The Power of Procyanidins

the REAL French Paradox

Imagine that in future procyanidin pills are recommended just as aspirin is today. Such are the healthy properties of procyanidin, this is a possibility. Procyanidins have been identified as high performance, low toxicity and highly bio-available health protecting compounds. Some red wines have been identified as containing extremely high concentrations of this powerful heart healthy compound.
 
A steady stream of animal and in vitro studies supplemented by epidemiological evidence and human studies reveal numerous health benefits. Chief among the benefits is antioxidant protection against heart disease and some cancers.
 
This report, compiled by Rob Lauder, www.Lifestylewines.co.nz, is a summary of some of the considerable international research that has been conducted into the health benefits of procyanidins.
 

Consider these Imperatives

Procyanidins have been identified as high performance, low toxicity and highly bio-available.

Procyanidins, available in some red wines, 70% cocoa solids dark chocolate and other foods, is a healthy compound in the highest doses and part of a natural diet - NOT an unnaturally high-dose supplement (as with other compounds) that is not proven to be safe over the long term and possibly not even absorbed fully as has been observed with some supplements   Research identifies that after two weeks of a daily glass of procyanidin rich red wine positive support for cardiovascular health was observed, including reduced blood pressure. This is good news for protection against heart disease and strokes.

The health statistics are significant and important – Almost half of us die of HEART DISEASE - World Health Organization 50% of STROKES are caused by high blood pressure

"Nowhere in the world where populations are given drug treatments to manage cardiovascular health, have they achieved the low levels of heart disease related deaths, as occurs in Gers (France)where they drink these wines"Professor Giovanni de Gaetano, M.D., Ph.D,

In south west France where they have make and consume wines high in procyanidins, census data shows there is twice the number of 90 year old males as the national average.

Perhaps there is significance for our health that with today's prevalence of processed and refined foods, our consumption of procyanidins is much lower than the amount we likely evolved with!

In New Zealand, consumers who begin a strategy of a daily glass of the wines of south west France are experiencing blood pressure improvements consistent with the research. This occurs without change to lifestyle, diet, exercise or medication.   Procyanidins provide the same benefits, naturally, as would possibly be achieved with the “polypill”. The polypill is a mixture of already in use drugs that is intended to prevent heart attacks and strokes. Governments and drug companies internationally are trying to develop such a drug, to be taken daily, that is aimed to protect older populations from heart disease. In procyanidins it already exists in the natural form.

 

What is Procyanidin

Procyanidins are a mixture of antioxidant molecules, variously called -

• procyanidins
• proanthocyanidins,
• oligomeric procyanthocyanidins(OPC)
• proanthocyanidolic oligomers (PCO)
• leukocyanidins

Procyanidin, a polyphenol compound with strong bioactivity and pharmacologic activity, resides widely in grape seeds, hawthorn, pine bark and other foods and plants. A number of potential mechanisms of procyanidin have emerged. These include, serving as an important in vivo antioxidant, decreasing blood pressure, reducing risk of cancer, inhibiting bacteria, and so on. In recent years, the beneficial health and longevity effects of procyanidin on the human body has been extensively researched internationally.
 
Research has reported that procyanidin has multiple anticancer effects, notably for being toxic to cancer cells, on cancers such as cutaneous carcinoma, oral carcinoma, breast carcinoma, bronchogenic carcinoma, liver carcinoma, prostate carcinoma, pancreatic carcinoma, gastric carcinoma, and more, along with growth promoting effects on normal cells.
 
Commonly referred to as OPC in scientific circles, procyanidin is expert at treating vascular diseases because it actually increases the structural strength of weakened blood vessels, maintaining their permeability and elasticity. This occurs because OPCs help neutralize the underlying chemical cause (oxidation of living cells by free radicals) that promotes many diseases.
 
OPC is one of the most potent antioxidants known -- 50 times more powerful than vitamin E and 20 times more so than vitamin C, according to some tests.
 
OPCs are a group of flavonoids which, until 1936, were known as Vitamin P. The discovery of proanthocyanidins is attributed to the Frenchman, Professor Jacques Masquelier, who devoted a half century to researching them. He also invented techniques for extracting them from plants. Grape seeds and pine bark are two of the richest known sources of OPCs. Grape seeds can have 7 to 15 percent more OPCs than pine bark and can be more potent¹. Procyanidins have also been identified as abundant in walnuts husks, cranberries, certain apple varieties, pomegranates, horse chestnuts, hazelnut leaves, hawthorn, rhubarb and barley (also beer made from barley). However tests have shown that significant variation in procyanidin content can exist within these foods. This is demonstrated with red wines and the tests performed by Professor Roger Corder. It is interesting to note that it is procyanidin that is the high dose polyphenol in the much discussed healthy dark chocolate (70% cocoa solids).
 
