In this blog-article, i will review one of red wine’s key health promoting molecules, proanthocyanidins, also known as pygnogenol. As long as wine is made traditionally with its skin and especially grape seeds in the fermentation bin, these antioxidant molecules will bestow upon red wine lots of health benefits. (Section A). Thereafter, I will analyse its therapeutic relevance and clinical dosing. (Section B)
Having looked at the scientific litteration, I can confirm that there is an abundance of animal and in vitro studies that are complemented by epidemiological evidence and human studies that corroborate the health benefits of this polyphenol, chief among these being its antioxidant effects.
Proanthocyanidins (ie, technically oligomeric proanthocyanidins or OPC) constitute a class of flavonoids. Formerly called “condensed tannins,” all proanthocyanidins are chemically similar, the only differences being slight changes in shape and attachments of their polyphenol rings. In nature, multiple and diverse types of proanthocyanidins are always found together, in particular in grape seeds (Vitis vinifera) and the white pine (Pinus maritima, P. pinaster) of southern Europe. (1) When grape juice is fermented in white pine or blackjack oak, that potentiates its effects. Comparatively, grape seeds can have 7 to 15 percent more OPCs than pine bark. (2)
An antioxidant quenches free radicals (3) and potentiate other antioxidants and vitamins. (4) Thus, because cancer, cardiovascular diseases and aging are in part caused by an onslaught or prooxidants, taking small amounts of quality red wine each day or most days makes sense.
OPCs also help to inhibit atherosclerosis. The role of oxidation in most chronic diseases and aging, including in atherogenesis has been established for years.–development of hardened arteries–is becoming clearer. In clear, oxidized low-density lipoproteins (LDL) damage the cells that line blood vessel walls, thus making them harder, by provoking numerous responses including but not limited to inflammation, smooth muscle cell proliferation and clotting mechanisms. (See HMI’s blog-article on holistic cardiology for a better understanding of the mechanisms).
Text under construction
In this perspective, proanthocyanidins were shown to offer hope. A grape seed extract with 50 percent OPCs and 50 percent phenolic acids prevented such oxidation of pig LDL in vitro.  OPCs may also prevent atherosclerosis in other ways. For example, two recent in vitro studies found that a patented pine bark extract modulated the release of nitric oxide, which affected the dilation diameter of blood vessels. [9,10]
Researchers compared the effects of patented pine bark extract OPCs with aspirin on smoking-induced platelet aggregation in three groups of smokers. They found that platelet aggregation was inhibited by both 500 mg aspirin as well as 100125 mg pine bark extract. Because of the increased bleeding time caused by aspirin, the authors conclude that pine bark offers an “advantageous risk-benefit ratio.” [ 11]
OPCs appear to inhibit several factors contributing to atherosclerosis, but do they actually prevent the condition? Yes, at least according to recent animal experiments. Researchers at a soy sauce manufacturing plant in Noda City, Japan, fed rabbits a diet that caused high blood cholesterol and severe atherosclerosis in the control animals. Their blood levels of peroxides–a measure of oxidation–increased by 10 times. Another group of rabbits ate the same diet but supplemented with grape seed OPC extract amounting to either 0.1 or 1 percent of their diet. The supplemented rabbits also developed high cholesterol levels; however, they had no detectable peroxides in their blood. Even more impressive, their blood vessels had no atherosclerosis whatsoever.  These findings have been confirmed by other research on grape seed and pine bark OPCs. [13,14]
Although promising data on OPCs and atherosclerosis prevention primarily come from test tube and animal studies, epidemiological research may lend credence to the value of OPCs in human health. In fact, proanthocyanidins may help explain the “French Paradox,” or why low coronary heart disease rates exist in French provinces known for high-fat foods and red wine consumption. Red wine could be considered an alcohol tincture of several potent flavonoids, including proanthocyanidins from grape seeds. In a provocative study, Fulvio Ursini, M.D., from the University of Padova, Italy, fed volunteers a high-fat meal with and without red wine. He found post-meal plasma peroxide levels were much lower in those who drank wine. 
