WO2013175386A1 - Compositions et procédés pour l'augmentation de la force et de la masse musculaire - Google Patents

Compositions et procédés pour l'augmentation de la force et de la masse musculaire Download PDF

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WO2013175386A1
WO2013175386A1 PCT/IB2013/054137 IB2013054137W WO2013175386A1 WO 2013175386 A1 WO2013175386 A1 WO 2013175386A1 IB 2013054137 W IB2013054137 W IB 2013054137W WO 2013175386 A1 WO2013175386 A1 WO 2013175386A1
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phosphatidic acid
lyso
phospholipase
phosphate
glycerol
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PCT/IB2013/054137
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English (en)
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Lorenzo De Ferra
Ralf Jaeger
Martin Purpura
Marvin Heuer
Scott Hagerman
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Chemi Nutra Inc.
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Priority claimed from PCT/IB2012/052543 external-priority patent/WO2013175266A1/fr
Application filed by Chemi Nutra Inc. filed Critical Chemi Nutra Inc.
Priority to EP13734499.0A priority Critical patent/EP2852390A1/fr
Priority to CA2873840A priority patent/CA2873840A1/fr
Priority to RU2014148918A priority patent/RU2014148918A/ru
Publication of WO2013175386A1 publication Critical patent/WO2013175386A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/189—Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/24—Compounds of alkaline earth metals, e.g. magnesium
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/20—Feeding-stuffs specially adapted for particular animals for horses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/06—Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • Phosphatide acid, lyso-phosphatidic acid, glycerol-3-phosphate and/or phospholipase D can be administered to exercising mammals to increase muscle mass and strength. These actives can be administered orally to aging, bedridden or cachectic patients to improve nitrogen balance.
  • a highly suitable form of phosphatidic acid for administration is phosphatidic acid-enriched lecithin. Creatine can be co-administered orally to increase muscle-building and strength- enhancing effects.
  • Other additives can include nutritional and herbal supplements,
  • Muscles are the engines that move the body. Muscles are composed of the contractile proteins myosin and actin, which together form myofibrils. Contraction occurs when actin ratchets over myosin, shortening the length of myofibrils. Like all proteins, these contractile proteins begin with the genetic response, through the ribosomal synthetic apparatus. The resulting proteins are incorporated into existing myofibrils to increase the size of a muscle or to repair any damage that occurs during contraction. The increase in size of a muscle is called muscular hypertrophy. This system requires adequate nutrition to provide amino acids to form the protein, and the pathways are controlled by various activating factors.
  • Muscular hypertrophy can be is achieved by exercise, especially exercise vigorous enough to reach the anaerobic threshold. Within a short time of commencing such exercise, a mammal can achieve measurable increases in muscle mass and strength. The increased demand causes the synthetic machinery to be up regulated.
  • the activating factors that can initiate up-regulation in response to demands include the "second messenger system", which is known to include phospho lipases, protein kinases and other enzymes.
  • the metabolism is in the anabolic phase, that is, more muscle is added than is broken down during the catabolic phase.
  • the anabolic/catabolic balance is an important factor in disease and disease management. Muscle wasting in patients on bed rest is a common and problematic clinical issue. Patients in intensive care units often become catabolic. In many cases muscle tissue begins to deteriorate almost immediately after confinement. Astronauts become catabolic in the weightless environment of space and also begin losing muscle tissue and strength almost immediately in that environment. Even exercise is not completely sufficient to keep up with the muscle lost through catabolism the weightless environment of space. Significant loss of muscle has also been shown even in healthy, young volunteers whose leg has been immobilized a cast for only two weeks (Hespel et al. J. Physiol.536:625-633, 2001). Extreme loss of muscle tissue leads cachexia, which is often seen in cancer, trauma and burn patients.