All OPCs are chemically similar, the only differences being slight changes in shape and attachments of their polyphenol rings. In nature, a jumble of different procyanidins is always found together, ranging from individual units to complex molecules of many linked units (oligomers).  Note that resveratrol is a non-flavonoid polyphenol.
 

Toxicity

In 2002 a safety evaluation of OPC rich grape seed extract was undertaken to determine the toxicology of proanthocyanidins, especially in oral administration. In the studies, proanthocyanidin-rich extract from grape seeds was subjected to a series of toxicological tests to document its safety for use in various foods.²
 
The grape seed extract (GSE) was examined for acute and sub chronic oral toxicity and for mutagenic potential. The tests were undertaken using mice and rats. No evidence of acute oral toxicity at dosages of 2 and 4 g/kg, and no evidence of mutagenicity was found. Administration of GSE as a dietary admixture at levels of 0.02, 0.2 and 2% (w/w) to the rats for 90 days did not induce noticeable signs of toxicity. The no-observed-adverse-effect level (NOAEL) of GSE in the sub chronic toxicity study was 2% in the diet (equal to 1410 mg/kg body weight/day in males and 1501 mg/kg body weight/day in females). The results of the studies indicate a lack of toxicity and support the use of proanthocyanidin-rich extract from grape seeds for various foods.
 

Cardiovascular Disease

Roger Corder, Professor of Experimental Therapeutics at the William Harvey Research Institute in London, identified that procyanidin in some red wine is responsible for the reduction in the risk of coronary heart disease and the lowering of overall mortality in regular, moderate consumers of red wine.³
 
On 30 November 2006 a research article was published in “Nature” magazine on the significant health-giving benefits of some red wines.
 
Epidemiological studies revealed that two populations in Europe have exceptional longevity. People in the Nuoro province of Sardinia and those in the department of Gers in the midi-Pyrenees in the south west of France, especially men, have a significantly greater longevity than the national average. These populations do NOT consume the "Mediterranean Diet".
 
Corder and his team looked at these populations and their lifestyles and determined that there was something about the wines in these regions and so began a study of the components and compounds in the wines. They designed their study so they wouldn't know which compound worked best until the end of the trial. The researchers cultured endothelial cells and then added small amounts of red wine. The team used chromatography to isolate and measure the biological activity of each polyphenol in red wine. In hundreds of experiments, using wines from all over the world, procyanidin proved to be the best at regulating production of endothelin-1 to achieve the most favourable levels. Procyanidins suppressed overproduction by 50 percent.
 
Other compounds, such as resveratrol (a non-flavanoid polyphenol) and quercetin, were found to have an irrelevant effect.
 
The researchers discovered that red wines from those two regions are particularly high in procyanidins. This is because a large proportion of the grapes used to produce the local wines in these regions are the flavanoid-rich Tannat. Furthermore the traditional wine-making techniques in the south west of France, where the grape skins and seeds remain in contact with the juice for an extended period during fermentation and maceration, significantly increased the concentration of procyanidins in the red wines.
 
The groundbreaking research by Professor Roger Corder and colleagues established that:

1. Procyanidins lower blood pressureby suppressing endothelin-1,

a peptide that has an undesirable vasoconstriction effects. They also increase nitric oxide in the blood causing vasodilation and increased blood flow

1. Procyanidins decrease platelet aggregation,

thus preventing clot formation and blockage of arteries

1. Procyanidins prevent oxidation of LDL-cholesterol.

High blood cholesterol levels are a major risk factor for heart disease because LDL-cholesterol can accumulate in the artery wall where after oxidation it causes inflammation and the formation of plaque. When LDL-cholesterol is protected from oxidation it is less likely to cause atherosclerosis.

1. Very few wines have exceptionally high concentrationsof procyanidins.

Corder tested many wines and identified only a few regions of the world that consistently have the highest concentrations of procyanidins

 

Powerful Antioxidants

OPCs have a deservedly high reputation as antioxidants that quench free radicals and potentiate other antioxidants. In one in vitro study OPCs prolonged the life span of vitamin C by 400 percent⁴. Another in vitro study showed that exposing blood vessel linings to pine bark OPCs boosted their vitamin E content by 15 percent.⁵ 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.⁶
 
A mouse study, at the Creighton University School of Pharmacy in Omaha, Neb., found that a patented grape seed extract protected tissue from oxidation better than the antioxidant vitamins C and E or beta-carotene⁷.
 
