Morazzoni b

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Morazzoni b

  1. 1. Polifenoli del vino e prevenzione di patologie cronico-degenerative P. Morazzoni, W. Cabri Indena R&D Corporate Twitter: @IndenaSpA
  2. 2. TOP 10 CAUSES OF DEATH (1900 vs 2010) New England Journal of Medicine 366, 2333 (2012)
  3. 3. ROLE OF DIET AND EDIBLE PLANTS The role of diet, even at epigenetic level, in contributing to modulate chronic-degenerative pathologies has been established in a number of epidemiological studies. In this contest, the role of secondary (and even primary) metabolites contained in edible plants seems to be pivotal in human homeostasis and in the modulation of the risk of pathological conditions including cardiovascular diseases and cancer.
  4. 4. EPIGENETIC REGULATIONS AND ROLE OF DIETARY PHYTONUTRIENTS Epigenetic regulations consist of potentially reversible changes in DNA methylation, histone modifications, alteration in microRNA (miRNA) expression, without any change in DNA sequence. Several phytonutrients are demonstrated to modulate these epigenetic regulators inducing heritable changes in gene expression (i.e. those codifying for pivotal inflammationregulating factors, such as NF-kB …..). S. Reuter et al., Genes Nutr. 6, 93 (2011)
  5. 5. INDENA MISSION IN CONSUMER HEALTH R&D Indena focus is to identify phytonutrients provided with a solid scientific background and to develop these ingredients by optimizing their biological benefits for improving quality of life.
  6. 6. IS THERE A REASONABLE BASIS IN ORDER TO INTEGRATE PHYTONUTRIENTS (AS SUPPLEMENTS OR FUNCTIONALIZED FOOD) IN THE MODERN DIET?
  7. 7. EDIBLE PLANTS ARE TODAY USUALLY CHARACTERIZED BY A LOWER CONTENT OF PHYTONUTRIENTS Agricultural selection has reduced the contents of phytochemicals in edible plants which have been selected for factors like appearance, succulence and yields (by means of pesticides).
  8. 8. INTENSIVE AGRICULTURE IS A WORLDWIDE NEED Hectares dedicated to agriculture Productivity
  9. 9. Journal of the American College of Nutrition 2004, 25% less proteins
  10. 10. MODERN DIET IS MARKEDLY REDUCED IN DIVERSITY •Only 1% of the total 300,000 higher plants has been historically utilized for food. Roughly 150 species are commercially cultivated. •Caloric intake is derived mostly from 4 plant species (wheat, rice, soy, corn). These plants represent the basis upon which the world’s population is fed.
  11. 11. The concept of optimized nutrition arises from the convergence of information from basic biomedical science with epidemiological data.
  12. 12. THE PROCESS OF OPTIMIZING NUTRITION CAN BE ENVISAGED ALSO AS A CONSTANT SUPPLY OF SELECTED PHYTONUTRIENTS (MOSTLY FROM EDIBLE PLANTS) CHARACTERIZED BY WELL ESTABLISHED BIOLOGICAL PROPERTIES DIETARY SUPPLEMENTS FUNCTIONALIZED FOOD HIGH QUALITY INGREDIENTS FULFILLING OF HEALTH CLAIM CRITERIA COMPATIBILITY WITH FOOD PREPARATION PROCESSES
  13. 13. INDENA STRATEGIC APPROACHES FOR THE DEVELOPMENT OF EDIBLE PLANT-DERIVED PRODUCTS •Rediscovery of plants from Eastern and Western area Grape, artichoke, lupin…. •Optimization of extract “characteristics” (bioavailability, standardization, new formulation) Phaseolus vulgaris, curcumin…. •Targeted combinations Combination for appetite control, cholesterol lowering formulation….
  14. 14. INDENA MAJOR AREA IN HEALTH NUTRITION CARDIOVASCULAR HEALTH Metabolic disorders GASTROENTEROLOGY Functional dyspepsia IBS/IBD MENTAL HEALTH Cognitive decline
  15. 15. EXAMPLES OF INDENA EDIBLE PLANTS DERIVED STANDARDIZED EXTRACTS LEUCOSELECT® ENOVITA® Vitis vinifera L. Vitis vinifera L. MIRTOSELECT® Vaccinium myrtillus L. GREENSELECT® BEANBLOCK® Phaseolus vulgaris L. Camellia sinensis (L.) O. Kuntze MERIVA® OLEASELECT® Curcuma longa L. Olea europaea L. SOYSELECT® Glycine max L. PYCRINIL® Cynara cardunculus L. subsp. Scolymus MADEGLUCYL® PRO-GAMMA™ Syzygium cumini (L.) Skeels Lupinus albus L.
