WO2012097061A1 - Nutritional compositions and methods for improving skeletal muscle protein metabolism - Google Patents

Nutritional compositions and methods for improving skeletal muscle protein metabolism Download PDF

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WO2012097061A1
WO2012097061A1 PCT/US2012/020937 US2012020937W WO2012097061A1 WO 2012097061 A1 WO2012097061 A1 WO 2012097061A1 US 2012020937 W US2012020937 W US 2012020937W WO 2012097061 A1 WO2012097061 A1 WO 2012097061A1
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method
individual
prune extract
muscle
hmb
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PCT/US2012/020937
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French (fr)
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Suzette L. Pereira
Paul W. Johns
Neile K. Edens
Catherine D. Johnson
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Abbott Laboratories
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/73Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736Prunus, e.g. plum, cherry, peach, apricot or almond
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A23B - A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105Plant extracts, their artificial duplicates or their derivatives
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A23B - A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

Disclosed are nutritional compositions and methods of using the compositions for treating or preventing sarcopenia and related muscle wasting diseases. The nutritional compositions include prune extract and optionally calcium HMB and are effective in stimulating protein synthesis to maintain and build muscle.

Description

NUTRITIONAL COMPOSITIONS AND METHODS FOR IMPROVING SKELETAL MUSCLE PROTEIN METABOLISM

TECHNICAL FIELD

[0001] The present disclosure relates to nutritional compositions and methods for improving skeletal muscle protein metabolism. More specifically, the present disclosure relates to nutritional compositions and methods that include or utilize a prune extract alone or in combination with beta-hydroxy-beta-methylbutyric acid (HMB) for preventing skeletal muscle loss.

BACKGROUND OF THE DISCLOSURE

[0002] There are numerous metabolic defects generally associated with aging and chronic diseases. Central to the manifestation of chronic diseases associated with aging is inflammation. Sarcopenia is one specific metabolic defect, which is the degenerative loss of skeletal muscle mass and strength associated with aging. This loss of muscle mass is a result of a drastic reduction of protein synthesis in skeletal muscles, which disrupts the normal equilibrium between protein synthesis and protein degradation required for maintaining muscle mass. Because many older adults face the problem of loss of appetite along with satiety, sarcopenia can significantly impact the lives of older adults. Sarcopenia is known to be associated with Frailty Syndrome, which is a collection of markers or symptoms primarily due to the aging-related loss and dysfunction of skeletal muscle and bone.

[0003] The loss of skeletal muscle due to sarcopenia may lead to a number of problems in older adults, including mobility and dexterity issues, and potentially hyperglycemia due to diminished capacity for glucose disposal and metabolism and insulin resistance. Human aging is also associated with the development of glucose intolerance, abnormal β-cell secretion, and insulin resistance. Chronic hyperglycemia can lead to increased morbidity and mortality and has been linked to a cognitive decline in older adults. [0004] To combat sarcopenia and its associated problems, exercise and general increases in activity are ordinarily generally recommended. In older adults where exercise may not be a viable alternative to properly combat sarcopenia and its related hyperglycemia, pharmaceutical solutions may be utilized, although their success to date has been limited. To specifically address the hyperglycemia issue, patients may be advised to consume oral anti-hyperglycemic agents, however, these have numerous side effects associated with long-term use.

[0005] As such, there is a need for nutritional compositions and methods for treating and managing sarcopenia, as well as its related metabolic defects including hyperglycemia. It would be beneficial if such nutritional compositions and methods could also treat and manage other diseases that involve muscle loss, hyperglycemia, and insulin resistance, such as COPD, obesity, cancer, cachexia and others.

SUMMARY OF THE DISCLOSURE

[0006] One embodiment is directed to a method for treating or preventing skeletal muscle loss in an individual affected by a disease condition. The method comprises administering to the individual a composition comprising an effective amount of a prune extract.

[0007] Another embodiment is directed to a method for increasing muscle mass in an individual in need thereof. The method comprises administering to the individual a composition comprising an effective amount of a prune extract.

[0008] Another embodiment is directed to a method for preventing or treating skeletal muscle loss in an individual in need thereof. The method comprises administering to the individual a composition comprising an effective amount of beta- hydroxy-beta-methylbutyric acid, its salts, metabolites, or derivatives thereof, and an effective amount of a prune extract.

[0009] Another embodiment is directed to a method for increasing muscle mass in an individual in need thereof. The method comprises administering to the individual a nutritional composition comprising an effective amount of beta-hydroxy-beta- methylbutyric acid, its salts, metabolites, or derivatives thereof, and an effective amount of a prune extract.

[0010] Another embodiment is directed to a method for decreasing the loss of appetite in an individual in need thereof. The method comprises administering to the individual a nutritional composition comprising an effective amount of beta-hydroxy- beta-methylbutyric acid, its salts, metabolites, or derivatives thereof, and an effective amount of a prune extract.

[0011] Another embodiment is directed to a method for treating or preventing sarcopenia in an individual in need thereof. The method comprises

administering to the individual a nutritional composition comprising an effective amount of beta-hydroxy-beta-methylbutyric acid, its salts, metabolites, or derivatives thereof, and an effective amount of a prune extract.

[0012] Another embodiment is directed to a method for mitigating anorexia in an individual affected by anorexia. The method comprises administering to the individual a nutritional composition comprising an effective amount of beta-hydroxy-beta- methylbutyric acid, its salts, metabolites, or derivatives thereof, and an effective amount of a prune extract.

[0013] Another embodiment is directed to a method for preventing muscle protein degradation in an individual in need thereof. The method comprises administering to the individual a nutritional composition comprising an effective amount of a prune extract.

[0014] It has now been discovered that skeletal muscle loss can be prevented and muscle mass built in individuals by administering to the individual a nutritional composition including an effective amount of a prune extract alone, or a prune extract in combination with beta-hydroxy-beta-methylbutyric acid (HMB). Prune extract has been found to stimulate protein synthesis in muscle cells and prevent muscle protein degradation, leading to an increase in muscle mass while also decreasing inflammation, which can lead to increased appetite. Further, it has been found that a combination of prune extract and HMB also stimulates protein synthesis in muscle cells and leads to muscle hypertrophy. [0015] Additionally, it has been surprisingly found that the combination of prune extract and HMB act in a synergistic manner and can be utilized to reduce the blood glucose levels in an individual, and specifically blood glucose levels over time.

Significantly, although prune extract alone and HMB alone show very little, if any, impact on chronically controlling blood glucose levels, when used in combination, they show a synergistic benefit by reducing blood glucose levels in individuals.

[0016] Accordingly, the nutritional compositions and methods of the present disclosure offer an alternative therapeutic option that may contribute to the maintenance of healthy muscle mass and a reduction in blood glucose levels in individuals, and particularly adults and older adults. These benefits are advantageously achieved without the complications seen with the previously used oral synthetic pharmacological approaches.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows the results of prune extract in stimulating muscle protein synthesis in the C2C12 myotubules.

[0018] Figure 2 shows the results of Ca-HMB in stimulating muscle protein synthesis in the C2Ci2 myotubules.

[0019] Figure 3 shows the results of prune extract in combination with Ca- HMB in stimulating muscle protein synthesis in C2Ci2 myotubules.

[0020] Figure 4 shows the results of prune extract on blood glucose levels during an 8-week intervention period (start versus end of study).

[0021] Figure 5 shows the results of Ca-HMB on blood glucose levels during an 8-week intervention period.

[0022] Figure 6 shows the results of prune extract in combination with Ca- HMB in reducing blood glucose levels over time in an 8-week intervention period.

[0023] Figure 7 shows that prune extract in combination with Ca-HMB causes a significant increase in body weight following an 8-week intervention. [0024] Figure 8 shows that prune extract in combination with Ca-HMB causes a significant increase in muscle fiber cross section area following an 8-week intervention.

[0025] Figure 9 shows the effect of prune extract on inhibiting the activation of NF-κΒ in response to TNF-a simulation.

[0026] Figure 10 shows the results of prune extract for reducing acute blood glucose levels.

