Our educational interview involved Anil Shrikhande, President of Polyphenolics and VP of R & D of its parent corporation, Constellation Wines, U.S., Inc. and Dr. C. Tissa Kappagoda, M.B.B.S., Ph.D., Professor of Medicine, Division of Cardiovascular Medicine, University of California, Davis and director of Preventive Cardiology Program, UCDMC. Dr. Shrikhande has responsibility for business, marketing, and technical development issues for the company, and Dr. Kappagoda manages the majority of the clinical work on the MegaNatural® product line for Polyphenolics.
NPI: What is the background of Polyphenolics in the Grape Seed/Skin Extract category? Who is the parent company of Polyphenolics?
Dr. Shrikhande : After DSHEA in 1994, the company at that time, Canandaigua Wines, saw the opportunity to develop antioxidant products from grape seed. There were epidemiological studies which suggested health benefits associated with consumption of grape products, and they (grapes) were good for general nutrition. I was charged with looking into California and New York varieties to determine which seeds were more suitable (total phenolics, etc.), and for this project, we were not looking at wine seeds.
In 1996, we started seed separation in California, and Polyphenolics was created as a separate division to produce and market grape seed products. Polyphenolics is currently a division of Constellation Wines U.S., Inc., part of the largest wine company in the world, Constellation Brands, Inc. (NYSE: STZ), which is a Fortune 500 and S & P 500 company. The company operates numerous large wineries with systems in place to produce millions of cases of wines annually, including generic and varietal types, with significant operations in California’s Central Valley, as it turns out, the largest operation in the United States.
NPI: There are other suppliers of Grape Seed/Skin Extract. What differentiates and makes Polyphenolics a leader in this category?
Dr. Shrikhande: We have a unique, patented, water-based extraction process and a purification process to obtain 90-95% polyphenols in grape seed. (US patent 2003) The process allows the selective extraction of bioactive phenols.
We also have complete control of our raw material feeds. We use white wine and grape juice seeds (never red wine) sourced from within our operation. We’ve characterized our extract for its antioxidant properties, we’ve done in vitro and in vivo work in animals on the product, and as importantly, and this is a huge plus, we monitor and control the entire winery process, and there are no chemicals or solvents used in the extraction, it’s a hot water-based process. The volume in which we operate is certainly an advantage. We own a huge seed supply base. In comparison, in Europe for instance, operations are typically not large, and producers source from co-ops. This means that from year to year, the composition of their seed supply base could change.
NPI: Is the market potential growing for the use of grape seed extract in foods, beverages and dietary supplements?
Dr. Shrikhande: Yes, definitely, although statistics and data are hard to come by. From our own business and the number of inquiries for information as well as the number of sample requests, we know the interest is there and growing.
The dietary supplement sector for us is expanding. A few years ago, with an alternative offering, China-based suppliers began entering the market with cheaper product, and some of our clients switched, but they experienced disappointment at the lack of information and support. We’re seeing them revert back to us now as they are looking for consistent supply, the science backing and the substantiation we can offer.
In food and beverage, interest is also high. Numerous customers are thinking of incorporating our products, with supplement companies even exploring their own beverage lines. The traditional beverage company interest is primarily large and mid-size organizations.
NPI: How do the opportunities differ between functional foods and dietary supplements?
Dr. Shrikhande: It is extremely challenging in the functional food and functional beverage area with some impediments to getting products developed. When companies take generic ingredients, they examine them to ensure they’re suitable for incorporation into these product formats. There are usually issues with regard to taste and, in beverages, solubility issues and freedom from ‘haze’. In general, stability is always good. With our water extraction, we selectively isolate smaller weight components with no sediment. A solvent-based extraction will give some high molecular weight compounds, ones that are typically not biologically inassimilable, as well as producing haze in solution.
In the dietary supplement environment, we’ve been able to make structure function claims that are now finding their way into food and beverage. The challenge though is that the food and beverage market wants health claims, and there is uncertainty over what the FDA will do and permit with qualified health claims, etc. We’ve gone through our GRAS (Generally Recognized as Safe) self-affirmation process, which is really a requirement for this sector; otherwise innovation would be stifled. We realized we needed this status now.
NPI: Can you speak a bit about the development and evolution process for MegaNatural?