Grape seed OPCs were observed to be a stronger antioxidant than vitamins C and E, even when the two vitamins were combined, in an in vitro experiment testing the response of human mouth cells to the free radical damage caused by smokeless tobacco.⁸
 

Preventing Atherosclerosis

The role of oxidation in the development of hardened arteries (atherogenesis) is increasingly understood. Oxidized LDL (low-density lipoproteins) cholesterol provokes numerous adverse responses including inflammation, smooth muscle cell proliferation and clotting mechanisms to the cells that line blood vessel walls. All this leads to atherosclerosis.
 
A grape seed extract with 50 percent OPCs and 50 percent phenolic acids prevented such oxidation of pig LDL in vitro.⁹ OPCs may also prevent atherosclerosis in other ways. For example, two in vitro studies found that a patented pine bark extract modulated the release of nitric oxide, which affected the dilation diameter of blood vessels.^10,11.
 
Similarly this is one of Corder’s primary finding – that high blood cholesterol levels are a major risk factor for heart disease and stroke because LDL-cholesterol can accumulate in the artery wall where after oxidation it causes inflammation and the formation of plaque. When LDL-cholesterol is protected from oxidation it is less likely to cause atherosclerosis.
 
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 100-125 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."¹²
 
Increasingly, studies are raising questions of safety with long term use of aspirin by the “worried well” to prevent heart attach. Studies have found sustained use almost doubles the risk of admittance to hospital due to internal bleeding.
 
OPCs appear to inhibit several factors contributing to atherosclerosis, but do they actually prevent the condition? Yes, is the conclusion 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.¹³  These findings have been confirmed by other research on grape seed and pine bark OPCs.^14,15  This emphasizes that the issue is the degree of oxidation of the cholesterol and not high cholesterol itself per se.
 
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, OPCs 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. These populations do NOT have a ‘Mediterranean diet’.
 
The French Paradox was first proposed by Dr Serge Renaud in 1991. Dr Renaud's attendance at the Wine & Health Symposium (headlined by Professor Corder) in Pau, France, in 2007 was confirmation he supports Corder’s research that identified procyanidins as the explanation of The French Paradox. Corder concludes from his research and epidemiological studies that OPCs are the cause of the exceptional longevity in some populations in south-west France and Sardinia. Corder proposes this is the REAL French Paradox.
 
Red wine could be considered an alcohol tincture of several potent flavonoids, including OPCs from grape seeds. 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.¹⁶
 
OPCs also appear to prevent damage caused by atherosclerosis by preventing ischemic reperfusion injury. With 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 had 38 percent less heart damage and 50 percent less creatine kinase release, a marker of tissue damage.¹⁷
 

Breast Cancer

Studies have shown that the production of estrogens in breast cancer tissue plays a major role in tumor progression. In vitro studies have shown that procyanidin B dimers were able to reduce androgen-dependent tumor growth, indicating that these chemicals reduce the production of estrogens from the androgen substrates.
 
In a study researchers demonstrated that procyanidin B dimers in red wine could be used as chemopreventive agents against breast cancer by inhibiting the conversion of androgens to estrogens in breast tissues. The researchers estimated that a single four-ounce glass of red wine daily could provide enough procyanidin B dimer to inhibit aromatase activity in an average post-menopausal woman. ¹⁸
 

Prostate Cancer Protection

A study concluded that procyanidin can induce apoptosis (self-destruction of cancer cells) and necrosis (death of cells as a result of an outside agent) of prostate cancer PC-3 cells in a mitochondrion-dependent manner. ¹⁹. The significant changes observed occurred to varying degrees according to dose and time dependant manners within a few hours of treatment beginning.
 
Prostate carcinoma (PCa) is one of the most prevalent cancers in men. The rate of PCa-related death increases every year. Until now, there has been no effective therapy that has an obvious effect on extending the life span of PCa sufferers. Other traditional therapies, such as radiotherapy, chemotherapy, and surgery, cannot prevent PCa from developing into metastatic clones and becoming androgen-refractory. Therefore, developing new therapeutic strategies targeting apoptosis induction would be of real value in controlling the proliferation as well as the invasiveness of advanced PCa.
 
