Granted Patent
B2
US 12,544,399 · App. 18/199,322 · Granted Feb 10, 2026
Compositions of nitrates and methods of use thereof
Assignee:
Heartbeet, Ltd.
A61K33/00A23L2/02A23L2/52A23L33/105A23L33/135A23L33/16A61K9/0056A61K9/0095A61K9/08A61K31/198A61K31/375A61K33/14A61K33/30A61K36/185A61K36/21A61K45/06A61P9/12A23V2002/00C01D9/00
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Inorganic anions nitrate and nitrite influence metabolic rate and glucose homeostasis. Infusion of nitrite iv caused an acute drop in resting energy expenditure (oxygen consumption) and nitrate, when given perorally, caused a reduction in oxygen consumption during exercise and a depression of the increase in blood glucose observed after an oral glucose tolerance test. The doses of nitrate and nitrite did not cause any detectable change in methemoglobin levels of blood. Also, nitrate and nitrite did not alter lactate levels in blood. This discovery provides useful treatments to regulate the energy expenditure and glucose homeostasis of a mammal by administration of inorganic nitrite and/or nitrate.
Claims (23)
1 . A method of promoting health by improving circulation in a human in need thereof, the method comprising administering inorganic nitrate (NO 3 − ) to the human in an amount of about 0.001-100 mmol inorganic nitrate (NO 3 − ) per kg body weight of the human, whereby administration of the inorganic nitrate (NO 3 − ) improves circulation in the human.
2 . The method of claim 1 , wherein about 0.01-100 mmol inorganic nitrate (NO 3 − ) is administered per kg body weight of the human.
3 . The method of claim 1 , wherein about 0.01-10 mmol inorganic nitrate (NO 3 − ) is administered per kg body weight of the human.
4 . The method of claim 1 , wherein about 0.01-1 mmol inorganic nitrate (NO 3 − ) is administered per kg body weight of the human.
5 . The method of claim 1 , wherein 0.1 mmol inorganic nitrate (NO 3 − ) is administered per kg body weight of the human.
6 . The method of claim 1 , whereby administration of the inorganic nitrate (NO 3 − ) reduces systolic blood pressure of the human.
7 . The method of claim 1 , whereby administration of the inorganic nitrate (NO 3 − ) reduces diastolic blood pressure of the human.
8 . The method of claim 1 , wherein the inorganic nitrate (NO 3 − ) is administered in the form of beetroot juice.
9 . The method of claim 1 , wherein the inorganic nitrate (NO 3 − ) is administered in a composition consisting of the inorganic nitrate (NO 3 − ) and at least one additive.
10 . The method of claim 9 , wherein the composition is a nutritional supplement.
11 . The method of claim 9 , wherein the additive is selected from the group comprising: natural flavor, artificial flavor, sweetener, flavor enhancer, color additive, emulsifier, stabilizer, fat, and preservative.
12 . The method of claim 9 , wherein the inorganic nitrate (NO 3 − ) is provided from a natural nitrate source.
13 . The method of claim 12 , wherein the natural nitrate source is juice or dried concentrate from at least one of spinach, lettuce, fennel, cabbage, Chinese cabbage, and beetroot.
14 . The method of claim 9 , wherein the source of the inorganic nitrate (NO 3 − ) is in the form of a nitrate salt.
15 . The method of claim 14 , wherein the nitrate salt is selected from the group consisting of: sodium nitrate, potassium nitrate, calcium nitrate, zinc nitrate, ammonium nitrate, and arginine nitrate.
16 . The method of claim 1 , wherein the inorganic nitrate (NO 3 − ) is administered orally.
17 . The method of claim 1 , wherein the inorganic nitrate (NO 3 − ) is administered in a composition in the form of a liquid, a paste, a gel, a bar, a cake, a powder, a granulate, an effervescent tablet, a chewing gum, a tablet, a capsule, a lozenge, a fast melting tablet or wafer, a sublingual tablet, or a spray.
18 . The method of claim 1 , wherein the inorganic nitrate (NO 3 − ) is administered in a composition comprising the inorganic nitrate (NO 3 − ) and a polyphenol.
19 . The method of claim 18 , wherein the polyphenol provided is from at least one natural source selected from the group consisting of: apple, pear, grapes, lemon, orange, lime, peach, pomegranate, grapefruit, kiwi, ginger, pineapple, blackberries, black raspberries, blueberries, cranberries, red raspberries, cherries, bog whortleberry, lingonberries, black elderberry, black chokeberry, black currant, cloudberries, strawberries, carrots, chili, rhubarb, onions, cacao products, green tea, black tea, nuts, Yerba mate, and coffee.