  16. 16. Vitis vinifera L. (Vitaceae family) sylvestris (Gmelin) Hegi sativa Hegi (South-West Asia, South-Central Europe) (Many of these cultivated species are derived from the sylvestris subspecies) occidentalis pontica orientalis (from Nile valley and Western Europe) (intermediate area) (from Jordan valley)
  17. 17. Vitis vinifera L. CULTIVATIONS: THE HISTORICAL TRACK – OLD PERIOD Gaul (6th c. B.C.) Italy (9th-7th c. B.C.) Caspian Sea region Greece (18th-16th c. B.C.) WEST North Africa, Egypt (23th c. B.C.) (Asia minor) EAST Turkey, Persia, India, China (128 B.C.)
  18. 18. Vitis vinifera L. CULTIVATIONS: THE HISTORICAL TRACK – NEW WORLD (16th c. A.D.) USA (East Coast  FAILED) South Africa (West Coast  SUCCESS) Mexico South America Australia New Zealand
  19. 19. Vitis vinifera L. CULTIVATIONS: THE HISTORICAL TRACK Wall paintings from the Kha'emwese's tomb of ancient Thebae: various steps of grape harvest. Egypt (23th c. B.C.)
  20. 20. Vitis vinifera L. THROUGH THE CENTURIES Fruits and leaves (and their derivatives) have been utilized for both edible and medicinal purposes by basically most of the populations involved in the cultivation of grapevine. Ancient Egyptians, the Hippocratics (5th-4th c. B.C.), Theofrastus (4th c. B.C.), Dioscorides, Pliny (1st c. A.D.), (2nd c. A.D.) described the medicinal properties of grapes. Galen
  21. 21. MAIN MEDICINAL PROPERTIES AND THERAPEUTICAL USES OF Vitis vinifera L. DERIVATIVES LEAVES FRUITS
  22. 22. Vitis vinifera L. SEEDS ARE THE PART OF THE PLANT WITH THE HIGHEST CONCENTRATION OF POLYPHENOLS
  23. 23. OLIGOMERIC PROANTHOCYANIDINS: ONE OF THE MOST CHARACTERIZING GROUPS OF POLYPHENOLS IN Vitis vinifera L. Modified from: Sharmila Shankar, Brahma N. Singh, and Rakesh K. Srivastava, in: Nutrition, Diet and Cancer, Chapter 10, Plant Polyphenols and Their Role in Cancer Prevention and Chemotherapy, p 209, S. Shankar and R.K. Srivastava (Eds.), Springer, 2012
  24. 24. OPC: THE PHARMACEUTICAL APPROACH… The pharmaceutical utilization of OPC (starting from the 1980s) has been mostly concerned with a proprietary product (Endotelon) which contains as active principle a highly standardized extract from grape seeds.
  25. 25. … AND MODERN INSIGHTS INTO OPC HEALTH BENEFITS THERAPY •PHARMACEUTICAL PRODUCTS (Mostly concerned with vascular protection) PREVENTION/RISK REDUCTION •DIETARY SUPPLEMENTS (Mostly in the area of CVDs and stimulated by the “French Paradox”* induced cascade of literature) *S. Renaud and M. de Lorgeril, Lancet 339, 1523 (1992); M. de Lorgeril et al., Cardiovas. Res. 54, 503 (2002).