The study aimed to determine whether procyanidin-induced apoptosis and necrosis of PC-3 cells is related to Mitochondrial membrane potential. The mitochondrion is a structure in the cytoplasm (outside the nucleus) of all cells except bacteria in which food molecules (sugars, fatty acids, and amino acids) are broken down in the presence of oxygen and converted into energy. So as the cell “powerhouse” it is vital to human health.  It is also an important structure within the cells that regulates cell death. The study showed that Mitochondrial membrane potential was significantly reduced in PC-3 cells by treatment with procyanidin. Thus toxicity of procyanidin to these cancer cells was demonstrated.
 

Other Cancer Protection

Other in vitro studies also suggest OPCs provide cancer protection. OPCs in Vaccinium-family berries, including blueberry, lingonberry and cranberry, block tumor growth by preventing protein synthesis in tumor cells, thereby preventing them from multiplying.²⁰ Also in the laboratory, barley bran OPCs transformed human myeloid leukemia cells into cells that were no longer cancerous.²¹ 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.²²
 
Betel nut, a stimulant chewed by millions of Asians, also contains OPCs. In a small study into the inhibitory effect of betel nut extracts on endogenous nitrosation in humans, the researchers noted that OPCs may play a major role in natural cancer prevention.²³
 

Other Health Benefits

Protection again viruses may also occur with OPCs. In vitro studies with OPCs from hawthorn (Crataegus oxyacantha) killed the herpes (HSV-1) and HIV viruses.^24,25
 
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.²⁶ 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.
 
The body is also protected from toxins by OPCs. 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.²⁷
 

Procyanidins and Beauty

More than just disease prevention, OPCs 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.²⁸ 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.²⁹
 
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, between70 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.³⁰
 
The health benefits of OPCs have prompted some researchers to suggest there should be 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. However according to Corder, one glass per day of procyanidin rich red wine provides cardiovascular benefits. This has been the experience of New Zealand consumers of the wines from south west France. Those wines, which have been tested for the procyanidin content, have up to 330 mg per 125ml serving.
 
While there is more research to be undertaken the evidence mounts for the healthy benefits of procyanidin. The good news is that procyanidins are abundantly available in various food types without waiting for the processes of commercial certification to be completed. To emphasize – procyanidins are available in beneficial doses naturally. Unnaturally high and unproven to be safe doses are not required with procyanidin.
 

References

<sub>1. Masquelier J. Historical note on OPC. France: Martillac; 1991.

2.. Yamakoshi J, et al. Safety evaluation of proanthocyanidin-rich extract from grape seeds.  Chiba Pref. 278-0037, Japan

3. Roger Corder, et al. Nature|Vol 444|30 November 2006. Roger Corder, The Wine Diet, published 2007.

4. 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.

5. 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. FEBS Lett 1998 Jul 24;431(3):315-8.

6. Maffei F, et al. Sparing effect of procyanidins from Vitis vinifera on vitamin E: in vitro studies. Planta Med 1998; 64: 343-347.

7. Bagchi D, et al. Creighton University School of Pharmacy in Omaha, Neb.  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.

8. 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.

9. 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.

10. Fitzpatrick DF, et al. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol 1998 Oct;32(4):509-15.

11. 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.

12. Putter M, et al. Inhibition of smoking-induced platelet aggregation by aspirin and Pycnogenol. Thromb Res 1999 Aug 15;95(4):155-61.

13. 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.

14.Ursini F, et al. Optimization of nutrition: polyphenols and vascular protection. Nutr Rev 1999, 57:8, 241-8.

15. 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.

16. Ursini F, et al. Post-prandial plasma peroxides: a possible link between diet and atherosclerosis. Free Radic Biol Med 1998; 25:250-2.

17. Sato M, Maulik G. Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury. J Mol Cell Cardiol 1999 Jun;31(6):1289-97.

18. Shiuan Chen, Ph.D.  Beckman Research Institute of the City of Hope, Duarte California.  ES8258

19. X J. SHANG et al. Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing, P. R. China. 2008. Procyanidin Induces Apoptosis and Necrosis of Prostate Cancer Cell Line PC-3 in a Mitochondrion-Dependent Manner

20. Bomser J, Madhavi DL. In vitro anticancer activity of fruit extracts from Vaccinium species. Planta Med 1996 Jun;62(3):212-6.

21. 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.

22. 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.

23. 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.

24. Erdelmeier CA, Cinatl J. Antiviral and antiphlogistic activities of Hamamelis virginiana bark. Planta Med 1996 Jun;62(3):241-5.

25. De Bruyne T, Pieters L. Biological evaluation of proanthocyanidin dimers and related polyphenols. J Nat Prod 1999 Jul;62(7):954-8.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

M. Sterling, R.D. Extracts referring to various research references.</sub>