20 . The method of claim 18 , wherein the amount of the inorganic nitrate (NO 3 − ) in the composition is at least 50% by weight or by volume.
21 . The method of claim 18 , wherein the composition is a functional food.
22 . The method of claim 18 , wherein the inorganic nitrate (NO 3 − ) is administered in the form of beetroot juice.
23 . A method of increasing circulation in a human, the method comprising administering inorganic nitrate (NO 3 − ) to the human in an amount of about 0.001-100 mmol inorganic nitrate (NO 3 − ) per kg body weight of the human.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 6, 2023
From: LUNDBERG, JON; WEITZBERG, EDDIE
To: HEARTBEET LTD.
Reel/Frame 063860/0420 →
Priority Claims (2)
SE 0700520-0
· Feb 26, 2007
· national
SE 0700729-0
· Mar 22, 2007
· national
Continuity (8)
Continuation
12528798
Provisional Application
60919709
· Mar 22, 2007
References Cited (202)
US 4702922A
· Wiesenberger
· 1987
[cited by applicant]
US 4853237A
· Prinkkila
· 1989
[cited by applicant]
US 4868179A
· Cohn
· 1989
[cited by applicant]
US 5476847A
· McKittrick
· 1995
[cited by applicant]
US 6024992A
· Yoo
· 2000
[cited by applicant]
US 6117872A
· Maxwell
· 2000
[cited by applicant]
US 6348465B1
· Baker
· 2002
[cited by applicant]
US 6419900B2
· Placke
· 2002
[cited by applicant]
US 6689403B1
· Gehring
· 2004
[cited by applicant]
US 6890529B1
· Annika
· 2005
[cited by applicant]
US 8303995B1
· Bryan
· 2012
[cited by applicant]
US 9180140B2
· Lundberg
· 2015
[cited by applicant]
US 20020110512A1
· Rigby
· 2002
[cited by applicant]
US 20030036565A1
· Parkin
· 2003
[cited by applicant]
US 20030235571A1
· Gojon-Romanillos
· 2003
[cited by applicant]
US 20040204371A1
· Cohn
· 2004
[cited by applicant]
US 20050036949A1
· Tucker
· 2005
[cited by applicant]
US 20050036996A1
· Roussel
· 2005
[cited by applicant]
US 20050226906A1
· Moneymaker
· 2005
[cited by applicant]
US 20050256192A1
· Gardiner
· 2005
[cited by applicant]
US 20050266018A1
· Boreyko
· 2005
[cited by applicant]
US 20060057118A1
· Toride
· 2006
[cited by applicant]
US 20060182815A1
· Gladwin
· 2006
[cited by applicant]
US 20070010581A1
· Esteve-Soler
· 2007
[cited by applicant]
US 20070105817A1
· Page
· 2007
[cited by applicant]
EP 0511587A1
· 1992
[cited by applicant]
EP 1747786
· 2007
[cited by applicant]
EP 2008661A2
· 2008
[cited by applicant]
GB 962209A
· 1964
[cited by applicant]
JP 05252905
· 1993
[cited by applicant]
JP 2004305088
· 2004
[cited by applicant]
JP 2010519336
· 2010
[cited by applicant]
KR 20020057695A
· 2002
[cited by applicant]
WO 199945797
· 1999
[cited by applicant]
WO 9966921
· 1999
[cited by applicant]
WO 2004017955
· 2004
[cited by applicant]
WO 2004056376A1
· 2004
[cited by applicant]
WO 2005004884A2
· 2005
[cited by applicant]
WO 2005062713
· 2005
[cited by applicant]
WO 200611601A2
· 2006
[cited by applicant]
WO 2006110601
· 2006
[cited by applicant]
WO 2007014334A2
· 2007
[cited by applicant]
WO 2007077210
· 2007
[cited by applicant]
Galley et al., Clin. Sci., 92, pp. 361-365 (Year: 1997).
[cited by applicant]
Hasegawa et al., J. Hypertension, 22, p. S200, abstract (Year: 2004).
[cited by applicant]
Grudzinski et al., Arch Environ Contam Toxicol. Sep. 1991;21(3):462-467.
[cited by applicant]
Guazzi et al., The American Journal of Cardiology, 84:1038-1043 (1999).
[cited by applicant]
Hamel et al., Critical Care Nurse, 31 (1 ):72-82 (2011).
[cited by applicant]
Harrison, D.G. et al., “The Nitrovasodilators, new Ideas About Old Drugs,” Circulation, vol. 87, No. 5, May 1993, pp. 1461-1467).