[0027] Figure 11 shows the results of prune extract and prune extract in combination with Ca-HMB for suppressing post-meal acute plasma insulin levels.

[0028] Figures 12 and 13 show that prune extract reduces muscle protein degradation.

[0029] Figure 14 shows the effects of Ca-HMB in stimulating muscle protein synthesis in C2C12 myotubules.

[0030] Figure 15 shows the effects of apple extract in stimulating muscle protein synthesis in C2C12 myotubules.

[0031] Figure 16 shows the effects of Applephenon in stimulating muscle protein synthesis in C2Ci2 myotubules.

[0032] Figure 17 shows that prune extract causes a significant increase in muscle fiber cross section area following an 8-week intervention.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0033] The nutritional compositions described herein, along with their methods of use, include a prune extract alone or a prune extract in combination with beta- hydroxy-beta-methylbutyric acid for preventing skeletal muscle loss and for building muscle mass, and for controlling blood glucose levels. The essential or optional elements or features of the various embodiments are described in detail hereinafter. [0034] The term "nutritional composition" means the referenced material is suitable for oral administration to a human. The nutritional composition may comprise vitamins, minerals and other ingredients and represent a sole or supplemental source of nutrition.

[0035] The term "acute blood glucose level" means the blood glucose level of an individual as measured at a time period of no more than 60 minutes post-meal. For example, the acute blood glucose level of an individual is the blood glucose level of the individual 60 minutes post-meal, more suitably, 45 minutes post-meal, and even more suitably, 30 minutes post-meal.

[0036] The term "acute plasma insulin level" means the plasma insulin level of an individual as measured at a time period of no more than 60 minutes post-meal. For example, the acute plasma insulin level of an individual is the plasma insulin level of the individual 60 minutes post-meal, more suitably, 45 minutes post-meal, and even more suitably, 30 minutes post-meal.

[0037] The term "post-meal" refers to the time period after consuming any nutritional or nutraceutical composition as known in the nutritional and nutraceutical arts.

[0038] The term "older adult" refers to individuals over the age of 50, including an age of 60 to 90, and including an age of 60 to 80.

[0039] The term "excessive" refers to more than a generally accepted or desired amount.

[0040] All percentages, parts and ratios as used herein are by weight of the total composition, unless otherwise specified. All such weights as they pertain to listed ingredients are based on the active level and, therefore, do not include solvents or byproducts that may be included in commercially available materials, unless otherwise specified.

[0041] All numerical ranges as used herein, whether or not expressly preceded by the term "about", are intended and understood to be preceded by that term, unless otherwise specified. [0042] The nutritional compositions and methods herein may also be free of any optional or other ingredient or feature described herein provided that the remaining composition still contains the requisite ingredients or features as described herein. In this context, the term "free" means the selected composition or method contains or is directed to less than a functional amount of the ingredient or feature, typically less than 0.1% by weight, and also including zero percent by weight, of such ingredient or feature.

[0043] Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0044] Any reference to a singular characteristic or limitation of the present disclosure shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0045] Any combination of method or process steps as used herein may be performed in any order, unless otherwise specifically or clearly implied to the contrary by the context in which the referenced combination is made.

[0046] The nutritional compositions and methods may comprise, consist of, or consist essentially of the elements and features of the disclosure described herein, as well as any additional or optional ingredients, components, or features described herein or otherwise useful in a nutritional application.

Product Form

[0047] The nutritional compositions of the present disclosure may be formulated and administered in any known or otherwise suitable oral product form. Any solid, liquid, or powder form, including combinations or variations thereof, are suitable for use herein, provided that such forms allow for safe and effective oral delivery to the individual of the essential ingredients as also defined herein. [0048] The nutritional compositions of the present disclosure include any product form comprising the essential ingredients described herein, and which is safe and effective for oral administration. The nutritional compositions may be formulated to include only the essential ingredients described herein, or may be modified with optional ingredients to form a number of different product forms. The nutritional compositions of the present disclosure are preferably formulated as dietary product forms, which are defined herein as those embodiments comprising the essential ingredients of the present disclosure in a product form that then contains at least one of fat, protein, and carbohydrate, and preferably also contains vitamins, minerals, or combinations thereof.

[0049] The nutritional compositions of the present disclosure may therefore include a variety of different product forms, including most any conventional or otherwise known food product form, some non-limiting examples of which include confectionary products, cereals, food condiments (e.g., spreads, powders, sauces, jams, jelly, coffee creamer or sweetener), pasta, baking or cooking materials (e.g., flour, fats or oils, butter or margarine, breading or baking mixes), salted or seasoned snacks (e.g., extruded, baked, fried), beverages (e.g., coffee, juice, carbonated beverage, non-carbonated beverage, tea, ice-cream based drinks), snack or meal replacement bars (e.g., Slimfast™ bars, Ensure™ bars, Zone perfect™ bars, Glucerna™ bars), smoothies, breakfast cereals, cheeses, gummy products, salted or unsalted crisp snacks (e.g., chips, crackers, pretzels), dips, baked goods (e.g., cookies, cakes, pies, pastries, bread, bagels, croutons, dressings), dry mixes (e.g., mixes for muffins, cookies, waffles, pancakes, beverages), frozen desserts (e.g., ice cream, popsicles, fudge bars, crushed ice, frozen yogurt), pasta, processed meats (e.g., corn dogs, hamburgers, hotdogs, sausage, pepperoni), pizza, pudding, flavored or unflavored gelatin, refrigerated dough (e.g., cookies, bread, brownies), milk or soy-based smoothies, yogurt or yogurt-based drinks, frozen yogurt, soy milk, soups, vegetable-based burgers, and popcorn-based snacks.

[0050] The nutritional compositions of the present disclosure may also be formulated in product forms such as capsules, tablets, pills, caplets, gels, liquids (e.g., suspensions, solutions, emulsions, clear solutions), powders or other particulates, and so forth. These product forms generally contain only the essential ingredients as described herein, optionally in combination with other actives, processing aids or other dosage form excipients. [0051] The nutritional compositions of the present disclosure, when formulated as a dietary product form, may potentially provide either a sole source or a supplemental source of nutrition to an individual. In this context, a sole source of nutrition is one that can be administered once or multiple times each day to potentially provide an individual with all or substantially all their fat, protein, carbohydrate, mineral, and vitamin needs per day or during the intended period of administration. A supplemental source of nutrition is defined herein as a dietary source that does not provide an individual with a potentially sole source of nutrition.

[0052] The nutritional compositions of the present disclosure are desirably formulated as milk-based liquids, soy-based liquids, low-pH liquids, clear liquids, reconstitutable powders, nutritional bites (e.g., plurality of smaller dietary product dosage forms in a single package), or nutritional bars (snack or meal replacement).

Prune Extract

[0053] The nutritional compositions of the present disclosure include a concentrated prune extract, wherein the concentrated prune extract includes at least three different polyphenol types, including hydroxycinnamic acid, flavanol, and flavonoid, as well as a combination of water soluble (chlorogenic acid) and oil soluble (quercetin) polyphenols. In one specific embodiment, a suitable prune extract is derived from the species Prunus domestica.

[0054] Prune extracts suitable for use in the nutritional compositions of the present disclosure desirably include a combination of flavonoids (e.g., quercetin, rutin, daidzin, genistin, epicatechin, 7-methoxycoumarin) and hydroxycinnamic acids (e.g., p- coumaric acid, caffeic, ferulic, chlorogenic, neochlorogenic).

[0055] The term "prune extract" as used herein refers to the extracted concentrate including polyphenolic compounds from prunes, plums, dates, grapes, figs, and combinations thereof and is in a concentrated form. The prune extract comprises at least about 5%, or at least about 10%, or at least about 15%, or at least about 25%, or at least about 30%), or at least about 40%>, or at least about 50%>, or at least about 60%>, or at least about 70%), or at least about 80%>, or at least about 90%>, or even 100%, including from about 5%> to 100%), including from about 10%> to 100%, including from about 25% to 100%, including from about 50% to 100%, and further including from about 75% to 100%, by weight polyphenolic compounds.

