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(12) United States Patent (10) Patent N0.: US 8,734,866 B2 Oak Et A] USOO8734866B2 (12) United States Patent (10) Patent N0.: US 8,734,866 B2 Oak et a]. (45) Date of Patent: May 27, 2014 (54) COMPOSITIONEXTRACTS OF LINDERA COMPRISING OBTUSILOBA THE FOR gKR 10_2007_0050998 5/2007 PREVENTION AND TREATMENT OF KR 10_0732888 6/2007 CARDIOVASCULAR DISEASES KR 10-2009-0079650 7/2009 (75) Inventors: Min-Ho Oak, Gyeonggi-do (KR); OTHER PUBLICATIONS Jung-0k Lee, Gyeonggi-do (KR); Park, J-C., Yu, Y-B., Lee, J-H (1996) Isolation and Structure Eluci Woon-Sun Choi, Ulsan (KR); dation of Flavonoid Glycosides from Lindera obtusiloba BL. J. Jung-Duk Sohn, Gyeonggi-do (KR); Korean Soc. Food Nutr. 25(1), 76-79.* J ong-Hoon Kim, Gyeonggi-do (KR); Ja Panza et al., “Abnormal endothelium-dependent vascular relax ation in the patients with essential hypertension,” The New England Jee Woong Lim, Gyeonggi-do (KR); Journal of Medicine, vol. 323, Jul. 5, 1990, pp. 22-27. Chung Keun Rhee, Seoul (KR) Hanspeter Brunner et al., “Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and disease. A state (73) Assignees: Yang Ji Chemical Co., Ltd. (KR); Han ment by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension,” Journal of Hypertension, Wha Pharma Co., Ltd. (KR) vol. 23, No. 2, 2005, pp. 233-246. Ulrich Forstermann et al., “Endothelial Nitric Oxide Synthase in ( * ) Notice: Subject to any disclaimer, the term of this Vascular Disease: From Marvel to Menace,” Circulation, Jul. 12, patent is extended or adjusted under 35 2010. R. J. Gryglewski et al., “Superoxide anion is involved in the break U.S.C. 154(b) by 20 days. down of endothelium-derived vascular relaxing factor,” Nature Pub lishing Group, vol. 320, Apr. 3, 1986, pp. 454-455. (21) Appl. No.: 12/863,368 Chang-Bok Lee, “Illustrated Book of Korean Plants,” 1980, p. 403. Jong-Hee Park, “Illustrated Book of Korean Folk Medicines,” 2005, (22) PCT Filed: Dec. 17, 2008 p. 256. Bo-Seop Jeong et a1,m, Encyclopedia of Local Medicines (Plant), 1990, p. 458. (86) PCT No.: PCT/KR2008/007484 Jong-Cheol Park et al., “Isolation and Structure Elucidation of § 371 (0X1)’ Flavonoid Glycosides from Lindera obtusiloba BL,” J. Korean Soc. Food Nutr., vol. 25, No. 1, 1996, pp. 76-79. (2), (4) Date: Oct. 18, 2010 Search Output of endothelial dysfunction (ClinicalTrialsgov). Results on Map: endothelial dysfunction (ClinicalTrialsgov). (87) PCTPub.No.: WO2009/091120 Search Output of Nafronyl oxalate (KIMS). PCT Pub. Date: Jul. 23, 2009 Tamara M. Paravicini et al., Increased NADPH Oxidase Activity, gp91phox Expression, and Endothelium-Dependent Vasorelaxation (65) Prior Publication Data During Neointima Formation in Rabbits, Circres, Jul. 12, 2010. Gregory J. Dusting et al., “Nitric Oxide in Atherosclerosis: Vascular US 2011/0045111A1 Feb. 24, 2011 Protector or Villain?,” Clinical and Experimental Pharmacology and Physiology, vol. 25, 1998, pp. S34-S41. (30) Foreign Application Priority Data S. K. Lo et al., “Hydrogen peroxide-induced increase in endothelial adhesiveness is dependenton ICAM-l activation,” AMJ-Lung Cellu Jan. 18,2008 (KR) ...................... .. 10-2008-0005672 lar and Molecular Physiology, vol. 264, Issue 4 406-L412, 1993. Kathy K. Griendling eta1., “Redox control of vascular smooth muscle (51) Int. Cl. proliferation,” J Lab Clin Med, vol. 132, Jul. 1998, pp. 9-15. A61K 36/00 Sean M. Lynch et al., “Mechanisms of copper-and iron-dependent (2006.01) oxidative modi?cation of human low density lipoprotein,” Journal of (52) US. Cl. Lipid Research, vol. 34, 1993, pp. 1745-1753. USPC .......................... .. 424/774; 424/725; 424/779 TomaSZ J. GuZik et al., Vascular Superoxide Production by NAD(P)H (58) Field of Classi?cation Search Oxidase: Association With Endothelial Dysfunction and Clinical None Risk Factors, Circ Res, vol. 86, 2000, pp. e85-e90. Sheila A. Doggrell, “New Drugs and New Targets” Drug News See application ?le for complete search history. Perspect, vol. 17, No. 9, 2004, pp. 615. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner * Chris R Tate Assistant Examiner * Russell Fiebig 5,135,746 A * 8/1992 Matsuno et al. ............ .. 