[cited by applicant]
Heusch et al., Endogenous Nitric Oxide and Myocardial Adaption to Ischemia, Circ. Res. 2000; 87:146-152, 2000.
[cited by applicant]
Hunter et al., Nature Medicine, vol. 10, Oct. 2004, pp. 1122-1127.
[cited by applicant]
Ijima et al., Gastroenterology, 122: 1248-1257 (2002).
[cited by applicant]
Imaizumi. Effects of L-Arginine on Forearm Vessels and Responses to Acetylcholine, Hypertension, vol. 20, No. 4, pp. 511-517 (Oct. 1992).
[cited by applicant]
J. Abrams, MD, Beneficial Actions of Nitrates in Cardiovascular Disease, The American Journal of Cardiology, vol. 77, pp. 31C-37C (May 30, 1996).
[cited by applicant]
J. Warner, Nitrates Lower Blood Pressure: Nutrient Found in Spinach, Other Vegetables Keeps Blood Vessels Healthy, WebMD Medical News (Dec. 27, 2006) (available at https://web.archive.org/web/ 20070119154017/htts://www.…
[cited by applicant]
Journal of Human Hypertension Webpage for EXI 042, Oct. 2007, 2 pages, (Table of Contents ONLY for Journal of Human Hypertension, vol. 21, Issue 10, Oct. 2007).
[cited by applicant]
Joyner et al., “Endurance exercise performance: the physiology of champions”, J. Physiol, 586(1), pp. 35-44, published online Sep. 27, 2007. (Year: 2007).
[cited by applicant]
Jungersten et al., “Both physical fitness and acute exercise regulate nitric oxide formation in healthy humans” Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology, American Physiological S…
[cited by applicant]
K Akhilender Naidu, Vitamin C in human health and disease is still a mystery? An overview, Nutrition Journal, vol. 2. No. 7 (2003).
[cited by applicant]
K. Cosby, et al., Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation, Nature Medicine, vol. 9, No. 12, pp. 1498-1505(Dec. 2003).
[cited by applicant]
K. Tsuchiya, et al., Malfunction of Vascular Control in Lifestyle-Related Diseases: Formation of Systemic Hemoglobin-Nitric Oxide Complex (HbNO) From Dietary Nitrite, J. Pharmacol Sci, vol. 96, pp. 395-400 (2004).
[cited by applicant]
Kahn, Anannas, Khazaain-al-Advia, vol. II (20th centurAD), Nadeem Yunus Printer/Sheikh Mohd Basheer & Sons, Lahore, 1911 AD, pp. 627-628, and translation.
[cited by applicant]
Kelly et al.,Effect of short term dietary nitrate supplementation on blood pressure, 02 uptake kinetics, and muscle and cognitive function in older adults, Am J Physiol Regul Integr Comp Physiol., 304(2):R73-83 (2013).
[cited by applicant]
Kirk et al. (Ann. Emerg. Med., Sep. 1993; 22 :1413-1418.).
[cited by applicant]
L. Brunton, An Address on Blood Pressure In Man: Its estimation and indications for treatment, The British Medical Journal, pp. 64-67 (Jul. 10, 1909).
[cited by applicant]
L. Brunton, et al., An Address on Longevity and the Means of Attaining It, The Lancet, vol. 168, Issue 4342, pp. 1330-1335 (Nov. 17, 1906).
[cited by applicant]
Lacerda et al., Neuroscience Letters, 393, pp. 260-263 (2006).
[cited by applicant]
Lansley et al., Dietary nitrate supplementation reduces the 02 cost of walking and running: a placebo-controlled study, J Appl Physiol., 110(3):591-600 (2011).
[cited by applicant]
Larsen et al., “Effects of Dietary Nitrate on Oxygen Cost During Exercise,” Acta Physiol. 191: 59-66, 2007.
[cited by applicant]
Larsen et al., “Dietary inorganic nitrate improves mitochondrial efficiency in humans”, Cell Metab., 13(2):149-159 Feb. 2011).
[cited by applicant]
Larsen, Effects of dietary nitrate on blood pressure in healthy volunteers, New England Journal of Medicine 355:2792-2793 (2006).
[cited by applicant]
Laycock et al., Role of Nitric Oxide in the Control of Renal Oxygen Consumption in the Regulation of Chemical Work n the Kidney , Circ. Res., 82:1263-1271, 1998.
[cited by applicant]
Liu et al.,“No effect of short-term arginine supplementation on nitric oxide prduction, metabolism and performance in Intermittent exercise in athletes”, J Nutr Biochem 20 (6): 462-468 (2008).
