US 20160213673A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0213673 A1 BARTOS et al. (43) Pub. Date: Jul. 28, 2016

(54) ENDURANCE FORMULATION AND USE Publication Classification (71) Applicant: GLANBLA NUTRITIONALS (51) Int. Cl. (IRELAND) LIMITED, KILKENNY A613 L/522 (2006.01) (IE) A63L/98 (2006.01) A2.3L 2/52 (2006.01) (72) Inventors: Jeremy D. BARTOS, San Marcos, CA A63L/216 (2006.01) (US); Elaine DRUMMOND, Carlsbad, (52) U.S. Cl. CA (US) CPC ...... A6 IK3I/522 (2013.01); A61 K3I/216 (2013.01); A61 K3I/198 (2013.01); A23L I/3051 (2013.01); A23L 2/52 (2013.01); A23L (21) Appl. No.: 15/003,130 I/302 (2013.01); A23L 1/304 (2013.01); A23L I/30 (2013.01); A23 V 2002/00 (2013.01) 22) Filed: Jan. 21, 2016 (57) ABSTRACT (22) Filed: al. Al The present disclosure provides compositions and formula tions containing dihydrocapsiate, caffeine and arginine as Related U.S. Application Data well as methods of making and using the compositions and formulations. The compositions and formulations of the (60) Provisional application No. 62/108.207, filed on Jan. present disclosure increase human endurance during times of 27, 2015. physical activity. US 2016/0213673 A1 Jul. 28, 2016

ENDURANCE FORMULATION AND USE 0010 Capsinoids such as dihydrocapsiate exert similar 0001. The present application claims benefit of U.S. Pro thermogenic and lipolytic effects as the red pepper compound visional Patent Application No. 62/108.207, filed Jan. 27. capsaicin but without noxious sensations of pungency or 2015, the entire contents of which is incorporated herein by "hotness.” In addition, dihydrocapsiate does not cause reference. increases in blood pressure and heart rate like those attributed 0002 The present disclosure provides compositions and to capsaicin ingestion. The thermogenic and lipolytic effects formulations containing dihydrocapsiate, caffeine and argin of dihydrocapsiate (and all other capsaicins and capsinoids) ine as well as methods of making and using the compositions are mediated through the Transient Receptor Potential Vanil and formulations. The compositions and formulations of the loid 1 (TRPV1) receptors throughout the gastrointestinal present disclosure increase human endurance during times of tract, which in turn are linked with the sympathetic nervous physical activity. system (SNS). When activated, they increase SNS activity 0003. The compositions and formulations of the present which results in the downstream activation of uncoupling disclosure are believed to increase or enhance endurance proteins UCP-1, UCP-2, and UCP-3. when ingested by sparing glycogen stores, increasing aerobic 0011. Of particular importance for endurance is UCP-2 activity over anaerobic activity during times of physical activ and UCP-3, the latter of which is expressed in the skeletal ity and thereby reducing metabolite buildup that would nor muscle of all mammals and plays a role in the transport of free mally lead to exhaustion and limitations on endurance by a fatty acids. UCP-2 is primarily expressed in adipocytes and person not ingesting a composition or formulation of the plays a key role in lipolysis, which is the release of free fatty present disclosure. acids from their storage in adipocytes. This release is trig 0004 Compositions and formulations of the present dis gered as the body is searching for a fuel store to induce closure enhance endurance when ingested before or during, thermogenesis brought on by the TRPV-1 receptor activation or before and during physical exertion. Increasing endurance, (for example, in shivering). or the amount of time the body can work out, for example 0012 Free fatty acids can be utilized as a fuel source in running longer distances or for longer time, increasing num endurance training as well, and since UCP-3 is expressed in ber of reps of workout, etc., is an increasingly important focus skeletal muscle and helps transport free fatty acids, it is rea of sports nutrition. sonable to believe that it will help increase free fatty acid 0005. A focus of the presently disclosure technology is uptake by the muscles. enhancing endurance by increasing the sparing of glycogen 0013. In one animal study (“Upregulation of uncoupling stores, forcing aerobic activity as compared to anaerobic, proteins by oral administration of capsiate, a nonpungent increasing vasodilation, and reducing the build-up of metabo capsaicin analog J Appl Physiol. 2003 December; 95(6): lites that can lead to the feeling of exhaustion during and after 2408-15), UCP3 mRNA expression in skeletal muscle physical activity. occurred within minutes of capsinoid ingestion and persisted 0006. The combination of dihydrocapsiate, caffeine and for 2 hours. A separate animal study ("Capsiate, a Nonpun arginine provided in compositions and formulations of the gent Capsaicin Analog, Increases Endurance Swimming present disclosure provide a unique combination designed to Capacity of Mice by Stimulation of Vanilloid Receptors' enhance endurance via one or more of these mechanisms. Biosci Biotechnol Biochem. 2006 April; 70(4):774-81) dem 0007 Two of the main mechanisms for ATP synthesis are onstrated that mice taking capsiate were able to Swim signifi aerobic respiration (glycolysis, citric acid cycle, oxidative cantly longer than mice who hadn't taken capsiate. In addi phosphorylation, etc.) and anaerobic respiration (glycolysis tion, after 30 min of Swimming, the residual glycogen in the only). Aerobic respiration pathways occur in an oxygen-rich gastrocnemius muscle was higher, the serum free fatty acid state, have a more efficient output of ATP (36-38 ATP/glu concentration tended to be higher, and the serum lactic acid cose), and are typically associated with endurance exercise. concentration was significantly lower in the capsiate-admin Anaerobic respiration occurs in an oxygen poor environment, istered mice. has less efficient output of ATP (2 ATP/glucose), and is typi 0014. This suggests that the capsiate increased the release cally associated with intense exercise (weightlifting, sprint of free fatty acids, which UCP-3 brought to the muscle to use ing, etc.). Anaerobic respiration is also much quicker than as fuel, sparing glycogen stores for later and thus lengthening aerobic respiration (because it is only going through the gly the Swimming time. This allows for increased aerobic exer colysis), and is only utilized by muscle cells. cise and delayed anaerobic exercise. This mechanism of 0008. In theory, if the body can endure longer periods of action was Subsequently proved in the same experiment when anaerobic respiration than aerobic respiration, or if it can researchers demonstrated significantly higher oxygen con utilize free fatty acids as fuel instead of glucose, it will help Sumption (aerobic) and fat oxidation (using fat as fuel) with extend the short-term, high intensity activities associated reduced carbohydrate oxidation (glycogen sparing) follow with weight training. Once glycogen stores are used up, ing capsiate administration. fatigue will also set in. Glycogen sparing is maximized with 0015 While these studies were performed using capsiate the use of non-carbohydrates as a source of energy during and not dihydrocapsiate, a previous study (Assessment of the exercise so that the depletion of muscle glycogen is delayed. biological similarity of three capsaicin analogs (Capsinoids) Glycogen is spared because the body burns fats for energy, found in non-pungent chili pepper (CH-19 Sweet) fruits' making a greater contribution to an athlete’s efforts during the Biosci Biotechnol Biochem 2010; 74(2):274-8; and “Activa initial stages of a race. This leaves more glycogen for the later tion of transient receptor potential A1 by a non-pungent cap stages of racing or exercise, for example, and muscle fatigue saicin-like compound, capsiate; Br J Pharmacol' 2012 will be delayed. March; 165(5): 1476-86) have shown that capsiate and dihy 0009 Increasing vasodilation will also increase the rate of drocapsiate have similar rates of TRVP-1 activation, Suggest oxygen and glucose to the muscles, lengthening the time of ing that dihydrocapsiate will have a similar effect on endur aerobic respiration and further sparing glycogen stores. aCC. US 2016/0213673 A1 Jul. 28, 2016

