USOO8809311B2 (12) United States Patent (10) Patent No.: US 8,809,311 B2 McCord (45) Date of Patent: *Aug. 19, 2014 (54) NUTRITIONAL SUPPLEMENTS 2007/0065396 A1 3/2007 Morariu 2010.0113611 A1 5, 2010 Raederstorff et al. (76) Inventor: Darlene McCord, Coralville, IA (US) 2013,0005682 A1 1/2013 Raederstorff et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 EP O123637 A1 10, 1984 U.S.C. 154(b) by 0 days. EP 2O70545 A1 6, 2009 JP 2007 119431 A 5/2007 This patent is Subject to a terminal dis WO WOOO36936 A2 6, 2000 claimer. WO WO2004/032873 A2 4/2004 WO WO2006/020588 A1 2, 2006 (21) Appl. No.: 12/853,908 WO WO2008/006581 A2 1, 2008 WO WO20081286.29 A1 10, 2008 (22) Filed: Aug. 10, 2010 OTHER PUBLICATIONS (65) Prior Publication Data Elisabet Miro-Casas etal, Clinical, Chemistry,49:6,945-952, 2003.* Rietjens et al. Am. J. Phisiolo. Heart, Circ. Physiol. 292:H1931 US 2011 FOO34519 A1 Feb. 10, 2011 H1936, 2007, published first in Dec. 2006.* Pubmed, accessed Apr. 3, 2012.* PCT Search Report for PCT/US2010/045049, dated Jan. 28, 2011. Related U.S. Application Data Angelo, S. D., et al., Hydroxytyrosol, a natural antioxidant from olive oil, prevents protein damage induced by long-wave ultraviolet radia (60) Provisional application No. 61/313,487, filed on Mar. tion in melanoma cells, Free Radical Biology & Medicine, 2005, 12, 2010, provisional application No. 61/235.203, 908-919, 38. filed on Aug. 19, 2009, provisional application No. Fabiani, R., et al., Cancer chemoprevention by hydroxytyrosol iso lated from virgin olive oil through G1 cell cycle arrest and apoptosis, 61/232,503, filed on Aug. 10, 2009. European Journal of Cancer Prevention, 2002, 351-358, 11. Ragione, F. D., et al., Hydroxytyrosol, a Natural Molecule Occuring (51) Int. Cl. in Olive Oil, Induces Cytochrome c-Dependent Apoptosis, Bio A6 IK 45/06 (2006.01) chemical and Biophysical Research Communications, 2000, 733 A6 IK3I/98 (2006.01) 739, 278. A6 IK3I/40 (2006.01) Deiana, M., et al., Protective effect of hydroxytyrosol and its metabo A6 IK3 L/455 (2006.01) lite homovanillic alcohol on H2O2 induced lipid peroxidation in A6 IK3I/05 (2006.01) renal tubular epithelial cells, Food and Chemical Toxicology, 2008, A6 IK3I/445 (2006.01) 2984-2990, 46. A6 IK3I/It (2006.01) Fabiani, R., et al., Inhibition of Cell Cycle Progression by A6 IK3I/85 (2006.01) Hydroxytyrosol Is Associated with Upregulation of Cyclin-Depen dent Protein Kinase Inhibitors p21 WAF1/Cip1 and p27 Kip1 and (52) U.S. Cl. with Induction of Differentiation in HL60 Cells, The Journal of CPC ................. A61 K3I/05 (2013.01); A61K 45/06 Nutrition: Nutrition and Disease, 2008, 42-48. (2013.01); A61 K3I/198 (2013.01); A61 K Guichard, C., et al., Dihydroxyphenylethanol induces apoptosis by 31/401 (2013.01); A61 K3I/455 (2013.01); activating serine/threonine protein phosphatase PP2A and promotes A6 IK3I/4415 (2013.01); A61 K3I/I0 the endoplasmic reticulum stress response in human colon carcinoma (2013.01); A61 K3I/I85 (2013.01) cells, Carcinogenesis, 2006, 1812-1827, 27(9). USPC ........... 514/183; 514/345; 514/731: 514/562; Liu, Z. et al., Hydroxytyrosol protects retinal pigment epithelial cells 514/355; 514/578; 514/423: 514/711; 514/561; from acrolein-induced oxidative stress and mitochondrial dysfunc 568/763 tion, Journal of Neurochemistry, 2007, 2690-2700, 103. Manna, C., et al., Protective Effect of the Phenolic Fraction from (58) Field of Classification Search Virgin Olive Oils against Oxidative Stress in Human Cells, Journal of CPC ... A61K 2300/00; A61 K31/05; A61K 31/10: Agricultural and Food Chemistry, 2002, 6521-6526, 50. A61K 31/185; A61 K31/198; A61K 31/401; A61K 31/4415: A61 K31/455; A61K 45/06 (Continued) See application file for complete search history. Primary Examiner — Wu-Cheng Winston Shen (56) References Cited Assistant Examiner — Jean Cornet U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — McKee, Voorhees & Sease 4,871,550 A * 10/1989 Millman ....................... 