[0056] The nutritional compositions of the present disclosure desirably include sufficient prune extract to provide an individual with from about 0.1 grams to about 20 grams, including from about 0.5 grams to about 10 grams, including from about 1 gram to about 8 grams, including from about 2 grams to about 7 grams, and also including from about 3 grams to about 6 grams, per day of prune extract. The total daily prune extract may be contained in one, two, three, or more individual product forms, e.g., one, two, three, or more meal or snack bars or beverages per day.

[0057] For solid embodiments of the nutritional compositions of the present disclosure, the solid embodiments generally comprise prune extract in quantities ranging up to about 15%, including from about 0.1 % to about 10%, and also including from about 0.1 % to about 8%, and also including from about 0.2% to about 5.0%>, and also including from about 0.3% to about 3%, and also including from about 0.4% to about 1.5%), by weight of the solid nutritional composition.

[0058] For liquid embodiments of the nutritional compositions of the present disclosure, including liquids derived from reconstituted powders, the liquid embodiments desirably comprise prune extract in quantities ranging up to about 10%, including from about 0.1% to about 10%, including from about 0.1% to about 8.0%>, and also including from about 0.2% to about 5.0%>, and also including from about 0.3% to about 3.0%), and also including from about 0.4% to about 1.5%, by weight of the liquid nutritional composition.

Calcium HMB

[0059] The nutritional compositions may additionally comprise calcium HMB in addition to the prune extract discussed above, which means that the nutritional compositions are either formulated with the addition of calcium HMB, most typically as a monohydrate, or are otherwise prepared so as to contain calcium and HMB in the finished product. Any source of HMB is suitable for use herein provided that the finished product contains calcium and HMB, although such a source is preferably calcium HMB and is most typically added as such to the nutritional compositions during formulation. [0060] The term "added calcium HMB" as used herein means a calcium salt of HMB, most typically a monohydrate calcium salt of HMB, as the HMB source added to the nutritional composition.

[0061] Although calcium HMB monohydrate is the preferred source of HMB for use herein, other suitable sources may include HMB as the free acid, a salt, an anhydrous salt, an ester, a lactone, or other product forms that otherwise provide a bioavailable form of HMB from the nutritional composition. Non- limiting examples of suitable salts of HMB for use herein include HMB salts, hydrated or anhydrous, of sodium, potassium, magnesium, chromium, calcium, or other non-toxic salt form. Calcium HMB monohydrate is commercially available from Technical Sourcing International (TSI) of Salt Lake City, Utah.

[0062] The nutritional compositions of the present disclosure desirably include sufficient HMB to provide an individual with from about 0.1 grams to about 10 grams, including from about 0.5 grams to about 10 grams, including from about 1 gram to about 8 grams, including from about 2 grams to about 7 grams, and also including from about 3 grams to about 6 grams, per day of HMB. The total daily HMB may be contained in one, two, three, or more individual product forms, e.g., one, two, three, or more meal or snack bars or beverages per day.

[0063] For solid embodiments of the nutritional compositions of the present disclosure, the solid embodiments generally comprise calcium HMB in quantities ranging up to about 15%, including from about 0.1 % to about 10%>, and also including from about 0.2%> to about 5.0%, and also including from about 0.3%> to about 3%, and also including from about 0.4% to about 1.5%, by weight of the nutritional composition.

[0064] For liquid embodiments of the nutritional compositions of the present disclosure, the liquid embodiments generally comprise calcium HMB in quantities ranging up to about 10%>, including from about 0.1 % to about 8%, and also including from about 0.2%) to about 5.0%>, and also including from about 0.3% to about 3%, and also including from about 0.4% to about 1.5%, by weight of the nutritional composition. Macronutrients

[0065] The nutritional compositions of the present disclosure may further comprise one or more optional macronutrients in addition the prune extract and/or the calcium HMB described herein. The optional macronutrients include proteins, lipids, carbohydrates, and combinations thereof. The nutritional compositions are desirably formulated as dietary products containing all three macronutrients.

[0066] Macronutrients suitable for use herein include any protein, lipid, or carbohydrate or source thereof that is known for or otherwise suitable for use in an oral nutritional composition, provided that the optional macronutrient is safe and effective for oral administration and is otherwise compatible with the other ingredients in the nutritional composition.

[0067] The concentration or amount of optional lipid, carbohydrate, and protein in the nutritional composition can vary considerably depending upon the particular product form (e.g., bars or other solid dosage forms, milk or soy based liquids or other clear beverages, reconstitutable powders etc.) and the various other formulations and targeted dietary needs. These optional macronutrients are most typically formulated within any of the embodied ranges described in the following tables.

Figure imgf000013_0001

Each numerical value preceded by the term "about':

Figure imgf000013_0002

Each numerical value preceded by the term "abouf Carbohydrate

[0068] Optional carbohydrates suitable for use in the nutritional compositions may be simple, complex, or variations or combinations thereof, all of which are optionally in addition to the prune extract and the optional calcium HMB as described herein. Non-limiting examples of suitable carbohydrates include hydrolyzed or modified starch or cornstarch, maltodextrin, isomaltulose, sucromalt, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof.

[0069] Optional carbohydrates suitable for use herein also include soluble dietary fiber, non-limiting examples of which include gum Arabic, fructooligosaccharide (FOS), sodium carboxymethyl cellulose, guar gum, citrus pectin, low and high methoxy pectin, oat and barley glucans, carrageenan, psyllium, and combinations thereof. Insoluble dietary fiber is also suitable as a carbohydrate source herein, non-limiting examples of which include oat hull fiber, pea hull fiber, soy hull fiber, soy cotyledon fiber, sugar beet fiber, cellulose, corn bran, and combinations thereof.

[0070] The nutritional compositions may therefore, and desirably, further comprise a carbohydrate component in addition to the prune extract, wherein in one specific embodiment, the prune extract is from about 3% to about 50%, including from about 5% to about 25%, by weight of the total carbohydrate in the composition.

Protein

[0071] Optional proteins suitable for use in the nutritional compositions include hydrolyzed, partially hydrolyzed or non-hydrolyzed proteins or protein sources, and can be derived from any known or otherwise suitable source such as milk (e.g., casein, whey), animal (e.g., meat, fish, egg albumen), cereal (e.g., rice, corn), vegetable (e.g., soy, pea, potato), or combinations thereof. The proteins for use herein can also include, or be entirely or partially replaced by, free amino acids known for use in nutritional products, non-limiting examples of which include L-tryptophan, L-glutamine, L-tyrosine, L- methionine, L-cysteine, taurine, L-arginine, L-carnitine, and combinations thereof. [0072] The nutritional compositions of the present disclosure may optionally comprise a soy protein component, sources of which include, but are not limited to, soy flakes, soy protein isolates, soy protein concentrate, hydrolyzed soy protein, soy flour, soy protein fiber, or any other protein or protein source derived from soy.

Commercial sources of soy protein are well known in the nutrition art, some non-limiting examples of which include soy protein isolates distributed by The Solae Company (St. Louis, Missouri) under the trade designation "Soy Protein Isolate EXP -H0118," ΈΧΡ-Ε- 0101", and "Supro Plus 675."

[0073] The optional soy protein component may represent from zero to 100%, desirably from about 20% to 100%, including from about 50% to 100%, including from about 75% to about 95%, and also including from about 80% to about 90% of the total protein calories in the composition.

Lipid

[0074] Optional lipids suitable for use in the nutritional compositions include coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, high GLA-safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, marine oils, flaxseed oil, borage oil, cottonseed oils, evening primrose oil, blackcurrant seed oil, transgenic oil sources, fungal oils, marine oils (e.g., tuna, sardine), and so forth.