  26. 26. THE RELEVANCE OF OPC AND RESVERATROL IN THE EPIDEMIOLOGICAL SCENARIO From “French Paradox” to “red wine paradox”? Oligomeric procyanidins in wine: 600 mg/L One glass of 250 mL/day = 150 mg = 2.14 mg/kg for a man of 70 kg b.w. Resveratrol in wine: 5 mg/L One glass of 250 mL/day = 1.25 mg = 18 µg/kg A. Giacosa et al., Eur. J. Cancer Prev. 22, 90 (2013)
  27. 27. OPC: AN unicum AMONG POLYPHENOLS • HIGH TROPISM FOR THE VASCULAR TISSUE • CAPACITY TO MODULATE ENDOTHELIAL FUNCTIONAL RESPONSE OH OH HO O 3 4 OH R OH OH n0-5 HO O 8 3 4 OLIGOMERIC PROCYANIDINS OH R OH OH HO O 8 3 R OH
  28. 28. HIGH TROPISM FOR THE VASCULAR TISSUE TISSUE DISTRIBUTION OF RADIOACTIVITY AFTER ORAL ADMINISTRATION OF 14C-LABELLED OPC IN RODENTS Tissue Total blood Muscle Heart Plasma Lung Adrenals Spleen Xiphoid cartilage Skin Kidney ( cortex ) Trachea Liver Duodenum Aorta dpm / g 6.310 6.885 7.459 8.677 10.424 11.370 12.822 17.504 17.864 22.534 24.427 34.056 42.579 49.205 J. Laparra et al.: Plantes médicinales et phytothérapie 11, 133 (1977) ± 1.671 ± 1.301 ± 1.588 ± 2.203 ± 2.220 ± 3.217 ± 3.141 ± 4.113 ± 4.216 ± 6.399 ± 5.740 ± 9.024 ± 10.346 ± 11.513 % radioactivity ( vs. blood ) 1 1.09 1.18 1.37 1.65 1.80 2.03 2.77 2.83 3.57 3.87 5.40 6.75 7.80
  29. 29. OPC: DEMONSTRATED BASIC MECHANISMS REGULATING FUNCTIONAL ASPECTS IN MAINTAINING CARDIOVASCULAR HEALTH • STIMULATION OF AN ENDOTHELIUM DEPENDENT RELAXATION OF BLOOD VESSELS OH OH • ACTIVATION AND UP-REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE HO O 3 4 OH R OH OH HO O 8 3 4 OLIGOMERIC PROCYANIDINS OH R OH OH HO O 8 3 R - M.B. Cishek et al., Clin. Sci. 97, 507 (1997) - I. Edirisinghe et al., Clin. Sci. 114, 331 (2008) - M. Ndiaye et al., Br. J. Pharmacol. 142, 1131 (2004); The FASEB Journal 19, 455 (2005) OH
  30. 30. Schematic diagram showing the OPC-induced endothelium-dependent NO-mediated relaxation in the isolated porcine coronary artery - M. Ndiaye et al., Br. J. Pharmacol. 142, 1131 (2004); The FASEB Journal 19, 455 (2005)
  31. 31. OPC: THE INDENA EXPERIENCE IN ORDER TO CAPITALIZE THIS IMPORTANT BACKGROUND WE STARTED YEARS AGO WITH THE CHALLENGING TARGET TO STANDARDIZED GRAPE SEEDS EXTRACTS
  32. 32. HIGHLY STANDARDIZED GRAPE SEEDS EXTRACTS: GENERAL MANUFACTURING PROCESS GRAPE SEEDS FILTRATION EXTRACTION PURIFICATION BY SELECTIVE COUNTEREXTRACTION DISSOLVE IN WATER CONCENTRATION TO AQUEOUS EXTRACT SOFT EXTRACT 2) Concentrate the percolates in vacuum, under ....mild and controlled temperature conditions, ....until elimination of the extraction solvent. 3) Filter the aqueous concentrate obtained, to ....eliminate any precipitated material. 4) Purify the filtered solution by selective ....counterextraction. 5) Concentrate the purified product in vacuum, ....under mild and controlled temperature ....conditions, to yield a soft extract. CONCENTRATION TO ATOMIZATION 1) Extract GRAPE SEEDS, at room temperature, ....until exhaustion. MIXING / SIEVING 6) Dissolve the soft extract in water. 7) Atomize the aqueous solution obtained. 8) Mix the dried product and sieve it. ANALYSIS ANALYSIS OF THE OF THE FINAL PRODUCT 9) Send the final product for quality control analysis (HPLC-UV, HPLC-GPC) and packaging.