424,601 (57) ABSTRACT 6,117.844. A 9, 2000 Fredrickson A process for improving the health of a subject, the process 6,165,475 A 12/2000 Crea et al. comprising orally administering a composition comprising 6, 197,308 B1 3, 2001 Crea et al. 6,309,652 B1 10/2001 Aeschbach et al. hydroxytyrosol to the subject to provide the subject with a 6,358,542 B2 3, 2002 Cuomo et al. daily dose of about 0.1 to about 750 ug hydroxytyrosol per kg 6,416,808 B1 7, 2002 Crea of body weight, and a dietary Supplement in dosage unit form 6,437,004 B1 8, 2002 Perricone for oral administration, the dosage unit form comprising a 6,746,706 B1 6/2004 van der Boom et al. 8,216,599 B2 7, 2012 Crea composition containing about 1 microgram to about 50 mil 2001/0001817 A1* 5/2001 Humes ....................... 604/892.1 ligrams hydroxytyrosol or an ester or salt thereof. 2004/0101507 A1 5, 2004 Predovan 2006/0257351 A1 11, 2006 Chiba 27 Claims, No Drawings US 8,809,311 B2 Page 2 (56) References Cited Sarsour, Ehab H., et al., “MnSOD activity regulates hydroxytyrosol induced extension of chronological lifespan'. American Aging Asso OTHER PUBLICATIONS ciation 2011, pp. 1-15. Haber, C. Andrew, et al., “N-acetylcysteine and taurine prevent Dog, T. L., Menopause: a review of botanical dietary Supplements, hyperglycemia-induced insulin resistance in vivo: possible role of The American Journal of Medicine, 2005, 98S-108S, 118(12B). oxidative stress'. Am J Physiol Endocrinol Metab 285 (2003), E744 Johnson, B. M.. In Vitro Formation of Quinoid Metabolites of the E753. Dietary Supplement Cimicifiaga racemosa (Black Cohosh), Chemi Victor, Victor M., et al., “N-acetylcysteine Protects Mice from Lethal cal Research in Toxicology, 2003, 838-846, 16(7). Endotoxemia by Regulating the Redox State of Immune Cells'. 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ES cells: a novel role for anamino acid in the regulation of pluripotent Matthews, D.M., et al... “Protein absorption”. J. clin. Path. 24. Suppl. cells in culture”, Am J Physiol Cell Physiol 298 (2010), C982-C992. (Roy. Coll. Path.), 5, 2012, pp. 29-40. Tuck, Kellie L., et al., “Major phenolic compounds in olive oil: EP0123637, Soto Lucien English Abstract, 1984. metabolism and health effects”, Journal of Nutritional Biochemistry JP2007 119431, Ichimaru Pharcos English Abstract, 2005. 13 (2002), 636-644. McCord, Darlene, PCT/US2010/045049 filed Jan. 12, 2012, “The SarSour, Ehab H., et al., “Manganese Superoxide Dismutase Regu Extended Europeans Search Report', dated Mar. 19, 2013. lates a Metabolic Switch during the Mammalian Cell Cycle”, 2012, pp. OF1-OF10. * cited by examiner US 8,809,311 B2 1. 2 NUTRITIONAL SUPPLEMENTS sodium ions into the cells interior. Repair of the cell's mem brane and improvement in the cells environment to more CROSS-REFERENCE TO RELATED homeostatic conditions are paramount to Survival APPLICATIONS Quiescence is the counterpart to proliferation and is a nor mal part of the cell cycle. The cell's replicative cycle involves This application claims priority to U.S. Provisional Appli a myriad of molecular events that occur during the quiescent cation Ser.