Another way OPCs appear to prevent damage wrought by atherosclerosis is by preventing ischemic reperfusion injury. In atherosclerosis, a clot can restrict blood flow to the heart. If this clot is broken up, blood comes pouring back into the tissue. That process, paradoxically, results in an incredible amount of free radical damage. M. Sato, M.D., of the University of Connecticut School of Medicine in Farmington, subjected animal hearts to blood-flow constriction and release. Compared with control animals, the animals supplemented with a patented grape seed extract (100 mg/kg of body weight) had 38 percent less heart damage and 50 percent less creatine kinase release, a marker of tissue damage. [16 ]
OPC cancer prevention: In vitro studies suggest OPCs also provide cancer protection. OPCs in Vaccinium-family berries, including blueberry, lingonberry and cranberry, block tumor growth by preventing protein synthesis in tumor cells, which prevents them from multiplying.  Also in the laboratory, barley bran OPCs transformed human myeloid leukemia cells into cells that were no longer cancerous.  Another in vitro study found that a patented grape seed extract killed cancer cells; inhibited growth of human breast, lung, stomach and myelogenous leukemia cells by up to 73 percent; and enhanced normal cell growth. 
In additional cancer areas, people exposed to tobacco smoke ingest highly carcinogenic nitrosamines. Recent research indicates witch hazel bark (Hamamelis virginiana) OPCs prevent nitrosamine formation and their ability to mutate DNA. 
Betel nut (Areca catechu), a stimulant chewed by millions of Asians, also contains OPCs. In a small study, two people consumed 300 mg each of the nitrosamine precursors sodium nitrate and L-proline. Afterwards, their urine contained 14.7 and 10.9 mcg of N-nitroso-L-proline. In the second experiment, the subjects consumed the nitrosamine precursors and chewed a quarter of a betel nut. Their subsequent urine samples showed no nitrosamines. The researchers note that OPCs may play a major role in natural cancer prevention. 
Proanothocyanins may also protect against viruses. In in vitro studies, OPCs from hawthorn (Crataegus oxyacantha) killed the herpes (HSV-1) and HIV viruses. [22,23]
Venous insufficiency is a common condition in which the veins and muscles, primarily in the legs, are not able to properly return blood to the heart. Walking becomes painful and difficult. Italian research has shown that grape seed extract can help. Twenty-four patients with chronic venous insufficiency were treated with 100 mg grape seed extract daily. The improvements were visible in 10 days: 70 percent of the patients had less edema and 50 percent had less pain.  Bilberry and other bioflavonoids have been used for vein problems for many years in Europe. They may have a similar mechanism of action, or their active constituents may include OPCs.
Proanthocyanidins also protect the body from toxins. Acetaminophen, the active ingredient in Tylenol, is a potent liver toxin, annually causing 75,000 cases of poisoning requiring hospitalization in the United States. Animal experiments showed that a week of pretreatment with 100 mg/kg of a patented grape seed extract prevented liver damage from acetaminophen. Organ damage was assessed by studying liver cells for damage and also by monitoring the animal’s health. 
Proanthocyanidins and natural beauty: may do even more than prevent disease; they may make us more youthful looking. Oxidation damage causes most visible signs of aging in our skin. By preventing this damage, skin will stay younger looking. One way to achieve this is to reduce the damaging effects of ultraviolet (UV) light. Sunscreen products have incorporated a variety of antioxidants with the intent that they will prevent sun injury to the skin. In one study, grape seed OPCs exerted a solo antioxidant effect at a level of potency on a par with vitamin E–protecting different polyunsaturated fatty acids from UV light-induced lipid peroxidation.26 In this same study, the grape OPCs synergistically interacted with vitamin E, recycling the inactivated form of the vitamin into the active form and thus acting as a virtual vitamin E extender.
Part of the aging process is the degradation of skin by the enzyme elastase, which is released with the inflammatory response. OPCs specifically block elastase, thus maintaining the integrity of elastin. 
OPCs may even help us grow a thick head of hair, if the results of animal experiments apply to humans. Japanese
researchers shaved mice and found that 40 percent of their hair grew back naturally. When a 1 percent solution of any of three proanthocyanidins was applied to the skin, however, between 70 and 80 percent of the hair grew back. Test tube studies confirm that OPCs actually stimulate the hair keratinocytes to produce three times more hair than the controls. . A little red wine in thy hair then…
this bottom out
Protecting us from atherosclerosis, cancer and environmental toxins while helping us maintain a youthful appearance–is there anything more we could ask from a plant compound? What about a sweet taste? Proanthocyanadins deliver here, too. Rhizomes of the Indonesian fern Selliguea feei contain the proanthocyanidin selligueain A, which is about 35 times as sweet as sugar. 