[0075] The nutritional compositions of the present disclosure optionally comprise a flaxseed component, non-limiting examples of which include ground flaxseed and flaxseed oil. Ground flaxseed is generally preferred. Non- limiting examples of flaxseed include red flaxseed, golden flaxseed, and combinations thereof. Golden flaxseed is generally preferred. Commercial sources of flaxseed are well known in the nutrition and formulation arts, some non-limiting examples of which include flaxseed and flax products available from the Flax Council of Canada, the Flax Consortium of Canada, and Heintzman Farms (North Dakota) (Dakota Flax Gold brand). Other Optional Ingredients

[0076] The nutritional compositions of the present disclosure may further comprise other optional components that may modify the physical, chemical, aesthetic or processing characteristics of the compositions or serve as pharmaceutical or additional nutritional components when used in the targeted population. Many such optional ingredients are known or otherwise suitable for use in nutritional compositions or pharmaceutical dosage forms and may also be used in the compositions herein, provided that such optional ingredients are safe and effective for oral administration and are compatible with the essential and other selected ingredients in composition.

[0077] Non-limiting examples of such other optional ingredients include preservatives, anti-oxidants, buffers, additional pharmaceutical actives, sweeteners including artificial sweeteners (e.g., saccharine, aspartame, acesulfame K, sucralose) colorants, flavors, branch chain amino acids, essential amino acids, free amino acids, flavor enhancers, thickening agents and stabilizers, emulsifying agents, lubricants, and so forth.

[0078] The nutritional compositions of the present disclosure preferably comprise one or more minerals, non-limiting examples of which include phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, iodine, calcium, potassium, chromium (e.g., chromium picolinate), molybdenum, selenium, and combinations thereof.

[0079] The nutritional compositions also desirably comprise one or more vitamins, non-limiting examples of which include carotenoids (e.g., beta-carotene, zeaxanthin, lutein, lycopene), biotin, choline, inositol, folic acid, pantothenic acid, choline, vitamin A, thiamine (vitamin Bl), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), cyanocobalamine (vitamin B 12), ascorbic acid (vitamin C), vitamin D, vitamin E, vitamin K, and various salts, esters or other derivatives thereof, and

combinations thereof. In some preferred embodiments, the nutritional compositions of the present disclosure comprise both vitamins and minerals. Methods of Use

[0080] The methods of the present disclosure utilize the nutritional compositions of the present disclosure. These methods include the oral administration of the nutritional compositions, which include a prune extract alone or in combination with HMB, to treat and/or prevent and/or manage and/or control and/or reduce appetite (in overweight or obese individuals), wasting associated with an inflammatory condition, sarcopenia, muscle disuse, hyperglycemia, blood glucose levels, muscle wasting diseases (e.g., skeletal muscle loss resulting from age-associated wasting, wasting associated with long-term hospitalization, wasting associated with muscle disuse, wasting associated with muscle immobilization, and wasting associated with chemotherapy or long-term steroid use), cachexia due to cancer, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/ AIDS), autoimmune diseases, chronic obstructive pulmonary disease (COPD), end stage renal disease (ESRD) and combinations thereof in individuals, including older adults. Additionally, prune extract alone or in combination with HMB could be utilized to reduce satiety and anorexia, due to its anti-inflammatory benefits. In addition, the prune extract alone or in combination with HMB could be used to increase body weight in older adults or to enhance muscle hypertrophy and/or muscle recovery (from disuse). The methods include administration of the nutritional compositions to individuals, including older adults specifically, in need thereof, including individuals, including older adults specifically, afflicted with a specific disease or condition as set forth herein, and/or individuals, including older adults specifically, at risk of developing a specific disease or condition as set forth herein due to heredity or other factors.

[0081] The individual desirably consumes at least one serving of the nutritional composition daily, and in some embodiments, may consume two, three, or even more servings per day. Each serving is desirably administered as a single, undivided dose, although the serving may also be divided into two or more partial or divided servings to be taken at two or more times during the day. The methods of the present disclosure include continuous day after day administration, as well as periodic or limited administration, although continuous day after day administration is generally desirable. The methods of the present disclosure are preferably applied on a daily basis, wherein the daily administration is maintained continuously for at least 3 days, including at least 5 days, including at least 1 month, including at least 6 weeks, including at least 8 weeks, including at least 2 months, including at least 6 months, desirably for at least about 18-24 months, desirably as a long term, continuous, daily, dietary supplement.

[0082] The methods of the present disclosure as described herein are also intended to include the use of such methods in individuals unaffected by or not otherwise afflicted with sarcopenia, muscle wasting diseases, hyperglycemia, glucose intolerance etc., for the purpose of preventing, minimizing, or delaying the development of such diseases or conditions over time. For such prevention purposes, the methods of the present disclosure preferably include continuous, daily administration of the compositions as described herein. Such preventive methods may be directed at adults or others who are at risk of developing muscle wasting and/or diabetes.

[0083] In one specific embodiment, the methods of the present disclosure are directed to the treatment or prevention of sarcopenia, by which is meant that the methods are used in individuals (generally older adults) afflicted by or otherwise at risk of developing sarcopenia, which includes age-related muscle wasting. These methods can be used to slow the onset or progression of sarcopenia and can also be used to reverse the effects of sarcopenia by stimulating muscle mass in the individual. These methods also include methods of (1) stimulating protein synthesis to build muscle; (2) reducing or attenuating muscle loss by preventing muscle protein degradation; (3) reducing the risk of loss of mobility and dexterity associated with sarcopenia; and (4) increasing muscle mass, all which are directed to the oral administration of the compositions of the present disclosure in the manner also described herein.

[0084] In another specific embodiment, the methods of the present disclosure are directed to the treatment or prevention or management of glucose intolerance or hyperglycemia, by which is meant that the methods are used in individuals afflicted by (generally prediabetics or diabetics) or otherwise at risk (generally obese individuals or individuals with a family history) of developing glucose intolerance or hyperglycemia. The methods can be used to slow the onset or progression of glucose intolerance or hyperglycemia and can be used to reverse the effects of glucose intolerance or

hyperglycemia. [0085] The methods of the present invention utilize the nutritional compositions described herein, wherein the individual desirably consumes at least about 0.1 grams, more desirably from about 1 gram to about 10 grams, desirably from about 3 grams to about 6 grams, including from about 3 grams to about 5 grams of the HMB per day; and wherein the individual also consumes at least about 0.1 grams, more preferably from about 1 gram to about 8 grams, even more preferably from about 2 grams to about 7 grams, and also including from about 3 grams to about 6 grams, of the prune extract per day. Preferred methods are directed to the use of HMB in combination with prune extract.

Method of Manufacture

[0086] The nutritional compositions of the present disclosure may be prepared by any known or otherwise effective manufacturing technique for preparing the selected product form. Many such techniques are known for any given product form such as nutritional liquids, nutritional powders, or nutritional bars and can easily be applied by one of ordinary skill in the nutrition and formulation arts to the nutritional products described herein.

[0087] The non-dietary compositions of the present disclosure can likewise be prepared by any known or otherwise effective manufacturing technique for preparing the selected product form. Many such techniques are well known, for example in the pharmaceutical industry, and can be applied by one of ordinary skill in the nutrition and formulation arts to produce forms such as capsules, tablets, caplets, pills, liquids (e.g., suspensions, emulsions, gels, solutions), and so forth, and can easily be applied by one of ordinary skill in those arts to the non-dietary products described herein. As described herein, non-dietary products are those nutritional compositions of the present disclosure that are not dietary products as also defined herein.

[0088] Liquid, milk or soy-based nutritional liquids, for example, may be prepared by first forming an oil and fiber blend containing all formulation oils, any emulsifier, fiber and fat- soluble vitamins. Additional slurries (typically a carbohydrate and two protein slurries) are prepared separately by mixing the carbohydrate and minerals together and the protein in water. The slurries are then mixed together with the oil blend. The resulting mixture is homogenized, heat processed, standardized with any water-soluble vitamins, flavored and the liquid terminally sterilized or aseptically filled or dried to produce a powder.