0016 Respiratory quotient (RQ) is a simple measurement jugates with molecules Such as resveratrol, and in the form of of the ratio of carbon dioxide eliminated to oxygen con Arginine Silicate Inositol (ASI). Arginine is necessary for the Sumed. This is particularly helpful when calculating an synthesis of creatine in the body. Creatine is thought to build organism's basal metabolic rate from carbon dioxide produc lean muscle mass and assist with short high intensity bursts tion, which is easily measured when the organism exhales. (weightlifting, sprinting, etc.) Creatine has also been shown Based on the respiratory quotient one can determine if the to induce glycogensparing in animal studies. Finally, creatine organism’s primary energy source is carbohydrates (RQ is known to assist with water retention, and studies in con around 1) Such as Sugar or if it is primarily from fats (RQ junction with glycerol Supplementation have demonstrated a around 0.7). A mixed diet offat and carbohydrate results in an measurable effect on hyperhydration and endurance (“The average value between 0.7 and 1 and therefore the lower the effects of creatine and glycerol hyperhydration on running RQ the more likely the source of energy is from fats. Com economy in well trained endurance runners' J Int Soc Sports pounds that increase the oxidation of fats for energy, even in Nutr. 2011 Dec. 16; 8(1):24). the presence of a carbohydrate Source, can be expected to 0022. The presently disclosed compositions and formula lower the RQ. In a human study ("Effects of dihydrocapsiate tions further increase endurance by blunting pain perception, on adaptive and diet-induced thermogenesis with a high pro allowing athletes to work through the warning signals the tein very low calorie diet: a randomized control trial Nutri body has in place, be it exhaustion/fatigue or micro tears in tion & Metabolism 2010, 7:78), consumption of 3 mg of 9 mg the muscles that actually increase strength when healed. Caf of dihydrocapsiate per day for 28 days led to a significantly feine has been shown to dampen pain perception through the lower RQ than that seen in the placebo group. This was blocking of adenosine receptors, which could result in exten coupled with a significant increase in post prandial energy sion of the timepoint by which the level of pain that would expenditure, demonstrating that dihydrocapsiate consump result in termination of exercise is reached. In addition, dihy tion increases the use of free fatty acids for ATP production, drocapsiate may help with pain blunting through the activa resulting in higher levels of energy available for use during tion of the TRPV1 receptor. Activation of TRPV1 can induce endurance exercise. Caffeine has the same effect on respira persistent depolarization of the nerve terminals, causing a tory quotient as dihydrocapsiate. A human study (Enhanced decrease in their ability to generate and propagate action metabolic response to caffeine in exercise-trained human potentials. Together, caffeine and dihydrocapsiate are subjects; JAppl Physiol (1985). 1985 September. 59(3):832 expected to blunt pain enough to increase endurance. 7) recorded significantly lower RQ following 4 mg/kg caf 0023 Compositions and formulations of the present dis feine consumption, as well as a greater increase in plasma free closure further increase endurance by increasing vasodila fatty acids, Suggesting enhanced lipid oxidation following tion. Vasodilation is important for many different aspects of caffeine consumption. exercise. The heart has an easier time pumping blood through 0017. A recent mouse study (A single intake of capsiate the circulatory system which in turn will lower the blood improves mechanical performance and bioenergetics effi pressure since there is less force within the blood vessels ciency in contracting mouse skeletal muscle' Am J Physiol (equal Volume with greater diameter equals lower pressure). Endocrinol Metab. 2014 May 15:306(10):E1110-9) demon Increasing the diameter of the circulatory system will also strated that although oxidative phosphorylation was not allow the heart to pump more efficiently, and also helps to affected during rest, when exercising the mice showed deliver key metabolic constituents such as oxygen, glucose, increased contribution of oxidative phosphorylation to total etc., more quickly to where they are needed. This allows for energy turnover with a reduction in glycolysis. This further more efficient energy production, waste removal and damage Supports that glycogen sparing as oxidative phosphorylation repair. can utilize products from fat oxidation for ATP production. In 0024. When there is an adequate amount of nitric oxide in addition, ATP cost of twitch force generation was reduced the body, the muscles around the circulatory system relax, while the twitch force-generating capacity was increased allowing the blood vessels to widen for better blood flow, with the capsiate, Suggesting that less energy could go farther increasing the transportation rate of oxygen, nutrients, hor in muscle performance while using capsiates. mones, etc. to areas of need. When working out or in times of 0018 Compositions and formulations of the present dis physical activity, blood flow increases to the muscles as pro closure include caffeine as muscle glycogen sparing occurs tection and repair. In the presence of a vasodilator like nitric early during endurance (aerobic) exercise following caffeine oxide, blood vessels open and increase blood flow. This ingestion. increases both endurance and energy levels systemically. See 0019. It is presently unclear however if glycogen sparing also “Nonuniform effects of endurance exercise training on is due to increased fat mobilization and Subsequent use by the vasodilation in ratskeletal muscle'J Appl Physiol 2005 Feb muscle. Studies (“Caffeine and endurance performance' ruary: 98(2):753-61. Sports Med. 1985 May-June; 203):165-74) suggest that 0025. Although a known vasoconstrictor, caffeine can also increasing the release of adrenaline into the blood can also help induce vasodilation by increasing intercellular calcium stimulate the release of free fatty acids from fat tissue and/or levels, stimulating the production of nitric oxide through the skeletal muscle. With increased fat availability to the muscle, expression of endothelial nitric oxide synthase (eNOS), the muscle uses less glucose early on, sparing glycogen for which can subsequently utilize free arginine to produce NO. use later in exercise and therefore delaying fatigue. increasing vasodilation (either increase intensity of vasodila 0020 Caffeine has been shown to decrease glycogen uti tion dose-dependently or reduce the amount of time it takes to lization by as much as 50% during the first 15 minutes of achieve similar levels of vasodilation seen in the absence of exercise, the result of which is saving that glycogen for later the combination with arginine oran arginine-containing com US pound Such as Arginine Silicate Inositol). 