  33. 33. GRAPE SEEDS EXTRACTS PRODUCED BY INDENA ENOVITA LEUCOSELECT GRAPE SEED MONOMERS All these products are standardized dry extracts from grape seeds, and contain the purified fraction of characteristic grapes polyphenols. The products are manufactured in the same authorized industrial plant, by means of food grade solvents according to EU and US specifications. ENOVITA complies also with Japanese specifications, being produced with water and ethanol only.
  34. 34. OPC: THE INDENA EXPERIENCE HIGHLY STANDARDIZED GRAPE SEEDS EXTRACTS ALLOW PRE-CLINICAL AND CONTROLLED CLINICAL INVESTIGATIONS
  35. 35. GRAPE SEEDS EXTRACTS PRODUCED BY INDENA Comparative analytical data (according to USP) WATER (%) INSOLUBLE RESIDUAL (%) ENOVITA 5.3 0.03 8.6 91.4 99 GRAPE SEED MONOMERS 3.3 0.50 21.4 82.3 103 PRODUCT MONOMERS (%) OPC (%) OPC + MONOMERS (%)
  36. 36. OPC rich grape seeds extract is made exclusively with grape seeds from white wine production. Using only water as extraction solvent, ENOVITA is a food grade grape seed extract whose development has capitalized on Indena's 40 years experience in grape seed extract production. ENOVITA is produced according to Indena 30 Quality system and under HACCP conditions in a GMPs and ISO 14001 certified facility, ensuring full traceability from grape harvest to the finished product. Furthermore, ENOVITA is Halal and Kosher certified and its environmental friendly production process is designed to minimize the production of waste.
  37. 37. Stratification of total CV risk in categories of low, moderate, high and very high risk according to SBP and DBP and prevalence of RFs, asymptomatic OD, diabetes, CKD stage or symptomatic CVD.
  38. 38. ENOVITA Registry study in mild hypertensive subjects (undergoing Best Standard Management) NUMBER OF SUBJECTS: 119 TREATMENT GROUPS: - Control (28 males + 19 females = 47) - ENOVITA 150 mg/day (17 males + 18 females = 35) - ENOVITA 300 mg/day (23 males + 14 females = 37) Mild hypertension: pre hypertension (120-139 / 80-89 mmHg) and Stage 1 hypertension (140-159 / 90-99 mmHg). All patients were undergoing Best Standard Management: weight control, exclusion of NaCl, caffeine, soft drinks and drinks containing caffeine; physical exercise 20 minutes/2 times/day. PERIOD OF TREATMENT: 16 weeks EVALUATION OF THE EFFECTS: Blood pressure and blood flow at microcirculation level (foot skin) by Laser Doppler flowmetry; heart rate and plasma free radicals. Evidence-Based Complementary and Alternative Medicine, Volume 2013, Article ID 313142, http://dx.doi.org/10.1155/2013/313142
  39. 39. ENOVITA: effects on blood pressure and peripheral blood flow in mild hypertensive subjects Evidence-Based Complementary and Alternative Medicine, Volume 2013, Article ID 313142, http://dx.doi.org/10.1155/2013/313142
  40. 40. ENOVITA: effects on heart rate and plasma free radicals in mild hypertensive subjects Evidence-Based Complementary and Alternative Medicine, Volume 2013, Article ID 313142, http://dx.doi.org/10.1155/2013/313142
  41. 41. ENOVITA: registry study in mild hypertensive subjects (undergoing Best Standard Management) CONCLUSIONS In healthy subjects bordering hypertension, the combination of the Best Standard Management with ENOVITA (150-300 mg/day for at least 4 weeks) can positively modulate blood pressure and blood flow at the level of microcirculation. This effect is paralleled by a significant reduction in heart rate. A relevant reduction of plasma free radicals has also been observed. ENOVITA has been well tolerated with a global positive compliance.
  42. 42. ENOVITA OVERALL CONCLUSIONS • OPC are the most characterizing polyphenols of Vitis vinifera L. • Standardization of grape seeds extracts containing OPC is still a challenging task • Highly standardized grape seeds extracts containing OPC are: – clinically documented as venotropic agents – strongly effective in modulating endothelial functionality – promising co-adjuvant agents in reducing intermediate – risk factors (i.e. ENOVITA on blood pressure) in CVDs
  43. 43. Twitter YouTube Flickr LinkedIn Indena.com

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