  • a shift toward catabolism may occur as a normal part of aging. Extraordinary measures are necessary to stave it off and shift the metabolism to a more anabolic state. Athletes also regularly seek to achieve a more anabolic state to enhance muscle development. In their training, especially in weight or cardiovascular training intense enough to reach the anaerobic threshold, they are regularly tearing down muscle fiber (catabolism) followed by rebuilding the fibers (anabolism). Muscle rebuilding is especially rapid during the first 90 minutes following vigorous exercise (the "anabolic window"). While daily training itself increases muscle mass and strength, the addition of certain elements, vitamins, and minerals to daily nutrition through supplementation helps increase muscle repair and growth.
  • Protein is the main nitrogen-containing compound in the human body. About 60%-70% of protein is found in muscle mass. A convenient measure of the anabolic/catabolic status is the nitrogen balance: the ratio between nitrogen ingested and nitrogen excreted. A positive nitrogen balance indicates net growth and an increase in muscle mass; equilibrium indicates a zero balance; while a negative nitrogen balance, if chronic, is an indication of bodily dysfunction that can lead to cachexia.
  • This invention provides compositions and methods for the administration of therapeutically effective amounts of naturally occurring, isolated compounds that are biologically active in increasing muscle mass and strength by stimulation of anabolic metabolism.
  • the invention therefore provides for the oral use of phosphatidic acid (PA) for the enhancement of muscle mass and/or strength in mammals such as humans, equines and canines.
  • PA phosphatidic acid
  • the invention further provides a particularly a novel form of PA from soy lecithin called PA-enriched lecithin, and methods for the administration of PA and PA-enriched lecithin.
  • the methods are also directed to reversing muscle catabolism that leads to sarcopenia, for example, in bedridden, aging or cachectic subjects, or those in a weightless environment.
  • compositions having a therapeutically effective amount of PA or PA-enriched lecithin sufficient to affect intracellular and extracellular concentrations of PA in a mammal can shift the metabolism from a catabolic state to an anabolic state. This shift counteracts the decrease in muscle tissue that occurs with normal aging, and in more extreme cases such as bed rest, cachexia, and weightlessness.
  • the compositions and methods can also increase exercise capacity in normal healthy mammals where increased muscle mass and strength is desired.
  • the administration of PA should be combined with as much exercise as the subject is able to perform on a regular basis, for example, according to an intense personal training plan.
  • the administration of PA is preferably combined with the exercise within the anabolic window, when the effect of ingesting PA is more pronounced.
  • This cycle of rebuilding can benefit from protein ingestion up to approximately 90 minutes before exercise and the cycle of rebuilding is especially rapid and intense during the 45-90 minutes following exercise.
  • An easily digested protein supplement such as whey protein increases the effect (for example, about 10 to about 50 grams of whey protein).
  • Another recommended protein is partially hydrolyzed collagen, in similar amounts. The protein should be taken approximately 90 minutes before until 90 minutes after exercise, for example, in two or more separate quantities, for best effect.
  • Creatine is stored mainly in muscle tissue, where it is phosphorylated to creatine phosphate by ATP.
  • the high energy phosphate bond of creatine phosphate is readily transferred to adenosine diphosphate by the enzyme creatine kinase forming ATP, which is available for muscle contraction and relaxation.
  • creatine phosphate may be considered a reservoir of muscle energy.
  • Creatine is readily available in the market place. However, about 30% of humans are creatine non-responders. In these subjects, no creatine is found in the tissues after creatine supplementation. PA has been found to switch creatine non-responders to creatine responders by a yet unknown mechanism. Creatine is generally administered at a dosage of about 3 to about 20 grams per day.
  • the invention provides a composition that includes one or more of essentially pure phosphatidic acid, phosphatidic acid-enriched lecithin, lyso-phosphatidic acid,
  • glycerol-3-phosphate and phospholipase D, optionally in combination with creatine.
  • the essentially pure phosphatidic acid or phosphatidic acid-enriched lecithin can be prepared from soybeans, peanuts, wheat, oats, safflower, fish, milk, bovine liver, eggs or egg yolks.
  • the creatine can be present in a ratio of about 5 to about 3 with respect to the phosphatidic acid, phosphatidic acid-enriched lecithin, or lyso-phosphatidic acid.