The health benefits of OPCs have prompted some researchers to suggest they should have an official “recommended optimal intake.” Doses used in many animal experiments are 100 mg/kg of body weight, which is equivalent to between 50 and 200 mg for the average adult, according to Bagchi. With the prevalence of refined foods today, our intake is much lower than the amount we likely evolved with, but there has been little attempt to quantify current OPC intake. One exception is the German National Food Consumption Survey, which found Bavarians consume an average of 3.7 mg/day of OPC.  According to Bagchi, one glass of red wine contains 45 mg of OPC, while white wine contains only a small amount.
Proanthocyanidins show tremendous promise. However, we still have much research to do before there is a single pill to keep us feeling healthy and looking youthful. Fortunately, consumers don’t need to wait for the results of large-scale clinical trials to begin enjoying the benefits of proanthocyanidins. These compounds are available today in food and supplements.
Reference and Precision Notes
(1). OPCs are also abundant in blackjack oak (Quercus marilandica), horse chestnut (Aesculus hippocastanum), witch hazel (Hamamelis virginiana) and hawthorn (Crataegus oxyacantha), as well as in apples, berries, barley (and beer made from it), bean hulls, chocolate, rhubarb, rose hips and sorghum.
(2). Masquelier J. Historical note on OPC. France: Martillac; 1991.
(3). A recent mouse study by Debasis Bagchi, Ph.D., and colleagues at the Creighton University School of Pharmacy in Omaha, Neb., also found that a patented grape seed extract protected tissue from oxidation better than the antioxidant vitamins C and E or beta-carotene. In Bagchi’s study, some mice served as controls while others were supplemented with either 25100 mg/kg body weight grape seed OPC extract, 100 mg/kg vitamin C, 100 mg/kg vitamin E or 50 mg/kg beta-carotene. They were then exposed to the oxidant and cancer promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA), which causes free radical production in white blood cells, liver and brain lipid peroxidation, and DNA fragmentation. The animals treated with 100 mg/kg grape seed extract demonstrated up to 70 percent protection from free radicals while those treated with other antioxidants had protection ranging from 15 to 47 percent. The grape seed-treated mice also had up to 50 percent protection from DNA fragmentation, compared with 10 to 31 percent protection provided by the other antioxidants. (Bagchi D, 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 1998 May;30(5):771-6). In an in vitro experiment testing the response of human mouth cells to the free radical damage caused by smokeless tobacco, grape seed OPCs were a stronger antioxidant than vitamins C and E, even when the two vitamins were combined. (Bagchi M, et al. Smokeless tobacco, oxidative stress, apoptosis, and antioxidants in human oral keratinocytes.
Free Radic Biol Med 1999 Apr;26(7-8):992-1000.)
(4). In one in vitro study, the OPCs in a patented pine bark extract prolonged the life span of vitamin C by 400 percent. Cf Cossins E, et al. ESR studies of vitamin C regeneration, order of reactivity of natural source phytochemical preparations. Biochem Mol Biol Int 1998 Jul;45(3):583-97. Another in vitro study showed that exposing blood vessel linings to pine bark OPCs boosted their vitamin E content by 15 percent. Virgili F, et al. Procyanidins extracted from pine bark protect alpha-tocopherol in ECV 304 endothelial cells challenged by activated RAW 264.7 macrophages: role of nitric oxide and peroxynitrite. Grape seed has also shown recycling and potentiating effects. The test tube-based activity of vitamin E, in a system mimicking cell membranes, has shown enhancement by grape seed OPCs. (Maffei F, et al. Sparing effect of procyanidins from Vitis vinifera on vitamin E: in vitro studies. Planta Med 1998; 64: 343-347)
8. Fremont L, et al.
Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids.
Life Sci 1999;64(26):2511-21.