[0089] Other product forms such as nutritional bars may be manufactured, for example, using cold extrusion technology as is known and commonly described in the bar manufacturing art. To prepare such compositions, typically all of the powdered components are dry blended together, which typically includes any proteins, vitamin premixes, certain carbohydrates, and so forth. The fat-soluble components are then blended together and mixed with any powdered premixes. Finally any liquid components are then mixed into the composition, forming a plastic like composition or dough. The resulting plastic mass can then be shaped, without further physical or chemical changes occurring, by cold forming or extrusion, wherein the plastic mass is forced at relatively low pressure through a die, which confers the desired shape. The resultant exudate is then cut off at an appropriate position to give products of the desired weight. If desired the solid product is then coated, to enhance palatability, and packaged for distribution.

[0090] The solid nutritional embodiments of the present disclosure may also be manufactured through a baked application or heated extrusion to produce solid product forms such as cereals, cookies, crackers, and similar other product forms. One knowledgeable in the nutrition manufacturing arts is able to select one of the many known or otherwise available manufacturing processes to produce the desired final product.

[0091] The compositions of the present disclosure may also be

manufactured by other known or otherwise suitable techniques not specifically described herein without departing from the spirit and scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive and that all changes and equivalents also come within the description of the present disclosure. The following non-limiting examples further illustrate the compositions and methods of the present disclosure.

EXAMPLES

[0092] The following Examples provide data and illustrate specific embodiments and/or features of the nutritional compositions and methods of the present disclosure. The Examples are given solely for the purpose of illustration and are not to be construed as limitations, as many variations thereof are possible without departing from the spirit and scope of the disclosure.

Example 1

[0093] In this Example, the effect of prune extract in stimulating muscle protein synthesis is evaluated in an in vitro cell-based assay using mouse C2C12 muscle myotubules. More particularly, the assay measures the incorporation of radiolabeled phenylalanine into muscle myotubules in response to an anabolic stimulus generated by treatment with a composition of prune extract. The prune extract (PE60) contains 60% polyphenols and is commercially available from PL Thomas (Morristown, New Jersey).

[0094] Initially, 375,000 C2C12 cells are plated on 12-well tissue culture plates coated with 2% gelatin. Cells are differentiated for 5 days in 5% horse serum (media is changed every 2 days) and then starved for 30 minutes by replacing the media with 1 ml PBS (Lonza Cat #17-512Q) containing 4.5 mM glucose prior to treatment. Cells are treated with prune extract in the PBS containing 4.5 mM glucose as follows:

Figure imgf000021_0001

[0095] Cells are spiked with [3H] phenylalanine (ΙμΟΛνεΙΙ) and incubated for 2 hours at 37°C. The reaction is stopped by placing the plates on ice. The wells are washed two times with DPBS-media containing 2 mM cold phenylalanine. One ml of 20% cold trichloroacetic acid (TCA) solution is added to each well and plates are then incubated on ice for 1 hour for protein precipitation. The wells are washed two times with cold TCA and then precipitated proteins are dissolved in 0.5 ml of 0.5N NaOH containing 0.2% Triton XI 00 overnight in a refrigerator. An aliquot (5 μΐ) of the NaOH-solubilized material is used for protein determination and the remaining dissolved proteins are mixed with scintillation fluid and counted. Results are computed as cpm/mg of proteins and then percent change over control is calculated (shown in Figure 1). The resulting data is shown in the following table.

Figure imgf000022_0001

[0096] As the data indicate, prune extract is an effective stimulator of muscle protein synthesis, stimulation of which appears to occur in a dose dependent manner. Maximum stimulation of about a 50% increase over baseline protein synthesis (control) is obtained with the 100 μg/ml prune extract sample. Without being bound to a particular theory, it is believed that this effect could be the result of activation of the IGF- 1/IRS l pathway.

Example 2

[0097] In this Example, the effect of Ca-HMB in stimulating muscle protein synthesis is evaluated in an in vitro cell-based assay using mouse C2Ci2 muscle myotubules. The assay method of Example 1 is used to measure the incorporation of radiolabeled phenylalanine into muscle myotubules in response to an anabolic stimulus generated by treatment with a composition of Ca-HMB.

Specifically, the cells are treated in the PBS (Lonza Cat #17-512Q) containing 4.5 mM glucose as follows:

Sample Ca-HMB (μΜ)

Control 0

1 25

2 50

3 100 [0098] Results are computed as cpm/mg of proteins and then percent change over control is calculated (shown in Figure 2). The resulting data is shown in the following table.

Figure imgf000023_0001

[0099] Ca-HMB is effective in stimulating protein synthesis above baseline (control) values. The stimulatory effect appears to be dose dependent and peaks at about 50 μΜ Ca-HMB (about a 45% increase over baseline protein synthesis). The stimulatory effect further persists at higher concentrations of Ca-HMB.

Example 3

[0100] In this Example, the effect of prune extract in combination with Ca-HMB in stimulating muscle protein synthesis is evaluated in an in vitro cell-based assay using mouse C2Ci2 muscle myotubules. The assay method of Example 1 is used to measure the incorporation of radiolabeled phenylalanine into muscle myotubules in response to an anabolic stimulus generated by treatment with a composition of prune extract and Ca-HMB.

[0101] Specifically, the cells are treated in the PBS (Lonza Cat #17-512Q) containing 4.5 mM glucose as follows:

Sample Ca-HMB (μΜ) Prune Extract (PE60) ^g/ml)

Control 0 0

1 10 0

2 0 10

3 10 10 [0102] Results are computed as cpm/mg of proteins and then percent change over control is calculated (shown in Figure 3). The resulting data is shown in the following table.

Figure imgf000024_0001

[0103] When the prune extract and Ca-HMB are used together in low concentrations, there appears to be an additive effect on the stimulation of protein synthesis. For example, 10 μΜ Ca-HMB stimulates protein synthesis by about 9% above baseline (control), 10 μg/ml prune extract stimulates protein synthesis by about 13% above baseline (control), and 10 μg/ml prune extract and 10 μΜ Ca-HMB stimulates protein synthesis by about 21% above baseline (control).

Example 4

[0104] In this Example, prune extract (PE60) is evaluated for selected polyphenols and for antioxidant activity. Particularly, HPLC is used to measure amounts of polyphenols in PE60. Other polyphenols which are reportedly present in at least some plum varieties, including 5-chlorogenic acid, epicatechin, myricetin, isoquercitrin, are not determined in this analysis. Antioxidant activity is analyzed using DPPH colorimetry.

[0105] The results are shown as percent by weight of the polyphenols in the prune extract.

Prune Extract (PE 60), Lot PE6009-1601

Chlorogenic Acid* 1.9% (w/w)

Rutin 1.2% (w/w)

Quercetin 0.72% (w/w) Procyanidins 50-70% (w/w)

Antioxidant Activity, Trolox μΕ /10(^ 370,000

*3-chlorogenic acid isomer only (the major isomer in this extract)

Example 5

[0106] In this Example, the effect of prune extract (PE60) for reducing blood glucose levels is analyzed.

[0107] The effect on blood glucose levels is tested in aged Sprague Dawley rats at the age of approximately 22 months. Animals are divided into two groups: a control group and a Test feed group. Initially, fasted blood glucose levels of the rats from each group are recorded. The control group is chronically fed ad libitum a purified rodent diet AIN-93M (American Institute of Nutrition Rodent Diets) over an 8-week period. The test study group of rats is simultaneously fed, ad libitum, a feed composition including the AIN-93M diet supplemented with prune extract at 500 mg/kg body weight over an 8-week period. Fasted blood glucose levels are then measured again at the end of the 8-week study from both groups.

[0108] The change in blood glucose levels over time is shown in the Table below and in Figure 4.

Figure imgf000025_0001

Example 6

[0109] In this Example, the effect of Ca-HMB for reducing blood glucose levels is analyzed. [0110] The effect on blood glucose levels is tested in Sprague Dawley rats at the age of approximately 22 months. Animals are divided into two groups: a control group and a Test feed group. Initially, fasted blood glucose levels of the rats from each group are recorded. The control group is chronically fed ad libitum a purified rodent diet AIN-93M over an 8-week period. The test study group of rats is simultaneously fed, ad libitum, a composition including AIN-93M diet supplemented with Ca-HMB at 340 mg/kg body weight over an 8-week period. Fasted blood glucose levels are then measured again at the end of the 8-week study from both groups.