0021 Compositions and formulations of the present dis 0026. In endothelial cells caffeine increases intracellular closure also include Arginine in Salt forms, pure forms, con calcium, stimulating the production of nitric oxide through US 2016/0213673 A1 Jul. 28, 2016 the expression of the endothelial nitric oxide synthase salt, sodium citrate, potassium chloride, calcium phosphate, enzyme. Nitric oxide (NO) is diffused to the vascular smooth Sodium glutamate, magnesium chloride, ascorbic acid, muscle cells to produce vasodilation. NO is synthesized by Cloudy, Emulsifying flavor, Essence and water. The patent eNOS from L-arginine and oxygen. Caffeine stimulates further describes a "Chocolate' containing Sugar, cocoa expression of eNOS and arginine is a precursor used by eNOS mass, total lipid pulverized milk, cocoa butter, lecithin, to make NO, which is in turn responsible for vasodilation. As vanilla flavor, and the dried and pulverized material of “CH noted above, vasodilation leads to increased blood flow to the 19 Sweet'. The patent describes the formulations of the patent muscles and an increase in oxygen Supply, thereby reducing as being useful for immunopotentiating activity and enhanc the environment for anaerobic respiration while also remov ing activity of energy metabolism ing/reducing levels of H., CO, and lactic acid that cause a decrease in muscle pH. 0032 U.S. Pat. No. 7,981,460 describes substituted ben 0027. An increase of ammonia in muscle (which is a Zyl ester derivatives of the following formula: byproduct of deamination of AMP in fast-twitch fibers) leads to fatigue due to ammonotoxemia and lactic acidemia. Among other things, ammonia activates phosphofructokinase O and prevents oxidation of pyruvate to acetyl CoA, thus lead ing to exhaustion. Both citruline and arginine mitigate R1 l ammonia toxicity in exhausted rats by interfering with the metabolism of ammonia (“Effect of arginine, ornithine and citrulline Supplementation upon performance and metabo R2 lism of trained rats' Cell Biochem Funct. 2003 March; 21(1): 85-91.). Additionally, compounds that promote vasodilation will accelerate the removal of toxic byproducts of endurance wherein R is exercise by increasing blood flow. 0028 Arginase is an enzyme in the urea cycle that helps with the elimination of urea from the body. The final step in the urea cycle, arginase converts arginine and water in to Y ornithine and urea, the last of which is the main outlet for N-1 S-S. ammonia removal. Use of arginine in the urea pathway limits its use as a Substrate for the production of creatine, nitric oxide, agmatine, glutamic acid, ornithine, proline and 0033. The patent describes the compounds of the patent as polyamines. However, it has also been shown that caffeine being useful to enhance blood circulation, in sympathetic inhibits arginase activity (see “Effect of caffeine on metabo activation action, in energy metabolism enhancing action, in lism of L-arginine in the brain Mol Cell Biochem. 2003 February: 244(1-2):125-8). Inhibition of arginase by caffeine immunostimulatory action, in lipolysis enhancing action, in provides more arginine for consumption in other metabolic antiobesity action, in body fat accumulation Suppressive pathways, optimizing its use for promotion of endurance. action, and in analgesic action. The patent states that the active may be used in food, pharmaceutical and cosmetic 0029. The combinations of dihydrocapsiate, caffeine and compositions. arginine provided in compositions and formulations of the present disclosure therefore provide a unique combination of 0034 U.S. Pat. No.8.212,068 describes compounds of the active ingredients designed to provide enhanced endurance following formula by multiple pathways. 0030 U.S. Pat. No. 6,333,421 describes capsaicinoid-like substances of the following formulas: MeO X

(I) HO HCO CH3 as being useful as an external blood circulation enhancer in it;is M cosmetic, pharmaceutical and food compositions. HO CH-O--CH-CH=CH I CH 0035 WO 2009061051A1 describes a capsiate- or dihy (II) drocapsidate-containing composition and their use for pre venting and treating inflammatory disease, angiogenesis-re HCO lated disease and autoimmune disease or for Suppressing CH immunity. HO CH-O-C-(CH)-CH2CHCH 0036 U.S. 20070020738 A1 describes a production | CH3 method of capsinoids by dehydrating condensation, stabiliz ing method of capsinoid, and capsinoid composition. 0031. The patent describes a “sports drink’ containing the 0037 U.S. 20050239883 A1 describes compositions for capsaicinoid-like Substances of the patent, orange juice con lowering internal lipid content with an active of the following centrate, Sugar, high fructose corn syrup (F-55), citric acid, Structures: US 2016/0213673 A1 Jul. 28, 2016

3'-digallate, theaflavin-3-gallate, theaflavin-3-gallate, HCO L-theanine, anthocyanidins, anthocyanins, catechin, epicat CH3 echin, gallocatechin, pepigallocatechin, epicatechin gallate, it;is A gallocatechin gallate, epigallocatechin gallate, procyanidin, HO CH-O-C-(CH)-CH=CH-CH chlorogenic acid, cardamonin, arctigenin, arctiin, asiatic I Y-H, and acid, asiaticoside, bergamotin, bergapten, betaine, dioScin, H3CO galangin, cimicifugoside, cinnamic acid, ferrulic acid, y H. fumaric acid, alpha.-lipoic acid, carnosine, L-carnitine, caf HO CH-O-C-(CH)-CH-CH-CH feic acid, ellagic acid, maslinic acid, phenylethyl caffeate, caffeic acid phenethyl ester, theobromine, theophylline, caf | CH3 feoylquinic acid, ursolic acid, allicin, gingerol, shogaol, ginkgolide, ginkgetin, ginsenoside, astragaloside, cycloas 0038 U.S. 200701.41 165 A1 describes method for manu tragenol, danshensu, danshenol, danshenxinkun, tanshinone, facturing microcapsules containing capsinoid. tanshindiol, roSmarinic acid, dosmin, nobiletin, tangeretin, 0039 U.S. 20020068365A1 describes a time released luteolin, lutein, beta-lycopene, Zeaxanthin, tyrosol, hyperin, composition for use in the treatment of sexual disorder with hyperoside, quercetin, quercetrin, isoquercitrin, hydroxyty compositions of L-arginine, its salts, peptides, and biological rosol, rosarin, B-rosasterol, rosavin, rosin, punicalagin, puni equivalents that enhances or modulates the endogenous pro calin, myricetin, myricitrin, kaempferol, dihydromyricetin, duction of nitric oxide, alone or incombination with botanical apigenin, maringin, maringenin, honokiol, magnolol. extracts for treating erectile dysfunction. mangiferin, mangostin, hesperetin, hesperidin, lupeol, 0040. None of this art describes or suggests the combina indole-3-carbinol, genistein, genistin, daidzein, daidzin, tions of dihydrocapsiate, caffeine and arginine in pure form, cynarin, bilobalide, bilobetin, epimedin, Sulforaphane, phlo salt form, conjugate form, or in the form of Arginine Silicate retin, phloretin-Xyloglucoside, phloridzin, proanthocyani Inositol (ASI) provided in compositions and formulations of dins, procyanidin B1, procyanidin B2, procyanidin C1, sili the present disclosure. binin, rutin, Wogonin, morin, morusin, mulberroside A, 0041 Compositions and formulations of the present dis mulberroside B, glycyrrhizic acid, glycyrrhetinic acid, closure may additionally include excipients such as microc linarin, protodioscin, protogracillin, Synephrine, rebaudio rystalline cellulose, crystalline cellulose, lactose, corn starch, side A, Stevioside, Vitexin, isovitexin, Vitexin-4, Vitexin-4"- Sucrose, glucose: binders Such as tragacanth, gum arabic, O-glucoside, Vitexin-2'-O-rhamnoside, Vitexin-4'-rhamno corn starch, gelatin, polyvinyl alcohol, polyvinyl ether, eth side, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, ylcellulose, methylcellulose, shellac, hydroxypropylcellu and delta-tocopherol. lose, hydroxypropyl Starch, polyvinylpyrrolidone; Swelling 0044. A composition or formulation of the present disclo agents such as corn starch, pregelatinated Starch, alginic acid, Sure may additionally or optionally also include a phy dextrin; lubricants such as magnesium Stearate; flowability tochemical from at least one of the following sources: bil improving agents such as fine silicon