[cited by applicant]
Lundberg et al., Arterioscler. Thromb. Vase. Biol., 25:915-922 (2005).
[cited by applicant]
Lundberg, “Inorganic Nitrate is a Possible Source for Systemic Generation of Nitric Oxide,” Free Radical Biology & Medicine, vol. 37, No. 3, pp. 395-400, 2004.
[cited by applicant]
M Hermann et al., “Nitric Oxide in Hypertension”, The Journal of Clinical Hypertension, Supp. 4, vol. 8, No. 12, pp. 17-29. (Year: 2006).
[cited by applicant]
M. Robinson, et al., Effects of antacid formulation on postprandial oesophageal acidity in patients with a history of episodic heartburn, Ailment Pharmacol. Therm., vol. 16, pp. 435-443 (2002).
[cited by applicant]
M. Smiechowska, The Content of Nitrates V and III and Vitamin C in Juices Obtained fi-om Organic and Conventional Raw Materials, Polish Journal of Food and Nutrition Sciences, vol. 12/53, No. 2, pp. 57-61 (2003).
[cited by applicant]
McKnight et al., “Review article: Dietary nitrate in man: friend or foe?”, British Journal of Nutrition, 81:349-358, 1999.
[cited by applicant]
Millar et al., Xanthine Oxidoreductase Catalyses the Reduction of Nitrates and Nitrite to Nitric Oxide Under Hypoxic Conditions, FEBS Letters 427, 225-228, 1998.
[cited by applicant]
Mishra, Madhuradi Manduram, Siddaprayogalatika, Translated by Vd. Shivakaran Sharma Chhangani, Chaukhamba Orientalia (Varanasi), Ed. 2nd 2005, p. 203, and translation.
[cited by applicant]
Modin et al., Nitrite-derived Nitric Oxide: a Possible Mediator of Acidic-Metabolic Vasodilation, Acta Physiol Scand, 171,9-16, 2001.
[cited by applicant]
Moncada et al., “The L-Arginine: Nitric Oxide Pathway”, Journal of Cardiovascular Pharmacology, 17(Suppl. 3):S1-S9, Raven Press, New York, 1991.
[cited by applicant]
NIHWebpage showing availability of EX1056 (NIH2) as of Feb. 12, 2006 (available at https://web.archive.org/web/20060212100027 /http.7/ www.nhlbi.nih.gov/guidelines/hypertension/jnc7full. htm).
[cited by applicant]
Nisoli et al., Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide, Science, 299(5608):896-899 2003).
[cited by applicant]
Ogden et al., Mean Body Weight, Height, and Body Weight Index, United States 1960-2002, Advanced Data From Vital and Health StatisticsNo. 347 (2004).
[cited by applicant]
Oldreive, C, Rice-Evans, C, “The Mechanisms for Nitration and Nitrotyrosine Formation in vitro and in vivo: Impact of Diet”, Free Rad. Res., vol. 35, pp. 215-231, 2001.
[cited by applicant]
Olek et al., “A Single oral intake of arginine does not affect performance during repeated Wingate anaerobic test”, J Sports Med Phys Fitness, 50(1):52-56 (2010).
[cited by applicant]
Osada et al. Cholesterol oxidation in meat products and its regulation by supplementation of sodium nitrite and apple polyphenol before processing. J Agric Food Chem. 2000; 48: 3823-9.
[cited by applicant]
P. Santamaria, Nitrate in vegetables: toxicity, content, intake and EC regulation, Journal of the Science of Food and Agriculture, 86:10-17 (2006).
[cited by applicant]
Parent et al, Nitroglycerin reduces myocardial oxygen consumption during exercise despite vascular tolerance, Am J Physiol Heart Circ Physiol 290: H1226-H1234, 2005.
[cited by applicant]
Peri et al, “Apples increase nitric oxide production by human saliva at the acidic pH of the stomach: A new biological function for polyphenols with a catechol group?”, Free Radical Biology and Medicine, Elsevier Scienc…
[cited by applicant]
Pickering et al., Why Don't We Use Nitrates to Treat Older Hypertensive Patients?, Journal of Clinical Hypertension, vol. 7, No. 11, pp. 685-690 (Nov. 2005).
[cited by applicant]
Poderoso et al., Nitric oxide Regulates Oxygen Uptake and Hydrogen Peroxide Release by the Isolated Beating Rat Heart, Am. J. Physiol. 274 (Cell Physiol. 43): C112-C119; 1998.