  • the composition can include about 50 mg to about 1 gram of phospholipase D (PLD).
  • PLD phospholipase D
  • the amount of essentially pure phosphatidic acid, phosphatidic acid-enriched lecithin, or lyso-phosphatidic acid can be 0.1 grams to about 40 grams.
  • the amount of creatine can be, for example, about 3 grams to about 10 grams. Each of these amounts can be administered one to about three times per day.
  • compositions can further include one or more nutritional supplements.
  • nutritional supplements include, but are not limited to, protein, one or more amino acids such as leucine or L-aspartic acid, beta alanine, leucine peptide, oc-lipoic acid, P-hydroxy-P-methyl butyrate, glycine propionyl L-carnitine, carnitine, Russian tarragon, gymnema sylvestre, bitter melon, cissus quadrangularis, cinnamon and fenugreek, CLA, tribulus, mulberry, ribose, caffeine, ZMA, betaine, carnosine, or a combination thereof.
  • Additional additives can include Co-Ql 0, chromium, magnesium, vanadium, or a combination thereof.
  • the composition can be in a form for oral administration, such as a tablet,
  • the invention also provides methods for increasing muscle mass and strength in mammals comprising orally administering an effective amount of a composition as described herein.
  • the composition can include, for example, an effective amount of essentially pure phosphatidic acid, phosphatidic acid-enriched lecithin, or lyso-phosphatidic acid.
  • the effective amount can be 0.1 grams to about 40 grams, administered orally one to three times daily.
  • the effective amount can be 0.5 to about 5 grams.
  • the effective amount can be 0.1 to about 3 grams
  • the effective amount can be about 10 to about 40 grams
  • the active or combination of actives can be administered to an exercising or previously exercised subject during the anabolic window.
  • the method can also include the ingestion of 20 to 100 grams of protein during the anabolic window.
  • the protein can be a complete protein containing all the essential amino acids for humans, horses, or dogs.
  • the protein can be whey or partially hydrolyzed collagen protein.
  • the invention also provides methods for improving the nitrogen balance of a mammal, such as human, canine or equine, and, in particular, such as an aging, bedridden or cachectic human or an aging or cachectic canine or equine, comprising the administration of a therapeutically effective amount of essentially pure phosphatidic acid, phosphatidic acid-enriched lecithin, lyso- phosphatidic acid, or a combination thereof, or a composition as described herein.
  • the effective amount can be 0.1 grams to 4 grams, given orally one to four times daily.
  • the effective amount can be administered orally or by parenteral infusion.
  • the method can further include the administration of an effective amount of creatine, such as about 3 to about 20 grams.
  • the invention further provides methods for increasing the response to the administration of creatine.
  • the methods can include administering an effective amount of essentially pure phosphatidic acid, phosphatidic acid-enriched lecithin, lyso-phosphatidic acid, or a combination thereof, concomitant with the co -administration of an effective amount of creatine, to a human subject 1 to 3 times daily.
  • the effective amount of can be 0.5 to about 4 grams, and the effective amount of creatine can be about 3 to about 10 grams.
  • the invention yet further provides methods for increasing muscle mass and strength in mammals comprising the administration of an effective amount of a composition as described herein, as well as methods for increasing muscle mass and strength in mammals comprising administering an effective amount of a composition as described herein, and a hormone.
  • the hormone can be, for example, testosterone, human growth hormone, insulin, or insulin-like growth factor.
  • Phospholipids occur widely throughout the plant and animal kingdoms.
  • the human spinal cord contains 6- 10% and the human brain 4-6% lecithin by weight (w/w).
  • Soybeans are the most important and economical source of commercial lecithin, which has many applications in foods and industrial processes. Although the following examples use lecithin (about 1.5 to about 3.1% w/w) and PA-enriched lecithin from soybeans (10% to 60% w/w), various embodiments of the invention can include lecithin, essentially pure PA, and/or
  • PA-enriched lecithin from any source including but not limited to peanuts (1.11% w/w), calf liver (0.85% w/w), wheat (0.61% w/w), oatmeal (0.65% w/w), or eggs (0.39% w/w).