dioxide; lubricants such berry, blueberry, cranberry, raspberry, cherry, mulberry, as glyceryl fatty acid ester, magnesium Stearate, talc, poly pomegranate, maqui berry, purple corn, Strawberry, grapes, ethylene glycol, silica, hydrogenated vegetable oil; Sweeten blackberry, gooseberry, black currants, grape, cocoa beans, ing agents such as Sucrose, lactose, aspartame, acesulfame-K, coffee beans, pine bark, cardamom, cinnamon bark, ginseng, Sucralose, monatin, Stevia, Saccharin and the like; flavors to astragalus, rhodiola, garcinia, ginger, ginkgo, citrus fruit, be used for various foods such as peppermint, Vanilla flavor, grape skins, grape seeds, hawthorn, artichoke, broccoli, broc cherry, raspberry ketone and the like; preservatives Such as coli seeds, apple, olive, orange, lemon, pepper, soybean, paraoxybenzoates, chlorobutanol, benzyl alcohol, Sorbic mango, tea leaves, tomato, turmeric, cabbage, purple corn, acid; an antioxidant, such as Sulfite, ascorbic acid, vitamin E, black rice, bitter lemon, Stevia, lohan, goji (wolfberry), sea butylhydroxytoluene, sodium sulfite; and/or coating agents buckthorn, kudzu, clove, hemp, cassia, magnolia, nutmeg, Such as shellac, Sucrose, gelatin, and hydroxypropylcellulose. jujube, honeysuckle, poria, bellflower, lotus, basil, Sesame, 0042 Compositions and formulations of the present dis angelica, cimicifuga, epimedium, Schisandra, Salvia, licorice, closure may also include, for example, food additives, such as ligustrum, ophiopogonis, aloe, dodder, fenugreek, gotu kola, fruit juice, dextrin, cyclic oligosaccharide, cyclodextrins (al guarana, purslane, and tribulus. pha, beta, gamma), Saccharides (monosaccharides Such as 0045 Compositions and formulations of the present dis fructose, glucose and/or polysaccharides), buffers, acidulant, closure may additionally and/or optionally further include— flavor, Hikicha powder or other taste modifiers, an emulsifier, in addition to arginine in the form of ASI—one or more free collagen, powdered milk, polysaccharide thickener, agar or amino acids or peptides, such as lysine, methionine, histidine, other texture modifiers, at least one vitamins, egg shell cal leucine, isoleucine, alanine, phenylalanine, asparagine, argi cium, calcium pantothenate, other minerals, royal jelly, pro nine, beta alanine, aspartic acid, tryptophan, proline, threo polis, honey, dietary fibre, Agaricus subrufescens, chitin, chi nine, cysteine, selenocysteine, serine, taurine, tyrosine, tosan, flavonoids, carotenoids, lutein, herbal medicine, Valine, glycine, glutamine, glutamic acid, ornithine, carnos chondroitin, and/or amino acids. ine, L-carnitine, glutathione. 0043 Compositions and formulations of the present dis 0046 Compositions and formulations of the present dis closure may additionally or optionally include at least one of closure may additionally and/or optionally include one or crocin, crocetin, acteoside, aloenin, aloesin, aloin, alpinetin, more vitamins or minerals, including, for example, Vitamin atractylenolide, atractylodin, aurantio-obtusin, cimigenol, A, vitamin C, vitamin B1, vitamin B2, vitamin B3, vitamin cimifugin, cimiside, garcinone, ascorbic acid, astragalin, B5, vitamin B6, vitamin B12, vitamin D, vitamin E, vitamin quercetin, resveratrol, pterostilbene, curcumin, demethoxy K (and/or derivatives), folic acid, biotin, calcium, Sodium, curcumin, bis-demethoxycurcumin, theaflavin, theaflavin-3, potassium, phosphorus, chromium, Vanadium, magnesium, US 2016/0213673 A1 Jul. 28, 2016

Zinc, manganese, selenium, copper, molybdenum, boron, tragacanth, microcrystalline cellulose, kaolin, dicalcium Vanadium, and/or iron (and/or derivatives). phosphate, calcium carbonate, Sodium chloride, or alginic 0047 Compositions and formulations of the present dis acid; disintegrators including, microcrystalline cellulose, or closure may also include creatine and derivatives thereof, alginic acid; binders including acacia, methylcellulose, ethyl capsiate, carnitine, nordihydrocapsiate, pterostilbene and cellulose, Sodium carboxymethylcellulose, polyvinylpyrroli other polyphenols, and agmatine (oragmatine Sulfate). done, or hydroxypropyl methylcellulose; and lubricants such 0048 Compositions and formulations of the present dis as magnesium Stearates, Stearic acid, silicone fluid, talc, oils, closure may further optionally include citrus bioflavonoids waxes, or colloidal silica. Compositions and formulations of (such as quercetin, rutin, isoquercetin, Synephrine, and octo the present disclosure may additionally include mixtures of pamine); CoQ10, thiamine, citrulline malate, nicotinamide acids (like citric, tartaric, malic and fumaric acid or combi adenoside dinucleotide (NAD), nicotinamide riboside (NR), nation thereof) and carbonates like Sodium, potassium bicar citrulline, lutein, lycopene, capsaicin, arginine alpha ketoglu bonate or carbonate; water soluble binders (starches, natural tarate (Arginine AKG), L-arginine pyroglutamate, arginine gums, cellulose gums, microcrystalline cellulose, methylcel ketoisocaproate, citric acid, ornithine alpha ketoglutarate lulose, cellulose ethers, ethylcellulose, sodium carboxymeth (Ornithine AKG), omega-3 fatty acids (DHA and EPA), ylcellulose, gelatin, dextrose, lactose, Sucrose, Sorbitol, man L-norvaline, nitrate, taurine, arginine ethyl ester, carnosine, nitol, polyethylene glycol, polyvinylpyrrolidone, pectins, Vanadyl Sulfate, L-alpha glycerophosphorylcholine (Alpha alginates, polyacrylamides, polyvinyloxoazolidone, polyvi GPC), Pinus pinaster (PycnogenolR), turmeric (curcumin, nylalcohols and mixtures thereof) and/or lubricants (sodium demethoxycurcumin, bis-demethoxycurcumin), rutacaer benzoate, polyethylene glycol, L-leucine, adipic acid, and pine, Epimedium spp., garlic (allicin, allin, and the like), combinations thereof). A composition or formulation of the flaxseed, flaxseed ligans (alphalinolenic acid (ALA), gamma present disclosure may also optionally include other ingredi linolenic acid (GLA)), Schisandria (such as Schisandrin, ents including, e.g., flavor agents, fillers, Surfactants, color Schisandrol A and B, and Gamma Schisandrin), green tea agents, and Sweeteners. catechins (such as catechin, ECGC, ECG, and EGC), black 0051 Compositions and formulations of the present dis tea, dong quai (ligustilide), Andrographis (Androgra closure may additionally include, for example, water or other pholides), grape extract (such as resveratrol), anthocyanins aqueous formulations including Suspending agents such as, (such as cyanidin 3-glucoside (C3G), cyanidin 3-rutinoside, for example, alginates, pectin, kelgin, carrageenan, acacia, delphinidin 3-glucoside, and malvidin 3-glucoside), Dan methylcellulose, polyvinyl alcohol, or polyvinylpyrrolidone. shen, Beta vulgaris root, celery (3-N-butylphthalide), Ber The compositions or formulations of the present disclosure berine, Feverfew, Jasmine, Lemon balm, Vinpocetine, Lotus, may be in the form of for example, a solution (aqueous or Whitehorehound, Lemongrass, Yerba mate, Peony, Mustard, nonaqueous not containing added water), emulsion, syrup, Motherwort, Cramp bark, Grapeseed, Proanthocyanidins gel, powder or elixir including or containing wetting agents, (PACs, including Procyanidin A1, Procyanidin A2, Procya Sweeteners, and coloring and flavoring agents. Various liquid nidin B1, Procyanidin B2, and the like), Spinach (containing and powder compositions and formulations according to the nitrates), Kale (containing nitrates), Broccoli (containing present disclosure may be prepared by conventional methods. nitrates), Beet (containing nitrates), theobromine, theophyl 0.052 Compositions and formulations of the present dis line, phenylethylamine (PEA), and the like), Hawthorn, Haw closure may include aqueous or nonaqueous carriers, dilu thorn