Dr. Shrikhande: From the outset, we wanted to differentiate ourselves based on quality and our brand, and to show that not all grape seed products were equal. Over the years, we have explored co-branding with companies such as GNC and Vitamin Shoppe, as well as with various multi-level marketing (MLM) companies. This approach allows us to support our products and program with science, technical support and the evidence we have of biological activity. We’ve been working on this for the past seven years and it’s a continuing effort. Our initial customers are either still with us or have returned for the value we offer. Our relationships with many of the largest dietary supplement companies are ongoing. Ron Martin, Polyphenolics’ VP of Sales and Marketing, has done an excellent job in establishing and maintaining these relationships, and Bob Kowalski, Medical Journalist and author of “The 8-Week Cholesterol Cure,” is also writing a new book on cardiovascular health with a chapter on hypertension that will help us support and expand our relationships.
NPI: What products are included in the Polyphenolics' MegaNatural line?
Dr. Shrikhande: The MegaNatural product line includes MegaNatural Gold grape seed extract, three MegaNatural grape pomace extracts, MegaNatural RubiRed grape juice extract, MegaNatural Red Wine Concentrate and the recently introduced MegaNatural BP grape seed extract.
NPI: How is Polyphenolics working with customers on a global basis?
Dr. Shrikhande: There are really two ways to consider. Firstly, we’re working internationally, for example, with companies like those in the MLM channel assisting them in the registration and product certification process. This involves supporting them with ingredient information and documentation for dossiers and binders. Secondly, we have developed a network through sales agencies in England, India, Canada and Japan, for instance, where we support these companies with ingredient support and documentation.
NPI: What steps did you take to self-affirm GRAS the MegaNatural products? Are they all GRAS? For what purpose did you self-affirm?
Dr. Shrikhande: To answer the first part of your question, we did the required toxicology and micro tests to demonstrate the safety of the product to the agency (FDA). The process we went through should be applicable to the entire line, including both seed products (MegaNatural BP and the pomace) – juice is already a food and does not require GRAS affirmation – and we needed to go through this route to effectively target food and beverage applications.
Our toxicology work took two years; we convened a panel of 4 researchers who evaluated the scientific information including the chemistry and both in vitro and in vivo studies. We notified the FDA by presenting them with a dossier, their evaluation went on for a year, and then we were informed the agency had no questions. We have found that the value of the GRAS affirmation also applies to dietary supplements as it boosts the confidence our clients have in the product, since the process involved the FDA. The Affirmation is unique to our products; it is process-specific.
NPI: How is Polyphenolics positioning MegaNatural in the marketplace?
Dr. Shrikhande: We are leading with communication around science, and this includes on websites regarding our research in the university environment, and through the use of medical writers such as Bob Kowalski and spokespeople such as Dr. Kathleen London. Our consumer communication includes radio, publications, and video news releases on key science as well as communicating to the trade with key press releases. A lot of our efforts are targeted directly towards consumers, focusing on magazines, both men’s and women’s. We’ve got our customer base well covered; our current challenge is how to get better communication with consumers.
NPI: What is the intellectual property position and approach of Polyphenolics with this line?
Dr. Shrikhande: Polyphenolics has a patented process covering the entire MegaNatural product line, and we have performed clinical trials at various institutions. There is a provisional patent filed for the MegaNatural BP associated with the work recently conducted at UC Davis, and there is a patent pending for composition of matter.
NPI: How would you describe consumer awareness of the health benefits of grape seed extract? Where do you see the most growth opportunities?
Dr. Shrikhande: Whole grape is well recognized by consumers, but there is a constraint regarding obesity: the whole issue of calorie consumption becomes a concern when considering significant amounts of grape. The grape seed is much better from this standpoint, much less caloric consumption when incorporated into food and beverage. And of course, when you consider other grape products such as wine, there is the alcohol impact as well, versus grape seed where the benefits are there without these negatives.
An exciting area for development is the doctor’s channel. In the United States, it is not so big, but in areas like India, the doctor market is absolutely huge. And with a product cleared by that country’s food and drug agency, it gives a lot of momentum to the product.
NPI: What are the biggest challenges you are facing?
Dr. Shrikhande: By far our biggest challenge is consumer awareness – we need to create much larger consumer awareness. Obviously, if we’re able to do this, our products will sell more. Our grape seed extract is pretty well studied, and there is a need to continue this effort. Polyphenols are somewhat recognized for their free radical scavenging ability which effects aging, with grape seed an approach to target free radicals.
NPI: How are you addressing product quality issues and concerns? What do you feel is your role as an ingredient supplier?
Dr. Shrikhande: Philosophically, we’re ahead of the curve with our commitment to GMP manufacturing, the consistency of our product, and of course, our analytical approach. In fact, we took our methodology for calculating total phenols to NNFA (National Nutritional Foods Association) and it was adopted. It’s a similar approach to measuring total protein concentration – first you define purity, then you assess the individual profile, which is what we’ve done in this category. Also on the subject of quality programs, our entire wine group has ISO 2002 accreditation and we have our Polyphenolics GMP’ third party certified by NSF (NSF International, The Public Health and Safety Company™, a not-for-profit, non-governmental organization).