[cited by applicant]
RediBeets™ Webpage (2006) (available at https://web.archive.org/web/20060206221 752/https:/l allonhealth.com/health-products/redibeets.htm).
[cited by applicant]
Richardson et al., “The ingestion of inorganic nitrate increases gastric S-nitrosothiol levels and inhibits platelet function in humans”, Nitric Oxide, 7:24-29, 2002.
[cited by applicant]
Roy, D., Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent, Am. J. Physiology, vol. 274, No. 4, pp. E692-E699 (Apr. 1998).
[cited by applicant]
Sar et al., Effects of Combination of Nitrate with _1-4Galacto-oligosaccharides and Yeast on Methane Emissioni from Sheep, Asian-Aust. J. Anim.Sci., vol. 17 No. 1:73-79,2004.
[cited by applicant]
Scardi, Chronic Treatment After Acute Myocardial Infarction: Which Drug for Which Patient? Nitrates, Journal of Cardiovascular Pharmacology 14 ( . 9): S84-S88, 1989.
[cited by applicant]
ScienceDirect Webpage for EXI033, Nov. 1906, 2 pages.
[cited by applicant]
Sharkey, B. J., Fitness and Work Capacity, Second Edition, USDA Forest Service, Technology & Development Program (Apr. 1997).
[cited by applicant]
Shen et al., “Nitric oxide production and NO synthase gene expression contribute to vascular regulation during exercise.”, Med Sci Sports Exerc, 27(8):1125-34, 1995.
[cited by applicant]
Shibata et al. (Jul. 22, 2005). Nitric oxide modulates oxygen consumption by arteriolar walls in rat skeletal muscle, American Journal of Physiology: Heart Circulation Physiology 289:H2673-H2679.
[cited by applicant]
Shiva et al. (2007). Deoxymyglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial espi ration, Circulation Research 100:654-661.
[cited by applicant]
Siddhaprayogasamgrahah, Phalasava, Part II; Krishan Gopal Ayureda Bhawan, Edn 8th 1990, pp. 620-621, and translation.
[cited by applicant]
Sies et al., Cocoa polyphenols and inflammatory mediators, Am. J. Clin. Nutr., vol. 81, No. 1pp. 304S-312S (2005).
[cited by applicant]
Sobko et al., Am. J. Physiol. Gastrointest. Liver Physiol. 287(5):0993-0997 (Nov. 2004).
[cited by applicant]
Stamler et al., Biochemistry of Nitric Oxide and Its Redox-Activated Forms, Science, vol. 258, Dec. 18, 1992, pp. 1898-1902.
[cited by applicant]
Stokes et al., “Long-Term Effectiveness of Extended-Release Nitrate for the Treatment of Systolic Hypertension”, Hypertension, 45:380-384, 2005.
[cited by applicant]
Sunderland et al.,V02max and ventilator threshold of trained cyclists are not affected by 28-day I-arginine supplementation, J Strength Cond Res, 25 (3):883-837 (2011).
[cited by applicant]
Tabau et al., Cardiovascular Research, 21:606-614 (1987).
[cited by applicant]
The Lancet Webpage for EX1033, Nov. 17, 1906, 5 pages.
[cited by applicant]
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, U.S. Dept. of Health and Human Services; National Institutes of Health; National Heart, Lung…
[cited by applicant]
Tian et al., Hypertension Research, 34:1221-1227 (2011).
[cited by applicant]
Tsuchiya, Nitrite is an alternative souce of NO in vivo, Am. J. Physil. Heart Circ, Physiol 288: H2163-H2170,2004.
[cited by applicant]
Vahatalo et al.,No effect of acute L-arginine supplementation on 0(2) cot or exercise tolerance, Eur J Appl Physiol. Feb. 20, 2013).
[cited by applicant]
Vaisya, Palakyasidhamatsya, Vangasena, Edited Shankar Ialji Jain, Khemraj Shrikrishna Das Prakashan, Bombay, Edn. 1996, p. 1062, and translation.
[cited by applicant]
Van Velzen et al., Toxicology Letters, 181:177-181 (2008).
[cited by applicant]
W.J. Corre, Nitrate and nitrite in vegetables, Centre for Agricultural Publishing and Documentation, Wageningen (1979.
[cited by applicant]
Weiqun Shen et al, “Role of Nitric Oxide in the Regulation of Oxygen Consumption in Conscious Dogs”, Circulation Research, (Jan. 28, 1994), vol. 75, doi:10.1161/01.RES.75.6.1086, pp. 1086-1095, XP055198527.