flavonoids (hyperoside, Vitexin, isoVitexin, and the ents, fillers, binders, humectants, disintegrating agents, solu like), Catauba extract, apple polyphenols, and combinations tion retarders, absorption accelerators, wetting agents, thereof. absorbents, or lubricating agents, solvents or vehicles includ 0049 Compositions and formulations of the present dis ing water ethanol, polyols (propylene glycol, polyethylene closure may further also include NO-inducers such as glyc glycol, or glycerol), Suitable mixtures thereof, vegetable oils eryl trinitrate (a.k.a. nitroglycerin), isosorbide mononitrate, (such as olive oil) and organic esters such as ethyl oleate. isosorbide dinitrate, clonitrate, ettriol trinitrate (ETTN), Further, the compositions and formulations of the present erythrity1 tetranitrate, pentaerythritol tetranitrate (PETN), disclosure may include stabilizers, Solubilizers, Suspending pentrinitrol, D-mannitol hexanitrate, trolnitrate phosphate, agents, emulsifiers. Soothing agents, buffers, preservatives, sodium nitroprusside, PDE5 inhibitors (slidenafil, tadalafil. isotonic agents, or antibacterial and antifungal agents. Other Vardenafil), papaverine, bamethan, bencyclane, beraprost, useful components may include magnesium Stearate, calcium betahistine, brovincamine, bufeniode, buflomedil, buta Stearate, mannitol. Xylitol, erythritol, maltodextrin, Sweeten lamine, cetiedil, chromonar, ciclonicate, cinepazide, cin ers, starch, carboxymethylcellulose, microcrystalline cellu narizine, clobenfurol, cloricromen, cyclandelate, dilaZep, lose, silica, gelatin, and silicon dioxide. droprenilamine, eburnamonine, efloxate, eledoisin, 0053 Compositions and formulations of the present dis etafenone, fasudil, fendiline, fenoxedil, flunarizine, hexoben closure may optionally and/or additionally beformulated for dine, ibudilast, ifenprodil, iloprost, inositol niacinate, itramin administration, and be administered, for example, orally, tosylate, kallidin, kallikrein, khellin, lidoflazine, lomerizine, parenterally (intravenous, intramuscular, intraperitoneal, moxisylyte, nafronyl, nicotinyl alcohol, nimodipine, nylid intrasternally, Subcutaneously, intraarticular injection and rin, pentifylline, pimefylline, piribedil, trapidil, trimetazi infusion), or by percutaneous, rectal, mucosal, intranasal or dine, Vincamine, Vinpocetine, Vicquidil, Visnadine, Xanthinol topical (transdermal, as by powders, ointments, creams, niacinate, bendazol, floredil, medibazine, tinofedrine, amot sprays, drops or patches) administration. riphene, benfurodil hemisuccinate, hepronicate, hepronicate, 0054 Compositions and formulations of the present dis nicofuranose, Suloctidil, or salts and/or prodrugs thereof. closure optionally contain free arginine. 0050 Compositions and formulations of the present dis 0055 Compositions and formulations of the present dis closure may additionally or optionally contain, for example, closure optionally contain arginine in a salt form, such as carrier materials such as corn starch, acacia, gelatin, malt, arginine HC1. US 2016/0213673 A1 Jul. 28, 2016

0056 Compositions and formulations of the present dis Smaller domestic mammals, such as, but not limited to, dogs, closure optionally contain arginine only in the form of Argi cats, rabbits, and rodents including rats, mice, hamsters, ger nine Silicate Inositol (ASI). bils, and guinea pigs. 0057 Compositions and formulations of the present dis 0065 Compositions and formulations of the present dis closure optionally contain arginine only in conjugate with closure may be administered in a manner and at intervals to resveratrol. increase endurance. The compositions and formulations of 0058 Compositions and formulations of the present dis the present disclosure may be administered, for example, closure optionally do not include cacao or cacao mass or prior to and/or during and/or after physical activity. Such as theobromine (3,7-dimethylxanthine or 3,7-dimethyl-1H-pu running, playing sports, weightlifting, etc. rine-2,6-dione). 0.066 For example, as a preworkout supplement the com 0059 Compositions and formulations of the present dis bination may be part of a ready to mix drink powder that is closure optionally do not include capsaicin or capsaicinoids. added to 10-12 ounces of cold water and consumed 30 min Compositions and formulations of the present disclosure utes prior to the beginning of a workout. optionally do not include capsaicin, dihydrocapsaicin, nordi hydrocapsaicin, homocapsaicin, and/or homodihydrocapsai 0067. The present disclosure provides compositions con cin, while optionally including dihydrocapsiate. Composi taining dihydrocapsiate, caffeine and various forms of argin tions and formulations of the present disclosure optionally do ine. Compositions of the present disclosure alternatively or not include N-(4-hydroxy-3-methoxybenzyl)-8-methylnon optionally do not contain capsaicin or a capsaicinoid. Com 6-enamide or trans-8-Methyl-N-Vanillylnon-6-enamide positions of the present disclosure alternatively or optionally (CAS Registry Number 404-86-4) or N-(4-Hydroxy-3- do not contain at least one of high fructose corn Syrup, methoxy-phenyl)methyl-8-methyl-nonanamide (CAS Reg Sucrose, maltose or lactose. istry Number 19408-84-5). 0068 Compositions of the present disclosure may be in 0060 Compositions and formulations of the present dis the form of a unit dosage or serving for a person. Composi closure optionally do not include allyl isothiocyanate (and/or tions of the present disclosure may be in the form of a ready optionally mustard, horseradish or wasabi containing same), to-mix (RTM) or ready-to-drink (RTD) formulation. or piperine (and/or black pepper or white pepper containing 0069 Compositions of the present disclosure may be in the same), or ginger (and/or any one or a mixture of the form of agel, chew, powder, capsule, tablet, Satchel, bar or Zingerone, shogaol, and gingerol). drink. Compositions of the present disclosure may be in the 0061 Compositions of the present disclosure may be for form of a fruit drink, a coffee, a tea, an energy drink, an adult mulated as comestibles—including fruit-based drinks, cof nutritional drink, an inhalant, a health drink, a lozenge, a fee-based drinks, tea-based drinks, sport drinks, nutrition Supplement, a tablet, a capsule or a sports drink. bars, Snack foods, gums, cereals, candies, energy drinks, 0070 Compositions of the present disclosure may contain adult nutritional drinks, health drinks, and other food prod dihydrocapsiate in an amount in the range of 10 ug to 50 mg. ucts. Sports drinks, energy drink and adult nutritional drinks Such as in the range of 20 ug to 50 mg. or in the range of 30 Jug described herein include, for example, beverages that rehy to 50 mg. or in the range of 40 ug to 50 mg, or in the range of drate athletes, as well as restoring electrolytes, carbohydrates 50 ug to 50 mg. or in the range of 60 ug to 50 mg, or in the and other nutrients, beverages that include legal stimulants, range of 70 ug to 50 mg. or in the range of 80 ug to 50 mg. or electrolytes, vitamins and minerals, and beverages that pro in the range of 90 ug to 50 mg. or in the range of 10 ug to 40 vide nutritional Support. Such sports drinks, sports products, mg, or in the range of 10 ug to 30 mg. or in the range of 10 ug bars, energy drinks and adult nutritional drinks include, for to 20 mg. or in the range of 10 ug to 10 mg, or in the range of example, Gatorade, POWERade, and All Sport, BSN Amino 10 ug to 5 mg. or in the range of 10 ug to 10 mg, or in the range X, Scivation XTend Endurance, Twin Lab Endurance Fuel, or 100LL to 5 mg, or in the range of 100 ug to 3 mg, or in the Power Bar Power Gel, Gu Chomps Energy Chews, Clif Bar range of 3 mg to 5 mg, or in ranges intermediate of any one of