Bord Med. 1978;11:1467-1473.
  30. View Abstract: Huang SH, Adamis AP, Wiederchain DG, et al. Matrix Metalloproteinases and Their Inhibitors in Aqueous Humor. Exp Eye Res. May1996;62(5):481-90.
  31. View Abstract: Barracchini A, Franceschini N, Filippello M, et al. Leukocyanidines and Collagenases: In Vitro Enzyme Inhibition Activity. Clin Ter. Jul1999;150(4):275-8.
  32. View Abstract: Ye X, Krohn RL, Liu W, et al. The Cytotoxic Effects of a Novel IH636 Grape Seed Proanthocyanidin Extract on Cultured Human Cancer Cells. Mol Cell Biochem. Jun1999;196(1-2):99-108.
  33. View Abstract: Castillo J, Benavente-Garcia O, Lorente J, et al. Antioxidant Activity and Radioprotective Effects Against Chromosomal Damage Induced In Vivo by X-rays of Flavan-3-ols (Procyanidins) from Grape Seeds (Vitis vinifera): Comparative Study Versus Other Phenolic and Organic Compounds. J Agric Food Chem. May2000;48(5):1738-45.
  34. View Abstract: Joshi SS, Kuszynski CA, Bagchi M, et al. Chemopreventive Effects of Grape Seed Proanthocyanidin Extract on Chang Liver Cells. Toxicology. Nov2000;155(1-3):83-90.
  35. View Abstract: Ray SD, Kumar MA, Bagchi D. A Novel Proanthocyanidin IH636 Grape Seed Extract Increases In Vivo Bcl-XL Expression and Prevents Acetaminophen-induced Programmed and Unprogrammed Cell Death in Mouse Liver. Arch Biochem Biophys. Sep1999;369(1):42-58.
  36. View Abstract: Maffei Facino R, et al. Procyanidines from Vitis vinifera Seeds Protect Rabbit Heart from Ischemia/Reperfusion Injury: Antioxidant Intervention and/or Iron and Copper Sequestering Ability. Planta Med. 1996;62(6):495-502.
  37. View Abstract: Maffei Facino R, et al. Free Radicals Scavenging Action and Anti-enzyme Activities of Procyanidines from Vitis vinifera. A Mechanism for Their Capillary Protective Action. Arzneim-Forsch/Drug Res. 1994;44(5):592-601.
  38. View Abstract: Hatano T, et al. Effects of Interaction of Tannins with Co-existing Substances. VII. Inhibitory Effects of Tannins and Related Polyphenols on Xanthine Oxidase. Chem Pharm Bull. (Tokyo). 1990;38(5):1224-29.
  39. View Abstract: Bernstein CK, Deng C, Shuklah R, et al. Abstract 1018 Double Blind Placebo Controlled (DBPC) Study of Grapeseed Extract in the Treatment of Seasonal Allergic Rhinitis (SAR). American Academy of Allergy, Asthma and Immunology (AAAAI) 57th Annual Meeting. Mar2001.
  40. Veluri R, Singh RP, Liu Z, Thompson JA, Agarwal R, Agarwal C. Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells. Carcinogenesis. Jul 2006;27(7):1445-1453. Epub 10 Feb 2006.
  41. Chacón MR, Ceperuelo-Mallafré V, Maymó-Masip E, et al. Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro. Cytokine. Aug 2009;47(2):137-142. Epub 27 Jun 2009.
  42. Wang YJ, Thomas P, Zhong JH, Bi FF, Kosaraju S, Pollard A, Fenech M, Zhou XF. Consumption of grape seed extract prevents amyloid-beta deposition and attenuates inflammation in brain of an Alzheimer's disease mouse. Neurotox Res. Jan 2009;15(1):3-14. Epub 10 Feb 2009.
  43. Ma L, Gao HQ, Li BY, Ma YB, You BA, Zhang FL. Grape seed proanthocyanidin extracts inhibit vascular cell adhesion molecule expression induced by advanced glycation end products through activation of peroxisome proliferators-activated receptor gamma. J Cardiovasc Pharmacol. May 2007;49(5):293-298.