424/725 (74) Attorney, Agent, or Firm * Cantor Colburn LLP 5,902,831 A 5/1999 Holland et al. 2007/0160699 A1 7/2007 Kim (57) ABSTRACT The present invention relates to a composition for treatment FOREIGN PATENT DOCUMENTS and prevention of cardiovascular diseases, containing an extract of Lindera obtusiloba. More particularly, the extract CN 001742801 3/2006 of Lindera obtusiloba strongly inhibits NAD(P)H oxidases, CN 1742801 3/2006 which are the main cause of vascular diseases, and at the same JP 06-135830 5/1994 time, regulates contraction and relaxation of vascular smooth JP 2000-344673 12/2000 muscles to manifest a potent vasorelaxant effect, thereby JP 2000344673 12/2000 improving the blood pressure regulation and vascular endot KR 10-2001-0015807 2/2001 helial dysfunction. Therefore, a composition containing this KR 10-2001-0042815 5/2001 as an active ingredient can be usefully utilized as a pharma KR 10-2002-0084230 11/2002 ceutical product or health functional food product for the KR 10-2003-0041965 5/2003 prevention and treatment of cardiovascular diseases. KR 10-2003-0055276 7/2003 KR 10-2003-0086340 7/2003 11 Claims, 4 Drawing Sheets US 8,734,866 B2 Page 2 (56) References Cited Peter C. 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Species in Coronary Arteries After Balloon Injury,” Arteriosclerosis, Ulrich Forstermann et al., “Endothelial Nitric Oxide Synthase in Thrombosis, and Vascular Biology, vol. 21, 2001, pp. 739-745. Vascular Disease: From Marvel to Menace,” Circulation. vol. 113, Karen Y. Stokes et al., “NAD(P)H Oxidase-Derived Superoxide 2006, pp. 1708-1714. Mediates Hypercholesterolemia-Induced Leukocyte-Endothelial M. K. Na, et al, Antioxidant Effects of Plant Extracts on Free Radicals Cell Adhesion,” Circulation Research, vol. 88, 2001, pp. 499-505. and Lipid Peroxidation, Natural Product Sciences, 2003, pp. 226 F.E. Rey et al., “Novel Competitive Inhibitor of NAD(P)H Oxidase 231 . Assembly Attenuates Vascular O 2-and Systolic Blood Pressure in Philippine Substantive Examination ReportiPhilippine Application Mice,” Circulation Research,vol. 89, Aug. 31, 2001, pp. 408-414. No. 1/2010/501596 issued on Apr. 17, 2013, citing Database Patricia A. Barry-Lane et al., “p47phox is required for atherosclerotic TCM(Online) SIPO, Jong-Cheol Park et al, Ruehl et al. And Kwon H lesion progression in ApoE-/- mice,” The Journal of Clinical Inves C et al. tigation, vol. 108, No. 10, Nov. 2001, pp. 1513-1522. J. C. Park et al., Isolation and Structure Elucidation of Flavonoid Katalin Szocs et al., “Upregulation of Nox-Based NAD(P)H Glycosides from Lindera obtusiloba BL., J. Korean Soc. Food Nutr., Oxidases in Restenosis After Carotid Injury,” Arteriosclerosis 1996, pp. 76-79. Thrombosis, and Vascular Biology, vol. 22, 2002, pp. 21-27. M. Ruehl et al., Antibrotic Effects of Lindera obtusiloba Extracts: Tamara M. Paravicini et al., “Redox signaling in hypertension,” Car Downregulation of TGF-Beta Induced Collagen Type 1 Expression diovascular Research, vol. 71, Jul. 15, 2006, pp. 247-258. and Neutralization of Peroxide Induced ROS Production in Hepatic L. Loffredo et al., "Oxidative-stress-mediated arterial dysfunction in Stellate Cells, Molecular and Cellular Biology, 2007 pp. 132-133. patients with peripheral arterial disease,” European Heart Journal, H. C. Kwon et al., Two New Lignans fromLindera obtusiloba Blume, vol. 28, 2007, pp. 608-612. Arch Pharm Res., 1999, pp. 417-422. Carlene A. Hamilton et al., Superoxide Excess in Hypertension and European Search Report-European Application No. 08 87 0964 Aging a common Cause of Endothelial Dysfunction, Hypertension, issued Mar. 25, 2011. vol. 37, 2001, pp. 529-534. M. Ruehl et al., “Anti?brotic Effects of Lindera Obtusiloba Extracts: Akiko Fukatsu et al., “Possible usefulness of apocynin, an NADPH Downregulation of TGF-B Induced Collagen Type 1 Expression and oxidase inhibitor, for nitrate tolerance: prevention of NO donor Neutralization of Peroxide Induced Pros Production in Hepatic Stel induced endothelial cell abnormalities,”Am J Physiol Heart Circ late Cells,” Journal of Hepatology, Munksgaard International Pub Physiol, vol.
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