Energy Bar, Stinger Energy Bar, Power Bar Energy Bar, these ranges. Power Bar Endurance Drink, Monster Energy Drink, 5 Hour 0071 Compositions of the present disclosure may contain Energy, Jolt Cola, RockStar, NOS Energy Drink, Red Bull, capsaicin in addition to or in place of dihydrocapsiate in an Ensure and Longetics. Health drinks include beverages that amount in the range of 10 ug to 50 mg. Such as in the range of have a beneficial health effect, such as reducing inflamma 20 ug to 50 mg, or in the range of 30 Jug to 50 mg, or in the tion, Supporting the immune system, neutralizing infectious range of 40 ug to 50 mg. or in the range of 50 ug to 50 mg. or agents, preventing blocked arteries, preserving cognitive in the range of 60 ug to 50 mg. or in the range of 70 ug to 50 function and inhibiting cancer growth. mg, or in the range of 80 ug to 50 mg. or in the range of 90 ug 0062 Compositions of the present disclosure may also be to 50 mg. or in the range of 10 ug to 40 mg, or in the range of drinks or formulations that are not coffee-based drinks or are 10 ug to 30 mg. or in the range of 10 ug to 20 mg, or in the not coffee-based formulations, or are not tea-based drinks, or range of 10 ug to 10 mg, or in the range of 10 ug to 5 mg. or are not tea-based formulations. in the range of 10 ug to 10 mg. or in ranges intermediate of any 0063 Compositions and formulations of the present dis one of these ranges. closure may be administered to a mammal in need of 0072 Composition of the present disclosure may contain increased and/or enhanced endurance. arginine in an amount in the range of 10 mg to 15 g, such as 0064. An individual subject benefiting from the composi in the range of 60 mg to 15 g, or in the range of 70 mg to 15 tions and formulations of the present disclosure may be an g, or in the range of 90 mg to 15 g, or in the range of 90 mg to animal, mammal or a human. Animal or mammal Subjects 15 g, or in the range of 100 mg to 15 g, or in the range of 10 include large domestic mammals, for example, cattle (or mg to 10g, or in the range of 10 mg to 5 g, or in the range of other bovine species), horses, pigs, sheep, goats, and other 10 mg to 1 g, or in ranges intermediate of any one of these livestock. Animal or mammal Subjects may also include ranges. US 2016/0213673 A1 Jul. 28, 2016

0073 Compositions of the present disclosure may contain maximum running time of the mammal and/or maximum ASI in an amount in the range of 10 mg to 10g, or in the range Swimming time of the mammal and/or other physical activity of 20 mg to 10g, or in the range of 30 mg to 10g, or in the as compared to the maximum running time, Swimming time range of 40 mg to 10g, or in the range of 50 mg to 10g, or in and/or other physical activity of the mammal prior to being the range of 60 mg to 10g, or in the range of 70 mg to 10 g, administered the composition. or in the range of 80 mg to 10g, or in the range of 90 mg to 10 0078. The present disclosure provides a method of g, or in the range of 100 mg to 10g, or in the range of 10 mg enhancing the endurance of a mammal. Such as a human (and to 9 g, or in the range of 10 mg to 8 g, or in the range of 10 mg alternatively a horse, dog, mouse, hamster, rat, etc.), by to 7 g, or in the range of 10 mg to 6 g, or in the range of 10 mg administering a composition of the present disclosure to the to 5 g, or in the range of 10 mg to 4g, or in the range of 10 mg mammalina Sufficient amount and overa course of time so as to 3 g, or in the range of 10 mg to 2 g, or in the range of 10 mg to enhance the endurance of the mammal, the enhanced to 1 g, or in ranges intermediate of any one of these ranges. endurance for example being measured by an increase in the 0074 Compositions of the present disclosure may contain maximum repetitions of physical activity, Such as in weight caffeine in an amount in the range of 2 mg to 400 mg. or in the lifting, as compared to the maximum repetitions of the mam range of 3 mg to 400 mg, or in the range of 4 mg to 400 mg. mal prior to being administered the composition. or in the range of 5 mg to 400 mg. or in the range of 10 mg to 007.9 The present disclosure provides a method of 400 mg. or in the range of 20 mg to 400 mg, or in the range of enhancing the endurance of a mammal. Such as a human (and 30 mg to 400 mg. or in the range of 40 mg to 400 mg. or in the alternatively a horse, dog, mouse, hamster, rat, etc.), by range of 50 mg to 400 mg. or in the range of 60 mg to 400 mg. administering a composition of the present disclosure to the or in the range of 70 mg to 400 mg, or in the range of 80 mg mammalina Sufficient amount and overa course of time so as to 400 mg. or in the range of 90 mg to 400 mg, or in the range to enhance the endurance of the mammal, the enhanced of 100 mg to 400 mg. or in the range of 2 mg to 350 mg. or in endurance being measured for example by a decrease in the the range of 2 mg to 300 mg, or in the range of 2 mg to 250 mg. rating of perceived exertion (RPE) during physical exertion, or in the range of 2 mg to 200 mg, or in the range of 2 mg to Such as during running, Swimming, weight lifting and/or 150 mg, or in the range of 2 mg to 100 mg. or in the range of walking, as compared to the RPE of the mammal prior to 2 mg to 50 mg. or in the range of 2 mg to 40 mg. or in the range being administered the composition. of 2 mg to 25 mg, or in the range of 2 mg to 10 mg. or in the 0080. The present disclosure provides a method of range of 2 mg to 5 mg, or in ranges intermediate of any one of enhancing the respiratory quotient (RQ)—by decreasing the these ranges. respiratory quotient in a mammal, Such as a human (and 0075 Compositions of the present disclosure may contain alternatively a horse, dog, mouse, hamster, rat, etc.), by a ratio, by weight, of caffeine to dihydrocapsiate in the range administering a composition of the present disclosure to the of 40000:1 to 8:1, or in the range of 40000:1 to 8:1, or in the mammalina Sufficient amount and overa course of time so as range of 30000:1 to 8:1, or in the range of 20000:1 to 8:1, or to enhance the respiratory quotient of the mammal. Enhanc in the range of 10000:1 to 8:1, or in the range of 5000:1 to 8:1, ing the respiratory quotient of a mammal according to the or in the range of 2500:1 to 8:1, or in the range of 1000:1 to present disclosure results in enhancing the availability of free 8:1, or in the range of 500:1 to 8:1, or in the range of 100:1 to fatty acids to the mammal, and reducing the respiratory quo 8:1, or in the range of 50:1 to 8:1, or in the range of 40000:1 tient, as a result of administering a composition of the present to 25:1, or in the range of 40000:1 to 25:1, or in the range of disclosure to the mammal. The present disclosure provides a 30000:1 to 25:1, or in the range of 20000:1 to 25:1, or in the method of increasing the levels of free fatty acids in a mam range of 10000:1 to 25:1, or in the range of 5000:1 to 25:1, or mal, leading to greater availability of the fatty acids for use in in the range of 2500:1 to 25:1, or in the range of 1000:1 to ATP production and ultimately increasing endurance for 25:1, or in the range of 500:1 to 25:1, or in the range of 250:1 physical activity, Such as, for example, weightlifting, biking, to 25:1, or in the range of 100:1 to 25:1, or in the range of 50:1 running, Swimming. to 25:1, or in the range of 25:1 to 8:1, or in ranges intermediate I0081 Although not limited, the course of time of admin of any one of these ranges. istration of a composition of the present disclosure in a 0076 Compositions of the present disclosure may contain method of enhancing the endurance of a mammal according a ratio, by weight, of arginine to caffeine in the range of 1:10 to the present disclosure may be in the range of 1 day to 4 to 100:1, or in the range of 2:10 to 100:1, or in the range of weeks, 2 days to 4 weeks, or in the range of 3 days to 4 weeks, 5:10 to 100:1, or in the range of 1:1 to 100:1, or in the range or in the range of 4 days to 4 weeks, or in the range of 5 days of 2:1 to 100:1, or in the range of 3:1 to 100:1, or in the range to 4 weeks, or in the range of 6 days to 4 weeks, or in the range of 4:1 to 100:1, or in the range of 5:1 to 100:1, or in the range of 7 days to 4 weeks, or in the range of 1 days to 27 days, or of 10:1 to 100:1, or in the range of 20:1 to 100:1, or in the in the range of 1 days to 26 days, or in the range of 1 day to 25 range of 30:1 to 100:1, or in the range of 40:1 to 100:1, or in days, or in the range of 1 day to 24 days, or in the range of 1 the range of 50:1 to 100:1, or in the range of 60:1 to 100:1, or day to 23 days, or in the range of 1 day to 22 days, or in the in the range of 70:1 to 100:1, or in the range of 8.0:1 to 100:1, range of 1 day to 21 days, or in the range of 1 day to 20 days, or in the range of 90:1 to 100:1, or in ranges intermediate of or in the range of 1 day to 19 days, or in the range of 1 day to any one of these ranges. 