[0111] The change in blood glucose levels over time is shown in the Table below and in Figure 5.

Figure imgf000026_0001

* statistically significant increase over time

Example 7

[0112] In this Example, the effect of a composition including a combination of prune extract and Ca-HMB for reducing blood glucose levels is analyzed.

[0113] The effect on blood glucose levels is tested in Sprague Dawley rats at the age of approximately 22 months. Animals are divided into two groups: a control group and a Test feed group. Initially, fasted blood glucose levels of the rats from each group are recorded. The control group is chronically fed, ad libitum, a purified rodent diet AIN-93M over an 8-week period. The test study group of rats is fed a composition including AIN-93M supplemented with a combination of Ca-HMB at 340 mg/kg body weight and prune extract (PE60) at 500 mg/kg body weight. Fasted blood glucose levels are then tested again at the end of the 8-week study. [0114] The change in blood glucose levels is shown in the Table below and in Figure 6.

Figure imgf000027_0001

* statistically significant decrease compared to control (p=0.04)

[0115] Chronic feeding of the combination of prune extract and HMB over a period of 8 weeks is surprisingly found to significantly lower blood glucose levels as compared to the control. Prune extract and HMB act synergistically to reduce blood glucose levels.

Example 8

[0116] In this Example, the effect of a combination of prune extract and Ca-HMB on body weight and muscle fiber cross section area (CSA) is analyzed.

Particularly, the size of the gastrocnemius muscle of Sprague Dawley (SD) rats

administered the combination of prune extract and Ca-HMB is analyzed.

[0117] The effect on body weight and muscle fiber CSA is tested in SD rats at the age of approximately 22 months. Initially, fasted body weights of the rats are recorded. The control group is chronically fed, ad libitum, purified rodent diet AIN-93M over an 8-week period. The test study group of rats is fed a composition including AIN- 93M supplemented with 340 mg/kg body weight Ca-HMB and 500 mg/kg body weight prune extract (PE60), ad libitum, over an 8-week period. The body weights are measured at weeks 1, 2, 3, 4, 6, and 8.

[0118] The change in body weight of the rats is shown in the Tables below and in Figure 7. Average Body Weights (grams)

Figure imgf000028_0001

Average Body Weights (grams)

Figure imgf000028_0002

* trend towards significance (p=0.09)

[0119] The effect on gastrocnemius muscle is measured by the change in size of the muscle fiber cross section area (CSA) as shown in the table below, and the results are shown in Figure 8.

Figure imgf000028_0003

* Significant increase (p<0.05) [0120] Additionally, the muscle wet weight (grams) is measured and the results are shown in the Table below.

Figure imgf000029_0001

[0121] Analysis of the gastrocnemius muscle of the test study rats shows that although the overall muscle weight did not increase over an 8-week period, there is a statistically significant increase in muscle fiber cross section area for the prune extract and Ca-HMB fed rats compared to that of the control. Muscle fiber CSA is an early indicator of changes occurring in the muscle and an increase on fiber CSA indicates muscle hypertrophy. This indicates that the combination of prune extract and Ca-HMB may protect aged muscles from atrophy. Additionally, the results show that the prune extract and Ca-HMB fed rats had increased average body weight gains as compared to the control.

Example 9

[0122] In this Example, the effect of prune extract on body weight and muscle fiber cross section area (CSA) is analyzed. Particularly, the size of the

gastrocnemius muscle of Sprague Dawley (SD) rats administered prune extract is analyzed.

[0123] The effect on body weight and muscle fiber CSA is tested in SD rats at the age of approximately 22 months. Initially, fasted body weights of the rats are recorded. The control group is chronically fed, ad libitum, purified rodent diet AIN-93M over an 8-week period. The test study group of rats is fed a composition including AIN- 93M supplemented with 500 mg/kg body weight prune extract (PE60), ad libitum, over an 8-week period. The body weights are measured at weeks 1, 2, 3, 4, 6, and 8. [0124] The change in body weight of the rats is shown in the table below (average body weight in grams).

Figure imgf000030_0001

[0125] The effect on gastrocnemius muscle is measure by the change in size of the muscle fiber cross section area (CSA) and the results are shown in the table below, and in Figure 17. Approximately 500 CSAs were counted for each animal per group.

Figure imgf000030_0002

* Significant increase (p<0.05)

[0126] Additionally, the muscle wet weight (grams) is measured and the results are shown in the table below.

Rat Group Week 8 Gastrocnemius

Weight

Control (AIN-93M) 2.73

Standard Deviation 0.64

ΑΓΝ-93Μ + Prune Extract 2.79

Standard Deviation 0.25 [0127] Analysis of the gastrocnemius muscle of the test study rats shows that although the overall muscle size did not increase over an 8-week period, there is a statistically significant increase in muscle fiber cross section area for the prune extract fed rats compared to that of the control. Muscle fiber CSA is an early indicator of changes occurring in the muscle and an increase in fiber CSA indicates muscle hypertrophy. This indicates that prune extract may protect aged muscles from atrophy.

Example 10

[0128] In this Example, the effect of prune extract (PE60) for its antiinflammatory activities in an in vitro model of chronic inflammation is analyzed.

Specifically, a cell based assay system is established by using a NFKB reporter stable cell line that is designed for measuring the activity of a NFKB transcription factor. This assay system is utilized to screen ingredients that inhibit the activation of NFKB induced by TNFa on A549/NFKB-1UC reporter stable cell line (available from Panomics), where the activity is measured in terms of luciferase activity.

[0129] The A549/ NFKB-IUC cell line is designed for monitoring the activity of NFKB transcription factor in cell-based assays. To obtain the cell line, A549 cells (ATCC P/N CCL-185) are co-transfected with PNFKB-IUC (Panomics P/N LR0051) and pHyg followed by hygromycin selection. Hygromycin-resistant cell clones are selected using a functional TNFa assay that induces luciferase activity. These cells maintain a chromosomal integration of a luciferase report construct regulated by multiple copies of the NFKB response element.

[0130] A549/NFKB-1UC cells at 3 X 105/well in 1 ml of initial growth media in a 12-well plate. The culture dish is incubated in a humidified incubator at 37°C and 5% C02 for 24 hours to allow cells to recover and attach. The cells are then washed and the media is replaced with 1 ml of Serum Free Media.

[0131] The cells are pretreated with the following concentrations for 1 hour at 37°C and 5% C02. TNFa is added to the cells, with the exception of the control untreated cells, to achieve a final concentration of 2 ng/ml. The culture dishes are then incubated in a humidified incubator at 37°C and 5% C02 for 6 hours. Sample Prune Extract (PE60) ^ /ml)

Control (TNF-2 ng/ml) 0

1 2.5

2 5.0

3 10.0

4 25.0

5 50.0

[0132] Baseline quenching determination is conducted by treating the cells with their respective active ingredients for 7 hours at 37°C and 5% C02 without TNFa activation.

[0133] Four volumes of water are added to 1 volume of 5X lysis buffer (Promega). The IX lysis buffer is equilibrated to room temperature prior to use. The growth medium is removed and washed with PBS once. The culture dishes are rocked several times to ensure complete coverage of the cells with lysis buffer and then frozen at - 80°C overnight. The assay is then conduced for luciferase activity according to the assay manufacturer's (Promega P/N El 500) recommendations.

[0134] The Luciferase Assay Reagent is prepared by adding Luciferase Assay Buffer (10 ml) to the vial containing the lyophilized Luciferase Assay Substrate. A 96-well white plate, containing 20 μΐ of cell lysate per well, is mixed and placed into the luminometer containing an injector. The injector then adds 100 μΐ of Luciferase Assay Reagent per well, and the well is immediately read. The plate is advanced to the next well for a repeat of the inject-then-read process.

[0135] To analyze the results, Winglow® software protocol is used to read the relative light units (RLU) for each well. The protocol is set for a 1 -second integrated reading. The average RLU values for each set of triplicate wells are calculated using Winglow® software and Microsoft Excel®. The RLU values are averaged for each cell concentration seeded in the 12-well tissue culture plate. The baseline quenching RLU values are subtracted from the mean RLU values. The mean RLU values are charted per concentration of PE60 as shown in Figure 9. The relative percent inhibition of TNFa- mediated NFKB activation on A549 cells is then calculated.