To answer your question about role, our role is to be responsible for the ingredient, to deliver what we say we will – in this case a more bioactive grape seed product.
NPI: What about analytical testing? There is an AOAC method on the horizon – how do you feel about that?
Dr. Shrikhande: As far as AOAC is concerned, we’re part of the method development committee- we actually were requested to come onto the committee and Steve Kupina, our director of Research, is participating. So we’re heavily involved as part of this collaboration to develop a validated method.
NPI: For what purpose did you NSF certify your ingredients?
Dr. Shrikhande: For a specific nutraceutical, this is an extremely strong process to ensure the quality of the ingredient, and leads into how we support our clients, by building in value. We can certainly say it’s been beneficial in the marketplace. Also, we are now set to use NSF to certify our GMPs when the final FDA ruling comes out on required GMPs for the industry.
NPI: Tell us more about MegaNatural BP - the newest product in the line.
Dr. Shrikhande: MegaNatural BP is specific to blood pressure lowering in a pre-hypertensive population. Our approach with this involves preventative, lifestyle oriented changes rather than treating with a drug-like approach. An increasing percentage of the population is being said to have a condition called metabolic syndrome, a condition that can lead to some severe health consequences as it progresses. If it is not controlled, then it can lead to, among other things, high blood pressure.
Through our innovation we’ve been able to perfect the isolation of specific grape seed components that provide blood pressure lowering for persons currently in the range of 140 over 90 or so. Dr. Kappagoda will provide more information on this.
NPI: What's down the road from a product and positioning standpoint? Where do you see the line and the company?
Dr. Shrikhande: We’ve currently got an extremely strong position in grape-based nutritional products, and we see a move towards increasing levels of scientific validation and more specific health benefits. We see potential in targeting atherosclerosis and an approach to developing products with extremely targeted condition-specific results, and some that are more general. In the future, expect to see us work on more and different endpoints and to seek more intellectual property protection.
Continuing with Dr. Kappagoda:
NPI: What is the scientific background that led to this current work on MegaNatural BP?
Dr. Kappagoda: We’ve had an interest in red wine for some time, including evaluating the basis for what is known as the French paradox. The incidence of coronary artery disease in the French and Mediterranean countries is not as high as might be expected, considering other cardiovascular risk factors. This effect is typically attributed to wine, particularly red wine. It was believed that either alcohol or other constituents of wine had a relaxant effect on arteries. This relaxation is dependent on the endothelium of the vessels.(The endothelium refers to the inner lining of the blood vessels). These cells produce nitric oxide which relaxes the vessel. Grape seed activates these cells, as we showed five to six years ago, with a previous version of the MegaNatural product. We were able to show also that this product protected rabbits from developing atherosclerosis when fed a high cholesterol diet.
The new version of the product is a modified, purified extract, and we were eager to re-investigate the activity of this product. Toxicology studies have been completed to ensure it was approved for use as a nutraceutical with a GRAS affirmation. As we did our clinical work, we observed that it appeared to help reduce blood pressure.
NPI: What did you observe in the current study?
Dr. Kappagoda: We investigated 24 individuals with metabolic syndrome. Metabolic syndrome is typically diagnosed if three out of five factors are present: modest elevation in blood pressure, truncal obesity, low HDL, high triglycerides and some degree of insulin resistance – if any three of these conditions are present, the subject is said to have metabolic syndrome. In fact, in the United States, nearly 40 percent of the population has this condition. From an ethnic perspective it is significantly prevalent in Hispanic and African American populations and the prevalence is higher in older populations as well. Metabolic Syndrome is a major risk factor for diabetes and cardiovascular disease.
We began a double blinded, placebo control trial, dividing our 24 subjects into three groups, one receiving 300mg per day of the grape seed extract, another group receiving 150 mg per day, and the third group received a placebo as a control. The supplementation took place over one month. We observed that blood pressure was significantly reduced in both supplementation groups by an equal amount, and we were encouraged since these findings were consistent with previous animal work in which we showed that the extracts relaxed blood vessels. Since the extract was a strong anti-oxidant, we decided to examine oxidized LDL to see what impact if any, supplementation had on these levels. (Oxidized LDL is a predictor of coronary artery disease.) We found that the 300 mg dose reduced oxidized LDL in a manner proportional to the starting level, that is, the effect was more substantial in individuals with high oxidized LDL to start with. The relationship was statistically significant.