18 days, or in the range of 1 day to 17 days, or in the range of 0077. The present disclosure provides a method of 1 day to 16 days, or in the range of 1 day to 15 days, or in the enhancing endurance in a mammal. Such as a human (and range of 1 day to 14 days, or in ranges intermediate of any one alternatively a horse, dog, mouse, hamster, rat, etc.), by of these ranges. administering a composition of the present disclosure to the I0082. The present disclosure provides a method of mammalina Sufficient amount and over a course of time so as enhancing the endurance of a mammal. Such as a human (and to enhance the endurance of the mammal, the enhanced alternatively a horse, dog, mouse, hamster, rat, etc.), by 5 to endurance for example being measured by an increase in the 20%, or in the range of 5 to 20%, or in the range of 6 to 20%, US 2016/0213673 A1 Jul. 28, 2016

or in the range of 7 to 20%, or in the range of 8 to 20%, or in EXAMPLE 3 the range of 9 to 20%, or in the range of 10 to 20%, or in the range of 11 to 20%, or in the range of 12 to 20%, or in the Ready to Drink Energy Beverage range of 13 to 20%, or in the range of 14 to 20%, or in the 0109 Caffeine: 75 mg range of 15 to 20%, or in the range of 16 to 20%, or in the 0110. Dihydrocapsiate: 1 mg range of 17 to 20%, or in the range of 18 to 20%, or in the 0111 Arginine Silicate Inositol Complex: 300 mg range of 19 to 20%, or in the range of 1 to 19%, or in the range 0112 Panax ginseng.: 45 mg of 1 to 18%, or in the range of 1 to 17%, or in the range of 1 0113 Taurine: 400 mg to 16%, or in the range of 1 to 15%, or in the range of 1 to 14%, 0114 Ginkgo biloba. 15 mg or in the range of 1 to 13%, or in the range of 1 to 12%, or in the range of 1 to 11%, or in the range of 1 to 10%, or in the 0115 Citric Acid: 50 mg range of 1 to 9%, or in the range of 1 to 8%, or in the range of EXAMPLE 4 1 to 7%, or in the range of 1 to 6%, or in the range of 1 to 5%, or in the range of 1 o 4%, or in the range of 1 to 3%, or in the Sports Chew range of 1 to 2%, or in ranges intermediate of any one of these ranges. 0116 Caffeine: 5 mg 0083. The present disclosure provides a method of 0117 Dihydrocapsiate: 100 mcg enhancing the endurance of a mammal. Such as a human (and 0118 Arginine Silicate Inositol Complex: 100 mg alternatively a horse, dog, mouse, hamster, rat, etc.), wherein 0119 L-Carnitine: 50 mg the rating of perceived exertion is decreased by at least 1, or at I0120 Choline: 10 mg least 2, or at least 3 or at least 4 on a scale of 1 to 10 as a I0121 N-Acetyl Cysteine: 50 mg measure of enhanced endurance. I0122) Resveratrol: 30 mg 0084. The presently disclosed technology is further illus (0123 Potassium: 35 mg trated by the following non-limiting examples of composi 0.124 Sodium: 48 mg tions and formulations. Note that examples only include 0.125 Magnesium: 20 mg active ingredients and do not include optional Sweeteners, flavors, colors, excipients, and the like. EXAMPLE 5 I0126. A study was conducted to assess the combinatory EXAMPLE 1. effect of dihydrocapsiate, arginine and caffeine (DAC) in an exercising population. The study group consisted of 10 Ready to Mix Beverage Powder for Preworkout healthy, recreationally fit males, aged 27t2 years, with an average BMI of 26.9+1.4 kg/m. The study was designed in a I0085 Caffeine: 150 mg single blind, placebo-controlled, crossover fashion so that I0086 Dihydrocapsiate: 2 mg each of the 10 males completed both the treatment and pla I0087 Arginine Base: 3500 mg cebo arm. The treatment consisted of a ready to mix (RTM) I0088 Leucine: 1500 mg beverage containing 3 mg dihydrocapsiate, 100 mg arginine I0089. Isoleucine: 750 mg and 40 mg caffeine: the placebo was a calorie and flavor 0090 Valine: 750 mg matched RTM lacking any bioactives. Indirect calorimetry was utilized to measure resting metabolic rate (RMR) rate 0091) Glutamine: 1000 mg prior to baseline blood and vital sign measurements. Each 0092 Beta-Alanine: 500 mg subject consumed either the treatment or placebo 30 minutes 0093 Quercetin: 50 mg before engaging in a series of eccentric exercises which con 0094. Betaine: 100 mg sisted of 4 sets of repetitions to failure of bench press at 100% 0095. Glycerol: 1000 mg of body weight and leg extension at 30% of body weight. The subjects maximum repetitions to failure (MRF) performance EXAMPLE 2 and rate of perceived exhaustion (RPE) were recorded. At time points 60, 120 and 180 minutes post-treatment and exer Protein Bar cise, the RMR, vital signs and blood sample measurements were repeated. 0096 Caffeine: 5 mg I0127. At 60 and 120 minutes post-treatment and exercise, 0097. Dihydrocapsiate: 3 mg oxygen consumption (expressed in absolute units as well as 0098 Arginine Alpha Keto Glutarate (AAKG): 900 mg relative to body weight) was greater in response to DAC 0099. Whey Protein Concentrate: 12 grams treatment than placebo. Similarly, respiratory quotient (RO) was lower at 120 and 180 minutes post-treatment and exercise 0100. Whey Protein Isolate: 6 grams after consumption of DAC treatment. The lowering of the RQ 0101 Hydrolyzed Whey Protein: 2 grams is a result of the depletion of stored lipids. These data were 0102 Pterostilbene: 25 mg reflected in the serum and plasma markers of lipolysis in that (0103 Vitamin B5: 1 mg glycerol and free fatty acids tended to be higher in response to 0104 Vitamin B12: 2 mcg DAC treatment over the entire post-exercise period; with fatty acids increased by 35.5% above placebo and glycerol 0105 Vitamin C: 10 mg increased by 2.13%. 01.06 Vitamin E: 5 IU 0128. There was an overall trend for increased maximal 0107 Magnesium: 10 mg repetitions to failure for bench press and leg extension in 0108 Chromium: 20 mcg response to treatment, with movements increasing by 2.9% US 2016/0213673 A1 Jul. 28, 2016