[0136] The dose response assay indicates that significant inhibition of TNFa-mediated NFKB activation is achieved using prune extract (PE60). Specifically, at a concentration of 25 μg/ml, about 40% inhibition is shown. At 50 μg/ml concentration, about 80% inhibition is shown.

Example 11

[0137] In this Example, the effect of prune extract (PE60) for reducing acute blood glucose levels is analyzed.

[0138] The effect on acute blood glucose levels is tested in Zucker obese diabetic rats at the age of approximately 10 weeks. The average weight of the rats is about 363 grams. Initially, after fasting overnight, blood glucose levels of the rats are recorded. The rats are divided into four groups: one control group and three test groups. The control group is fed a composition including 2.0 g/kg of body weight maltodextrin (commercially available as Maltrin-100) and water by gavage at a volume of 10 ml/kg of body weight. A first test group is fed the maltodextrin composition supplemented with 500 mg/kg body weight prune extract (PE60). A second test group is fed the maltodextrin composition supplemented with 314 mg/kg Ca-HMB. The third test group is fed the maltodextrin composition supplemented with a combination of 314 mg/kg body weight Ca-HMB and 500 mg/kg body weight PE60. Blood glucose levels are then tested using the Precision G blood glucose testing system (available from Medisense, Alameda, Georgia) after 30 minutes, 60 minutes, 90 minutes, and 120 minutes.

[0139] The change in blood glucose levels is shown in the Table below and in Figure 10. Post-meal Glucose Levels

Rat Group Pre-meal 30 minutes 60 minutes 90 minutes 120 minutes

Glucose

Levels

Control (Maltrin-100) 106.11 211.67 204.56 170.44 154.44

Standard Deviation 8.62 29.80 30.86 36.31 22.73

Maltrin-100 + Prune 13.89 153.78* 169.89* 166.11 157.11 Extract

Standard Deviation 7.64 19.52 25.56 22.29 23.91

Maltrin-100 + Ca-HMB 106.78 200.89 205.33 191.00 169.33

Standard Deviation 8.01 26.38 23.29 29.15 20.93

Maltrin-100 + Prune 103.67 151.89* 172.11 * 186.67 174.67 Extract + Ca-HMB

Standard Deviation 8.86 22.75 18.43 15.97 24.40 gnificantly lower compared to control

[0140] While Ca-HMB shows no effect on the blood glucose levels compared to the control, both the test groups fed PE60 alone, and in combination with Ca- HMB, surprisingly show reduced acute blood glucose levels. Specifically, after 30 minutes and 60 minutes of being fed, the test group fed PE60 and the test group fed the combination of PE60 and Ca-HMB have lower blood glucose levels as compared to the control.

Example 12

[0141] In this Example, the effect of prune extract (PE60) and the combination of prune extract (PE60) and Ca-HMB on plasma insulin levels post-meal is analyzed.

[0142] The effect on post-meal plasma insulin levels is tested in Zucker obese diabetic rats at the age of approximately 10 weeks. The average weight of the rats is about 363 grams. Initially, after fasting overnight, plasma insulin levels of the rats are recorded. The rats are divided into four study groups and fed as described in Example 11. Plasma insulin levels are then tested using Alpco Insulin (Rat) Ultrasensitive Elisa (Cat. # 80-INSRTU-lO) post-meal after 30 minutes, 60 minutes, 90 minutes, and 120 minutes. [0143] The change in plasma insulin levels is shown in the Table below and in Figure 1 1.

Figure imgf000035_0001

* significantly lower compared to control

[0144] While the level of insulin significantly increases in the control group, it is surprisingly found that feeding prune extract suppresses the plasma insulin level increase post-meal as compared to the control. Further, feeding the combination of prune extract and HMB even further suppresses the plasma insulin level increase post-meal as compared to the control. Prune extract and HMB act synergistically to suppress post-meal acute plasma insulin levels.

Example 13

[0145] In this Example, the effect of prune extract in preventing muscle protein degradation is analyzed.

[0146] Initially, 375,000 C2Ci2 cells are plated on 12-well tissue culture plates coated with 2% gelatin. Cells are differentiated for 5 days in 5% horse serum (media is changed every 2 days), and then starved for 30 minutes by replacing the media with 1 ml PBS (Lonza Cat #17-512Q) containing 4.5 mM glucose prior to treatment. Cells are labeled with [3H] Tyrosine ^Ci/mL in serum free-DMEM 9 (SF-DMEM) for 24 hours. The unincorporated [3H] Tyrosine is removed by washing the cell monolayer three times with SF-DME containing 50 μΜ cycloheximide (protein synthesis inhibitor) and 2 mM non-labeled Tyrosine. Proteolysis is induced by serum starving the cell for 48 hours in the presence or absence of test compounds as shown in the following Table.

Figure imgf000036_0001

[0147] The extent of protein degradation is assayed by monitoring radioactive tyrosine in the media after 48 hours of incubation. Results are expressed as % inhibition of tyrosine release in comparison to control (shown in Figures 12 and 13). The resulting data are shown in the following table.

Figure imgf000036_0002

[0148] As the data indicate, prune extract is effective in reducing muscle protein degradation in vitro as measured by tyrosine release assay using the C2Ci2 myotubules. Maximal inhibition of 32% is achieved with the 100 μg/ml prune extract sample. Example 14

[0149] In this Example, in vitro efficacy of additional dietary ingredients on the stimulation of muscle protein synthesis in C2C12 myotubules is analyzed.

Specifically, the in vitro efficacy of Ca-HMB, Apple Dry Extract, and Applephenon (commercially available from MAYPRO Industries Inc., Purchase, New York) on the stimulation of muscle protein synthesis in C2C12 myotubules is analyzed.

[0150] Initially, 375,000 C2C12 cells (passage maintained between 3 to 8) are plated in DMEM with 10% FBS on 12-well tissue culture plates coated with 2% gelatin. The next day, the media is changed to differentiation media (DMEM with 5% horse serum). Cells are differentiated for 4 days with a media change every alternate day in between. On the 5th day, the media is removed, cells are washed twice with PBSG buffer (DPBS with 4.5 mM glucose) and then starved for 30 minutes.

[0151] The sample compounds are dissolved and the recommended dilutions are prepared in PBSG. Cells are treated (n=3) with the sample compounds and are spiked with [3H] phenylalanine (ΙμΟΛνεΙΙ) and incubated at 37°C for 2 hours. The reaction is stopped by placing the plates on ice for 15 minutes. The plates are subsequently washed twice with 1 ml of 2 mM cold phenylalanine in PBSG.

[0152] For protein precipitation, the cells are incubated with 1 ml of cold 20% TCA on ice for 1 hour. They are then washed with 2.5% TCA twice, and the precipitated proteins are solubilized in 0.5 ml of 0.5 (N)NaOH containing 0.2% Triton-X 100 at 4°C overnight. 50 μΐ of the sample is used for radioactive enumeration in a GF-B plate and 10 μΐ of the sample is used for protein estimation.

[0153] To measure the uptake of 3H-Phenylalanine, 50 μΐ of sample from each well is transferred to a 96-well GF-B plate. The GF-B plates are allowed to dry for 2 hours at 60°C. 50 μΐ of Mircoscint is added and the plate is sealed and read in a Top Count (beta-counter).