9. Fitzpatrick DF, et al. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol 1998 Oct;32(4):509-15.
10. Virgili F, et al.
Procyanidins extracted from Pinus maritima (Pycnogenol): scavengers of free radical species and modulators of nitrogen monoxide metabolism in activated murine RAW 264.7 macrophages.
Free Radic Biol Med 1998 May;24(7-8):1120-9.
11. Putter M, et al.
Inhibition of smoking-induced platelet aggregation by aspirin and Pycnogenol.
Thromb Res 1999 Aug 15;95(4):155-61.
12. Yamakoshi J, et al.
Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits.
Atherosclerosis 1999 Jan;142(1):139-49.
13.Ursini F, et al.
Optimization of nutrition: polyphenols and vascular protection.
Nutr Rev 1999, 57:8, 241-8.
14. Rong Y, et al.
Pycnogenol protects vascular endothelial cells from t-butyl hydroperoxide induced oxidant injury.
Biotechnol Ther 1994-95;5(3-4):117-26.
15. Ursini F, et al.
Post-prandial plasma peroxides: a possible link between diet and atherosclerosis.
Free Radic Biol Med 1998; 25:250-2.
16. Sato M, Maulik G.
Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury.
J Mol Cell Cardiol 1999 Jun;31(6):1289-97.
17. Bomser J, Madhavi DL.
In vitro anticancer activity of fruit extracts from Vaccinium species.
Planta Med 1996 Jun;62(3):212-6.
18. Tamagawa K, Fukushima S.
Proanthocyanidins from barley bran potentiate retinoic acid-induced granulocytic and sodium butyrate-induced monocytic differentiation of HL60 cells.
Biosci Biotechnol Biochem 1998 Aug;62(8):1483-7.
19. Ye X, Krohn RL.
The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells.
Mol Cell Biochem 1999 Jun;196(1-2):99-108.
20. Dauer A, et al.
Proanthocyanidins from the bark of Hamamelis virginiana exhibit antimutagenic properties against nitroaromatic compounds.
Planta Med 1998 May;64(4):324-7.
21. Stich HF, Ohshima H.
Inhibitory effect of betel nut extracts on endogenous nitrosation in humans.
J Natl Cancer Inst 1983 Jun;70(6):1047-50.
22. Erdelmeier CA, Cinatl J.
Antiviral and antiphlogistic activities of Hamamelis virginiana bark.
Planta Med 1996 Jun;62(3):241-5.
23. De Bruyne T, Pieters L.
Biological evaluation of proanthocyanidin dimers and related polyphenols.
J Nat Prod 1999 Jul;62(7):954-8.
24. Costantini A, et al.
Clinical and capillaroscopic evaluation of chronic uncomplicated venous insufficiency with procyanidins extracted from vitis vinifera.
Minerva Cardioangiol 1999 Jan-Feb;47(1-2):39-46.
25. Ray SD, et al.
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 1999 Sep 1;369(1):42-58.
26. Carini M., et al.
The protection of polyunsaturated fatty acids in micellar systems against UVB-induced photo-oxidation by procyanidins from Vitis vinifera L., and the protective synergy with vitamin E.
Intl J Cosmetic Sci 1998;20:203-15.
27. Meunier MT, Villie F.
The interaction of Cupressus sempervirens L. proanthocyanidolic oligomers with elastase and elastins.
J Pharm Belg 1994 Nov-Dec;49(6):453-61.
28. Takahashi T, et al.
Procyanidin oligomers selectively and intensively promote proliferation of mouse hair epithelial cells in vitro and activate hair follicle growth in vivo.
J Invest Dermatol 1999 Mar;112(3):310-6.
29. Baek NI, Chung MS.
Selligueain A, a novel highly sweet proanthocyanidin from the rhizomes of Selliguea feei.
J Nat Prod 1993 Sep;56(9):1532-8.
30. Linseisen J, et al.
Flavonoid intake of adults in a Bavarian subgroup of the national food consumption survey.
Z Ernahrungswiss 1997 Dec;36(4):403-12
Proanthocyanidins in health and disease.
In a preliminary report, three patients with chronic pancreatitis were treated with grape seed extract in the amount of 100 mg 2–3 times per day. The frequency and intensity of abdominal pain was reduced in all three patients, and there was a resolution of vomiting in one patient.