and 1.6%, respectively. This coincided with a lower heart rate 10. The composition of claim 1 wherein the arginine is after exercise in response to treatment (65 bpm) versus pla present in the formulation in an amount in the range of 10 mg cebo (67 bpm), which would indicate a greater sense of com to 15 g. fort in performing max effort movements. For example, one 11. (canceled) 27 year old male improved his maximal repetitions to failure 12. The composition of claim 1 wherein the ASI is present for bench press by 11.8% and leg extension by 14.3%, with a in the formulation in place of or in addition to arginine in an simultaneous drop in respiratory quotient of 15.3% and an amount in the range of 10 mg to 10 g. increase in circulating free fatty acids of 50% compared with 13. (canceled) his performance after placebo. This individuals heart rate 14. The composition of claim 1 wherein the caffeine is remained stable across all measures. Looking at the top per present in the formulation in an amount in the range of 2 mg forming tertile in the population, after consuming the treat to 400 mg. ment the average improved bench press was 10.1%, leg exten 15. (canceled) sion was 21.7%, respiratory quotient dropped by 0.6% and 16. The composition of claim 8 wherein the arginine is free fatty acids increased by 30% compared with placebo. present in the formulation in an amount in the range of 10 mg 0129. While in the foregoing specification this presently to 15 g. disclosed technology has been described in relation to certain 17. (canceled) embodiments thereof, and many details have been put forth 18. The composition of claim 8 wherein the ASI is present for the purpose of illustration, it will be apparent to those in the formulation in place of or in addition to arginine in an skilled in the art that the presently disclosed technology is amount in the range of 10 mg to 10 g. susceptible to additional embodiments and that certain of the 19. The composition of claim 8 wherein the ASI is present details described herein can be varied considerably without in the formulation in place of or in addition to arginine in an departing from the basic principles of the disclosed technol amount in the range of 10 mg to 10g and whereincapsaicin is Ogy. 0130. The use of the terms “a,” “an,” “the and similar present in the formulation in place of or in addition to dihy referents in the context of describing the presently disclosed drocapsiate in an amount in the range of 10 ug to 50 mg. technology will be understood to include both the singular 20. (canceled) and the plural, unless otherwise indicated herein or clearly 21. The composition of claim 8 wherein the caffeine is contradicted by context. Recitation of ranges of values herein present in the formulation in an amount in the range of 2 mg are merely intended to serve as a shorthand method of refer to 400 mg. ring individually to each separate value falling within the 22. (canceled) range, unless otherwise indicated herein, and each separate 23. The composition of claim 10 wherein the ASI is present value is incorporated into the specification as if it were indi in the formulation in place of or in addition to arginine in an vidually recited herein. amount in the range of 10 mg to 10 g. 0131 All methods described herein can be performed in 24. (canceled) any suitable order unless otherwise indicated herein or oth 25. The composition of claim 10 wherein the caffeine is erwise clearly contradicted by context. The use of any and all present in the formulation in an amount in the range of 2 mg examples, or exemplary language (e.g., “such as') provided to 400 mg. herein, is intended merely to better illuminate the presently 26. (canceled) disclosed technology and does not pose a limitation on the 27. The composition of claim 12 wherein the caffeine is Scope of the technology unless otherwise recited. present in the formulation in an amount in the range of 2 mg 0132 All references cited herein are incorporated by ref to 400 mg. erence in their entirety. The presently disclosed technology 28. (canceled) may be embodied in other specific forms without departing 29. The composition of claim 1 wherein the dihydrocapsi from the spirit or essential attributes thereof. ate is present in the formulation in an amount in the range of 1. A composition comprising dihydrocapsiate, caffeine and 10 ug to 50 mg, the arginine is present in the formulation in an arginine. amount in the range of 10 mg to 15 g and the caffeine is 2. The composition of claim 1 wherein said composition present in the formulation in an amount in the range of 2 mg does not contain capsaicin or other capsaicinoid. to 400 mg. 3. The composition of claim 1 wherein said composition 30. (canceled) does not contain at least one of high fructose corn Syrup, 31. The composition of claim 1 wherein the dihydrocapsi Sucrose, maltose or lactose. ate is present in the formulation in an amount in the range of 4. (canceled) 10 ug to 50 mg, the arginine content in the formulation in an 5. The composition of claim 1 in the form of a ready-to-mix amount in the range of 10 mg to 20 g, and the caffeine is (RTM) or ready-to-drink (RTD) formulation. present in the formulation in an amount in the range of 2 mg 6. The composition of claim 1 in the form of agel, chew, bar to 400 mg. or drink. 32. (canceled) 7. The composition of claim 1 in the form of a fruit drink, 33. The composition of claim 1 wherein the dihydrocapsi a coffee, a tea, an energy drink, an adult nutritional drink, an ate is present in the formulation in an amount in the range of inhalant, a health drink, a lozenge, a Supplement, a tablet, a 10 ug to 50 mg, the arginine is present in the formulation in an capsule or a sports drink. amount in the range of 50 mg to 15 g, the ASI is present in the 8. The composition of claim 1 wherein the dihydrocapsiate formulation in an amount in the range of 10 mg to 10 g, and is present in the formulation in an amount in the range of 10 the caffeine is present in the formulation in an amount in the Jug to 50 mg. range of 2 mg to 400 mg. 9. (canceled) 34. (canceled) US 2016/0213673 A1 Jul. 28, 2016

35. The composition of claim 1 wherein the ratio, by compared to the maximum repetitions of said mammal prior weight, of caffeine to dihydrocapsiate is in the range of to being administered the composition. 40000:1 to 8:1. 41. A method of enhancing the endurance of a mammal 36. The composition of claim 1 wherein the ratio, by comprising administering a composition of claim 1 to said weight, of caffeine to dihydrocapsiate is in the range of 250:1 mammalina Sufficient amount and overa course of time so as to 25:1. to enhance the endurance of said mammal, said enhanced 37. The composition of claim 1 wherein the ratio, by endurance being measured by a decrease in the rating of weight, of arginine to caffeine is in the range of 1:10 to 100:1. perceived exertion (RPE) during physical exertion, such as 38. The composition of claim 1 wherein the ratio, by during running, Swimming, weightlifting and/or walking, as weight, of arginine to caffeine is in the range of 1:2 to 30:1. compared to the RPE of said mammal prior to being admin 39. A method of enhancing endurance in a mammal com istered the composition. prising administering a composition of claim 1 to said mam 42. The method of claim 39 wherein said mammal is a mal in a Sufficient amount and over a course of time so as to human. enhance the endurance of said mammal, said enhanced endur 43. The method of claim 39 wherein said course of time is ance being measured by an increase in the maximum running 1 day to 12 weeks. time of said mammal and/or maximum Swimming time of said mammal and/or other physical activity as compared to 44. The method of claim 39 wherein the endurance is the maximum running time, Swimming time and/or other increased by 5 to 20%. physical activity of said mammal prior to being administered 45. The method of claim 41 wherein the rating of perceived the composition. exertion is decreased by at least 1 on a scale of 1 to 10. 40. A method of enhancing the endurance of a mammal 46. A method of enhancing the respiratory quotient of a comprising administering a composition of claim 1 to said mammal comprising administering a composition of claim 1 mammalina Sufficient amount and over a course of time so as to said mammal in a sufficient amount and over a course of to enhance the endurance of said mammal, said enhanced time so as to enhance the availability of free fatty acids to said endurance being measured by an increase in the maximum mammal. repetitions of physical activity, Such as in weight lifting, as