NPI: Can you tell us a bit more about Metabolic Syndrome and pre-hypertensive conditions?
Dr. Kappagoda: As far as Metabolic Syndrome is concerned, most individuals with this condition have a blood pressure around 135/80. In fact, pre-hypertensive patients are typically considered to have a systolic pressure between 120 and 139, and a diastolic pressure between 80 and 99. Elevation in one or the other is an indication of pre-hypertension. The treatment for this condition is ideally lifestyle oriented, with weight management being a significant component. Antioxidant nutraceuticals with a capacity to maintain a normal blood pressure could be a useful adjunct.
NPI: What drop in blood pressure would people with Metabolic Syndrome or moderate hypertension expect if they take MegaNatural BP grape seed extract?
Dr. Kappagoda: First of all, I should mention that the blood pressure was measured in our study by an ambulatory device programmed to measure the blood pressure at periodic intervals during the day. This data was then used to generate a day-time average. We observed that the average decrease in systolic pressure was 12 mm Hg, while the diastolic drop was 9 mm Hg. The study was done on people with the metabolic syndrome. Nutraceuticals are not meant to be used as a substitute for medicines or medical advice. These compounds could help to maintain a normal blood pressure.
NPI: What would be the recommended dose for the use of MegaNatural BP for supporting the control of their blood pressure? Who should consider taking MegaNatural BP to help control their blood pressure?
Dr. Kappagoda: As I mentioned earlier, the effect of both the 150mg and 300mg dose appeared to be similar. We’re currently conducting a second study on a pre-hypertensive population with 300mg as the dose. It is possible that 150mg may work just as well.
NPI: Are there any complementary or synergistic mechanisms that you are aware of?
Dr. Kappagoda: We would expect to see some synergy with other antioxidants. These extracts are hydrophilic anti-oxidants, and MegaNatural may enhance the effect of other similar compounds.
NPI: Are there any safety issues or contraindications?
Dr. Kappagoda: Polyphenolics has commissioned extensive tests in animals at doses several orders of magnitude greater than those used in clinical studies. The FDA took these studies into consideration when they allowed the GRAS status. We have administered the extracts to over 50 individuals during the course of clinical trials, and there have been no instances where subjects reported side effects, adverse or otherwise. We are obliged to report any side effects to our Institutional Review Board, and there have been none.
NPI: What additional clinical work is planned on MegaNatural BP?
Dr. Kappagoda: As I mentioned earlier, we are doing a second study using 300 mg/day in subjects with pre-hypertension. A third study involving 150mg/day is also planned. We also have plans for an animal study investigating atherosclerosis, since our previous work has showed that the earlier version of the extract prevented the onset of this condition. We now want to investigate what happens if the vessels are already damaged – do they recover? We will have several options open if the study is successful.
NPI: Did you do any clinical work on other areas with MegaNatural BP or MegaNatural Gold? If so, what were the results of this work?
Dr. Kappagoda: We did a preliminary study on metabolism, investigating oxygen consumption. No data are available.
NPI: What's next on the horizon?
Dr. Kappagoda: We’d really like to do some work on reversing atherosclerosis.
NPI: Would you have anything else to add about using this product?
Dr. Kappagoda: There are dozens of extracts on the market creating a lot of confusion. As a researcher, one has to be certain about the product used. What is its composition? Can it be manufactured in a reliable manner that ensures reproducibility of the product? We have been fortunate in this regard with Polyphenolics. They have provided us with data on these issues so that we are able to plan these studies with confidence.
NPI: Where can the consumer buy MegaNatural BP or MegaNatural Gold products?
Dr. Shrikhande: The product offered on our website is "MegaNatural BP Grape Seed Extract", a 60 capsule, 300 mg per capsule offering which is a two month supply with a single dose per day.
Life Extension foundation has just launched a product called Natural BP Management, which is a blend of 150 mg of MegaNatural BP grape seed extract, 1700 mg of C12 Peption™ ACE casein Hydrosylate, and 50 mg of PomElla® Pomegranate Extract. This product provides efficacious dosages of three standardized ingredients shown in human clinical studies to promote healthy blood pressure and vascular function.
Several other companies are looking at the product and I will update our website www.polyphenolics.com when they are available.
NPI: What Structure Function Claims could be made with MegaNatural BP grape seed Extract?
Dr. Shrikhande: The structure function claims on the bottle are:
MegaNatural BP will:
Help support blood pressure levels that are already within the normal range.
Help support normal endothelium cell function.
Help support normal arterial function.