  44. Rabovsky A, Cuomo J, Eich N. Measurement of plasma antioxidant reserve after supplementation with various antioxidants in healthy subjects. Clin Chim Acta. Sep 2006;371(1-2):55-60. Epub 6 Mar 2006.
  45. Pérez-Jiménez J, Saura-Calixto F. Grape products and cardiovascular disease risk factors. Nutr Res Rev. Dec 2008;21(2):158-173. Review.
  46. Leifert WR, Abeywardena MY. Cardioprotective actions of grape polyphenols. Nutr Res. Nov 2008;28(11):729-737. Review.
  47. Sano A, Uchida R, Saito M, Shioya N, Komori Y, Tho Y, Hashizume N. Beneficial effects of grape seed extract on malondialdehyde-modified LDL. J Nutr Sci Vitaminol (Tokyo). Apr 2007;53(2):174-182.
  48. Sivaprakasapillai B, Edirisinghe I, Randolph J, Steinberg F, Kappagoda T. Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome. Metabolism. Dec 2009;58(12):1743-1746. Epub 15 Jul 2009.
  49. Hsu CP, Lin YH, Chou CC, Zhou SP, Hsu YC, Liu CL, Ku FM, Chung YC. Mechanisms of grape seed procyanidin-induced apoptosis in colorectal carcinoma cells. Anticancer Res. Jan 2009;29(1):283-289.
  50. Shang XJ, Yin HL, Ge JP, Sun Y, Teng WH, Huang YF. [Grape seed extract induces morphological changes of prostate cancer PC-3 cells] Zhonghua Nan Ke Xue. Dec 2008;14(12):1090-1093. Chinese.
  51. Akhtar S, Meeran SM, Katiyar N, Katiyar SK. Grape seed proanthocyanidins inhibit the growth of human non-small cell lung cancer xenografts by targeting insulin-like growth factor binding protein-3, tumor cell proliferation, and angiogenic factors. Clin Cancer Res. 1 Feb 2009;15(3):821-31.
  52. Kijima I, Phung S, Hur G, Kwok SL, Chen S. Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression. Cancer Res. 1 Jun 2006;66(11):5960-5967.
  53. Mantena SK, Baliga MS, Katiyar SK. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. Carcinogenesis. Aug 2006;27(8):1682-16891. Epub 5 Apr 2006.
  54. Li W, Xu B, Xu J, Wu XL. Procyanidins produce significant attenuation of doxorubicin-induced cardiotoxicity via suppression of oxidative stress. Basic Clin Pharmacol Toxicol. Mar 2009;104(3):192-197. Epub 8 Jan 2009.
  55. Wen W, Lu J, Zhang K, Chen S. Grape seed extract inhibits angiogenesis via suppression of the vascular endothelial growth factor receptor signaling pathway. Cancer Prev Res (Phila Pa). Dec 2008;1(7):554-561.
  56. Gao N, Budhraja A, Cheng S, Yao H, Zhang Z, Shi X. Induction of apoptosis in human leukemia cells by grape seed extract occurs via activation of c-Jun NH2-terminal kinase. Clin Cancer Res. 1 Jan 2009;15(1):140-149.
  57. Brooker S, Martin S, Pearson A, et al. Double-blind, placebo-controlled, randomised phase II trial of IH636 grape seed proanthocyanidin extract (GSPE) in patients with radiation-induced breast induration. Radiother Oncol. Apr 2006;79(1):45-51. Epub 20 Mar 2006.
  58. Wu CD. Grape products and oral health. J Nutr. Sep 2009;139(9):1818S-1823S. Epub 29 Jul 2009. Review.
  59. La VD, Bergeron C, Gafner S, Grenier D. Grape seed extract suppresses lipopolysaccharide-induced matrix metalloproteinase (MMP) secretion by macrophages and inhibits human MMP-1 and -9 activities. J Periodontol. Nov 2009;80(11):1875-1882.

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