[0154] To estimate the protein levels, 10 μΐ of a protein sample from each well of the 96-well plate is transferred to a fresh 96-well assay plate. The volume is increased to up to 20 μΐ in each well by adding water (dilution of 1 :2). Wells having 2-fold dilutions of 0.5 (N) NaOH containing 0.2% Triton-X 100 are used to determine the background absorbance in the assay. For the standard curve, BSA standard (Pierce) is used in the range of about 2 mg/ml to about 0.312 mg/ml (7, 2-fold serial dilutions in duplicates) prepared in 0.5 (N)NaOH containing 0.2% Triton-X 100, diluted 2-fold as in the samples. BC A reagent is prepared as per the kit instructions. 180 μΐ of BC A reagent is added to each well containing 20 μΐ of the sample/standard/blank, mixed for 30 seconds and incubated at 37°C for 30 minutes. The absorbance is read at 562 nm in a Spectramax plate reader. The standard curve is plotted and the protein content in each well is calculated from the slope and intercept values obtained from the standard curves. From the normalized cpm counts and the protein (mg per well) reads, the cpm/mg protein for each well of the test samples is calculated. (Shown in Figures 14-16).

[0155] As the data indicate, Ca-HMB is able to promote protein synthesis efficiently, although the effect seems to plateau at higher concentrations. Further, unlike the prune extract, the data indicate that Apple Dry Extract and Applephenon do not have any effect on protein synthesis. As such, it can be concluded that not all fruit polyphenols have a stimulating effect on protein synthesis.

Exemplary Nutritional Compositions

Examples 15-19

[0156] Examples 15-19 illustrate nutritional bars of the present disclosure including prune extract and HMB, the ingredients of which are listed in the table below.

[0157] In order to prepare the bar, the dry ingredients (Supro 661 , FOS, prune extract (which, in some embodiments, could be a liquid), soy crisp 60%>, DCP, and ground flaxseed) are weighed and added into a large mixing bowl. The dry ingredients are blended for 1 minute until well mixed. In a separate bowl, fructose and sorbitol are added to the liquid ingredients (HFCS 55, corn syrup 42 DE, and rice syrup). The liquid ingredients are mixed together for 1-2 minutes. The mixed liquid ingredients are then added to the blended dry ingredients and mixed until completely blended. The dough that forms is removed from the mixing bowl and kneaded to ensure that it is completely mixed. The dough is then placed onto a rolling mat and rolled to approximately 1.32 inch in thickness. The dough is cut into rectangular pieces, each weighing approximately 47 grams and baked. A coating is melted utilizing a kettle or double boiler, then added to a pastry bag, and then drizzled on top of the bar using about 2.5-3.5 grams of coating per bar. The bars are allowed to cool and are then covered with wrapping.

Figure imgf000039_0001

Examples 20-25

[0158] Examples 20-25 illustrate milk-based nutritional liquid embodiments of the present disclosure including prune extract and HMB, the ingredients of which are listed in the table below. [0159] All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified. The milk-based beverages are prepared by forming at least three separate slurries (e.g., carbohydrate -mineral slurry, protein-in-water slurry, protein-in-fat slurry) which are then blended together, heat-treated, and standardized. The resulting composition is then flavored, aseptically packaged into plastic bottles or retort sterilized.

Ingredient Example Example Example Example Example Example

20 21 22 23 24 25

Water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

Sucrose 38.9 32.9 34.9 38.9 32.9 34.9

FOS - - - 14 14 10

Prune Extract-PE60 0.1 1.5 3.0 0.3 0.4 5.0

Ca-HMB 12 10 34.9 - - -

Flaxseed - 14 - - 14 -

HO safflower oil 39.8 39.8 39.8 39.8 39.8 -

Milk protein isolate 33.4 33.4 33.4 33.4 33.4 33.4

Acid casein 9.44 9.44 9.44 9.44 9.44 9.44

Magnesium 6.74 6.74 6.74 6.74 6.74 6.74 phosphate dibasic

Whey protein 5.28 5.28 5.28 5.28 5.28 5.28 concentrate

Micronized tri- 4.27 4.27 4.27 4.27 4.27 4.27 calcium phosphate

Microcrystalline 4.00 4.00 4.00 4.00 4.00 4.00 cellulose

Flavor 4.00 4.00 4.00 4.00 4.00 4.00

Sodium chloride 2.11 2.11 2.11 2.11 2.11 2.11

Soy lecithin 1.66 1.66 1.66 1.66 1.66 1.66

Potassium citrate 1.63 1.63 1.63 1.63 1.63 1.63

Sodium citrate 1.05 1.05 1.05 1.05 1.05 1.05

Lemon oil 0.500 0.500 0.500 0.500 0.500 0.500 Carrageenan 0.400 0.400 0.400 0.400 0.400 0.400

Sensient Temeric 0.200 0.200 0.200 0.200 0.200 0.200 Concentrate

Sodium hydroxide 0.196 0.196 0.196 0.196 0.196 0.196

Liquid Sucralose 0.175 0.175 0.175 0.175 0.175 0.175

Ascorbyl palmitate 0.0498 0.0498 0.0498 0.0498 0.0498 0.0498

Acesulfame 0.0350 0.0350 0.0350 0.0350 0.0350 0.0350 potassium

Pyridoxine 0.0299 0.0299 0.0299 0.0299 0.0299 0.0299 Hydrochloride (B6)

Tocopherol-2 0.00830 0.00830 0.00830 0.00830 0.00830 0.00830

Folic acid 0.00500 0.00500 0.00500 0.00500 0.00500 0.00500

Vitamin D3 0.00300 0.00300 0.00300 0.00300 0.00300 0.00300

Cyanocobalamin 0.000337 0.000337 0.000337 0.000337 0.000337 0.000337

Claims

WHAT IS CLAIMED IS:
1. A method for treating or preventing skeletal muscle loss in an individual affected by a disease condition, the method comprising administering to the individual a nutritional composition comprising an effective amount of a prune extract.
2. The method of claim 1 , wherein the disease condition is selected from the group consisting of cancer cachexia, sarcopenia, HIV/ AIDS, COPD, ESRD, and combinations thereof.
3. The method of claim 1 wherein the skeletal muscle loss is the result of age- associated wasting, wasting associated with long-term hospitalization, wasting associated with muscle disuse, wasting associated with muscle immobilization, wasting associated with chemotherapy or long-term steroid use, or combinations thereof.
4. The method of claim 1 wherein the nutritional composition comprises from about 0.1% to about 8% of the prune extract by weight of the nutritional composition.
5. The method of claim 1 wherein the prune extract comprises at least about 25% (by weight) polyphenolic compounds.
6. A method for increasing muscle mass in an individual in need thereof, the method comprising administering to the individual a nutritional composition comprising an effective amount of a prune extract.
7. The method of claim 6 further comprising engaging the individual in exercise.
8. The method of claim 7 wherein the nutritional composition is consumed by the individual before exercise, during exercise, after exercise, or combinations thereof.
9. The method of claim 6 wherein the prune extract comprises at least about 25% (by weight) polyphenolic compounds.
10. A method for preventing or treating skeletal muscle loss in an individual in need thereof, the method comprising administering to the individual a nutritional composition comprising an effective amount of beta-hydroxy-beta-methylbutyric acid and an effective amount of a prune extract.
11. The method of claim 10 wherein the skeletal muscle loss is the result of a disease condition.
12. The method of claim 11 wherein the disease condition is selected from the group consisting of cancer cachexia, sarcopenia, HIV/ AIDS, COPD, ESRD, and combinations thereof.
13. The method of claim 12 wherein the disease condition is sarcopenia.
14. The method of claim 10 wherein the skeletal muscle loss is the result of age- associated wasting, wasting associated with long-term hospitalization, wasting associated with muscle disuse, wasting associated with muscle immobilization, or wasting associated with chemotherapy or long-term steroid use.
15. A method for treating or preventing sarcopenia in an individual, the method comprising administering to the individual a nutritional composition comprising an effective amount of beta-hydroxy-beta-methylbutyric acid and an effective amount of a prune extract.
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US8778994B2 (en) 2004-03-26 2014-07-15 Abbott Laboratories Method of using beta-hydroxy-beta-methylbutyrate and fatty acids for treating disease-associated wasting
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WO2014179526A1 (en) * 2013-05-01 2014-11-06 Abbott Laboratories Methods for enhancing aged muscle regeneration
CN106061291A (en) * 2013-12-18 2016-10-26 雅培公司 Methods for increasing skeletal muscle protein synthesis using green tea extract
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