[cited by applicant]
Whisonant etal., “Geology and History of Confederate Saltpeter Dave Operations in Western Virginia”, Virginia Minerals, 47(4):33-44, 2021.
[cited by applicant]
White, Relative Significance of Dietary Sources of Nitrate and Nitrite, J. Agric. Food Chem., vol. 23, No. 5, 6 pages (1975).
[cited by applicant]
Xu et al., Applied Microbiology and Biotechnology, vol. 56, No. 3-4, Aug. 2001, pp. 504-507.
[cited by applicant]
Yoon et al., Bioresource Technology 97 (2006) 1427-1430.
[cited by applicant]
U.S. Appl. No. 65/117,872, filed Sep. 12, 2000, Maxwell.
[cited by applicant]
“Meat and meat products—Determination of nitrate contact (Reference method)”, International Standard ISO 3091, Ref. No. ISO 3091-1975(E), 1975.
[cited by applicant]
21 CFR § 101.12 Reference amounts customarily consumed per eating occasion ( 4-1-3 Edition), 2014.
[cited by applicant]
A Butler et al., Medieval Chinese Medicine: The Dunhuang Medical Manuscripts (Chapter 16: A treatment for carenovascular dysfunction in a Dunhuang medical manuscript), Routledge (2005).
[cited by applicant]
AJ Webb et al., “4.2 Acute blood pressure (BP) lowering and vasoprotective effects of beetroot juice: relationship to nitrite derived from dietary nitrate”, Journal of Human Hypertension, vol. 21, No. 10, pp. 834-835. (…
[cited by applicant]
AJ Webb, et al., BHS Abstracts, Journal of Human Hypertension, vol. 21, pp. 828-850 (Sep. 20, 2007).
[cited by applicant]
Appel et al., “A Clinical Trial of the Effects of Dietary Patterns on Blood Pressure”, The New England Journal of Medicine, 336(16): 1117-1124, 1997.
[cited by applicant]
Archer, Douglas L., Evidence that Ingested Nitrate and Nitrite Are Beneficial to Health, Journal of Food Protection, vol. 65, No. 5, pp. 872-875 (2002).
[cited by applicant]
B. C. Challis, Nutrition and nitrosamine formation, Proceeds of the Nutrition Society, vol. 44, pp. 95-100 (1985).
[cited by applicant]
B. Spiegelhalder, et al., Influence of Dietary Nitrate on Nitrate Content of Human Saliva: Possible Relevance of N-Nitroso Compounds, Fd. Cosmet. Toxicol., vol. 14, pp. 545-548 (1976).
[cited by applicant]
B. Symonds, The Influence of Overweight and Underweight on Vitality, Journal of the Medical Society ofNew Jersey, vol. V, No. 4, pp. 159-167 (Sep. 1908)).
[cited by applicant]
Bailey et al. “Dietary nitrate supplementation reduces the 02 cost of low-intensity exercise and enhances tolerance to ligh-intensity exercise in humans”, J. Appl. Physiol., 2009, vol. 107, pp. 1144-1155. (Year 2009).
[cited by applicant]
Balzer, et al., Reductase activity of polyphenols?: A commentary on ‘Red wine-dependent reduction of nitrite to nitric Oxide in the stomach’, Free Radical Biology and Medicine 43:1226-128,2007.
[cited by applicant]
Benjamin, Nigel, Nitrates in the Human Diet—good or bad?, Ann. Zootech. vol. 49, pp. 207-216 (2000).
[cited by applicant]
Bescos et al., The Effect of Nitric-Oxide-related Supplements on Human Performance, Sports Med, 42 (2):99-117 2012).
[cited by applicant]
Bescos, “Effects of dietary L-Arginine intake on cardiorespiratory and metabolic adaptation in athletes”, Int J Sport Nutr Exerc Metab, 19:355-65 (2009).
[cited by applicant]
Bjone et al., Nitrite in Saliva Increases Gastric and Mucosal Blood Flow and Mucus Thickness, J. Clin. Invest. 113: 106-114, Jan. 2004.
[cited by applicant]
Bjorne, The Nitrite Ion: Its Role in Vasoregulation and Host Defenses, from the Department of Physiology and Pharmacology Section of Anesthesiology and Intensive Care medicine, Karolinska Instititutet, Stockholm, Sweden…
[cited by applicant]
Boguslavskiy. Effect of nitric oxide on the efficiency of oxygen usage by a working skeletal muscle under fatigue, Fiziol. Zhum., vol. 51, No. 1, pp. 33-42 (2005) & Certified Translation.
[cited by applicant]
Bohuslavs'Kyi, Effect of Nitric Oxide on the Efficiency of Oxygen Consumption by the Working Skeletal Muscles in Fatigue, Fiziol ZH, 51(1):33-42, 2005.
[cited by applicant]
Bryan et al., Free Radical Biology & Medicine 41, pp. 691-701 2006.
[cited by applicant]
Burtscher. The Proonged Intake of L-Arginine-L-Aspartate Reduces Blood Lactate Accumulation and Oxygen Consumption During Submaximal Exercise, Journal of Sports Science and Medicine, vol. 4, pp. 314-322 (2005).
[cited by applicant]
Cederqvist et al., Direct Demonstration of NO Formation In Vivo From Organic Nitrites and Nitrates, and Correlation to Effects of Blood Pressure and to In Vitro Effects, Biochemical Pharmacology, vol. 47, No. 6, pp. 104…
[cited by applicant]
Ceremuzynski et al., Effect of Supplemental Oral L-Arginine on Exercise Capacity in Patients with Stable Angina Pectoris, The American Journal of Cardiology, vol. 80, pp. 331-333,1997.
[cited by applicant]
Chong, Relationship Between Circulating levels of Nitrates and Steroid in Patients Admitted to Coronary Care Unit, a hesis submitted to fulfill the requirements of the Degree of Master of Science to the Chinese Universi…
[cited by applicant]
Classen et al., Journal of the American College of Nutrition, vol. 9. No. 5. 500-502 (1990).
[cited by applicant]
Cohn, et al., A Comparison of Enalapril with Hydralazine-Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure, The New England Journal of Medicine, 325:303-310 (1991).
[cited by applicant]
Crawford et al., Effect of nitrate on determinants of myocardial oxygen consumption during exercise, International Journal of Cardiology, 1, 307-314, 1982.
[cited by applicant]
Crawford et al., Hypoxia, Red blood Cells, and Nitrite Regulate NO-dependent Hypoxic Vasodilation, Blood 2006, 107:566-574.
[cited by applicant]
D. D. Rees, et al., Role of endothelium-derived nitric oxide in the regulation of blood pressure, Proc. Natl. Acad. Sci. USA, vol. 86, pp. 3375-3378 (May 1989).
[cited by applicant]
Davidson et al., (2006). Effect of NO onmitochondhal function in cardiomyocytes: Pathophysiological relevance, Cardiovascular Research 71:10-21.
[cited by applicant]
De Vries et al., Lactobacillus plantarum-survival, functional and potential probiotic properties in the human intestinal tract, International Dairy Journal, vol. 16, No. 9, Sep. 2006, pp. 1018-1028.
[cited by applicant]
Deng et al., “Formation of ethyl nitrite in vivo after ethanol administration”, Alcohol, Pergamon Press London, GB, vol. 34, No. 2-3, Oct. 1, 2004 (Oct. 1, 2004), pp. 217-223, XP004765251, ISSN: 0741-8329,001:10.1016/J.…
[cited by applicant]
E.G. Heisler, et al., Changes in Nitrate and Nitrite Content, and Search/or Nitrosamines in Storage-Abused Spinach and Beets, J. Agr. Food Chem., vol. 22, No. 6, pp. 1029-1032 (1974).
[cited by applicant]
Extra Strength Alka Seltzer Drug Facts (2004) (available at https://web.archive.org/web/ 20040422223603/http://www.alka-seltzer.com/as/ images/ Alka-Extra-Strength.gif.
[cited by applicant]
F. Murad, Cyclic Guanosine Monophosphate as a Mediator of Vasodilation, J. Clin. Invest., vol. 78, pp. 1-5 (Jul. 1986).
[cited by applicant]
Facts About The DASH Diet, U.S. Dept. of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute (2001).
[cited by applicant]
Fass, Suscard, Bipacksedel, 2006, 4 pgs.
[cited by applicant]
Ferrannini, Metabolism, 37(3):287-301 (1988).
[cited by applicant]
Foex, P., “Hypertension: pathophysiology and treatment”, Continuing Education in Anaesthesia, Critical Care & Pain, 4(3):71-75, 2004.
[cited by applicant]
Friberg et al., Journal of Hypertension, 4(2): 165-173 (1986), Abstract only.
[cited by applicant]
Fryer etal, “Mean Body Weight, Height, Waist Circumference, and Body Mass Index Among Adults: United States, 1999-2000 Through 2015-2016”, US Dept of Health and Human Services, Centers for Disease Control and Prevention…
[cited by applicant]
G. M. McKnight, et al., Chemical synthesis of nitric oxide in the stomachfi-om dietary nitrate in humans, Gut, vol. 40, pp. 211-214 (1997).
[cited by applicant]
G. R. J. Thatcher, Serial Review: Mechanisms and Novel Directions in the Biological Applications of Nitric Oxide Donors, Free Radical Biology & Medicine, vol. 37, No. 8, pp. 1122-1143 (2004).
[cited by applicant]
Gago et al., Red wine-dependent reduction of nitrite to nitric oxide in the stomach, Free Radical Biology and Medicine 43:1233-1242, 2007. 10 pages.
[cited by applicant]
Giulivi et al. (2006). Nitric oxide reduction of mitochondrial oxygen consumption I: cellular physiology, American Journal of Physiology—Cell Physiology 291:225-231.
[cited by applicant]
Gladwin et al., Nature Chemical Biology, vol. 1 No. Nov. 6, 2005, pp. 308-314 (2005).
[cited by applicant]
Gokce, L-Arginine and Hypertension, J. Nutr. 134: 2807S-2811S, 2004.
[cited by applicant]
Grossi et al., A New Synthesis of Alkyl Nitrites: The Reaction of Alkyl Alcohols with Nitric Oxide in Organic Solvents, Journal of Organic Chemistry 64:8076-8079, 1999.
[cited by applicant]
Grudzinski et al., Arch Environ Contam Toxicol. Sep. 1991;21 (3):468-74.
[cited by applicant]
“Beneficial”, “Benefit”, Merriam-Webster.com Dictionary, Merriam-Webster, https://www.merriamwebster. com/dictionary/benefit. Accessed Sep. 6, 2024. (Year: 2024) 2 pages.
[cited by applicant]
Mokdad et al., “Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001”, JAMA, vol. 289, No. 1, pp. 76-79 (Year: 2003).
[cited by applicant]
Rahmouni et al., “Obesity-Associated Hypertension”, Hypertension, vol. 45, Issue 1, pp. 9-14 (Year: 2005).
[cited by applicant]
Wood et al., “Effect of Adding Nitrate or Nitrite to Drinking Water on the Utilization of Carotene by Growing Swine”, Journal of Animal Science, vol. 26, Issue 3, pp. 510-513 (Year: 1967).
[cited by applicant]
Houston et al “Juice Powder Concetrate and Systemic Blood Pressure” eCAM, 4(4) 455-462 date: Feb. 7, 2007.
[cited by applicant]
Toldam-Anderson et al “Growth and development in black currants” Journal of Horticultural sciences; 72(1) Jul. 20, 1996; p. 155-169.
[cited by applicant]
Declaration of Jon Lundberg and Eddie Weitzberg Under 37 C.F.R. 1.132. Dec. 20, 2017.
[cited by applicant]
Jones, Andrew M., et al., “Nitric oxide synthase inhibition with L-NAME reduces maximal oxygen uptake but not gas exchange threshold during incremental cycle exercise in man,” J Physiol 560.1. 2004, pp. 329-338. 2004.
[cited by applicant]
Tanaka, Hiroaki, et al., “Effect of Nifedipine, Dilazep, Dinitrates and Propranolol on Blood Lactate Accumulation during Intensive Graded Exercise Testing in healthy Young Subjects,” Jpn Heart J. 1988, 617-630.
[cited by applicant]
How to Boost Your Circulation (And Why It's So Important For Your Health), Henry Ford Health, Oct. 27, 2020.
[cited by applicant]
NCI Dictionary of Cancer Terms, Nat'l Cancer Inst., https://www.cancer.gov/publications/dictionaries/cancer-terms/def/blood-circulation (last visited Sep. 9, 2025).
[cited by applicant]
Mauricio Di Fulvio et al., Diuretics: A Review of the Pharmacology and Effects on Glucose Homeostasis, 16 Front. Pharmacol., art. 1513125, at 1(Mar. 27, 2025).
[cited by applicant]
Jamadar, Moshin Jahangeer et al., Formulation Design and Evaluation of Chewable Tablet Containing Sucralfate and Diclofenac, 5 J. Med. & Pharm. Allied Sci. 198, 199 (2016).
[cited by applicant]
Sharma, Arya M. et al., b-Adrenergic Receptor Blockers and Weight Gain: A Systematic Analysis, 24 Obesity Revs. e13353, abstract (2023).
[cited by applicant]
Fried, Terri R. et al., The Effects of Comorbidity on the Benefits and Harms of Treatment for Chronic Disease: A Systematic Review, 9 Plos One e112593, at 3 (Nov. 2014).
[cited by applicant]