  • especially concentrated sources of lecithin include dehydrated egg yolk (14-20% w/w), natural egg yolk (7-10% w/w), wheat germ (2.82% w/w), soy oil (1.8% w/w) and butterfat (1.4% w/w).
  • Lecithin has been generally recognized as safe (GRAS) by the US FDA since 1979. Lecithin supplementation has been tested by numerous studies in healthy young athletes with no severe side effects (Jager et al, 2007 J. Internal Soc. of Sports Nutrition, 4:5). The effect of lecithin on lowering cholesterol levels (Cobb, 1980 Nutr. Metab. 24:228-237) has been studied. The daily consumption of lecithin in those studies, i.e., 22.5 grams per day for four weeks, contained from 0.4 to 0.7 grams of PA, compared to the 1.6 grams of PA or PA-enriched lecithin per day for four to eight weeks, as is described in the Example below.
  • PA is a common phospholipid and is a constituent of all cell membranes.
  • the administration of PA has been suggested to improve membrane stability.
  • the cell membrane portion is a minor component of the total phospholipid pool.
  • PA is the smallest of the phospholipids on a molecular weight basis, but is important because it acts as a major precursor to the other phospholipids, many of which are crucial for membrane health.
  • a further role of PA has been found to be as a key and crucial second messenger in muscular contraction, muscle cell growth and development.
  • PA is an important controller of protein synthesis.
  • the pathways that regulate PA concentration in response to mechanical demand are as yet not fully defined, especially in the intact body.
  • PLD phospholipase D
  • PA then binds the FKBP 12-rapamycin binding (FRB) domain of the protein mTOR and activates p70S6K, which is one of the key ribosomes of the protein translation phase of protein synthesis.
  • FKBP 12-rapamycin binding (FRB) domain of the protein mTOR and activates p70S6K, which is one of the key ribosomes of the protein translation phase of protein synthesis.
  • Blocking mTOR with the antibiotic rapamycin has been shown to block protein translation and stop up-regulation in response to mechanical stimulation, thereby inhibiting muscle growth.
  • PA binds to the FKBP12-rapamycin binding (FRB) domain of the protein mTOR and activates p70S6K, a ribosomal dual pathway signaling kinase, which is a key ribosome of the translation phase of protein synthesis.
  • FRB FKBP12-rapamycin binding
  • p70S6K a ribosomal dual pathway signaling kinase
  • PA binds to and activates p70S6K directly even in the absence of mTOR (Lehman et al. FASEB J. vol. 21 , 1075-1087, 2007). This suggests that PA can have an anabolic potential at other times of the day regardless of whether mechanical activation takes place. This finding is of importance in the case of the cachectic, bedridden, or elderly patient who is unable to perform sufficient exercise to induce mechanical activation.
  • AMPK can inhibit mTOR signaling through the phosphorylation of TSC2, an upstream regulator of mTOR (Inoki et al. 2003 Genes Dev. 17: 1829-1834). PA has been shown to increase AMPK activity, which can result in the inhibition of mTOR activity (Kimball 2007 Biochem. Soc. Trans.
  • whey protein is a complete protein, containing the proper balance of essential amino acids, and is easily digested.
  • Partially hydrolyzed collagen is another complete protein and is even more easily digested.
  • An athlete in the muscle building phase can require 20 to 120 grams of protein daily.
  • Protein supplement of an easily digestible protein such as whey or collagen is even more beneficial for the aging, cachectic or bedridden person.
  • oc-lipoic acids Recent emphasis on the oc-lipoic acids has indicated an additional benefit.
  • Some herbal products such as Russian tarragon, Cissus quadruangularis or Gymnema sylvestre can be beneficial.
  • Other beneficial products include amino acids, creatine, L-carnitine, glycine propionyl L-carnitine, bitter melon, cissus quadrangularis , cinnamon and fenugreek,
  • Creatine is phosphorylated by creatine kinase (CK) to form an energy reservoir, especially in muscle tissue, for the resynthesis of ATP expended during exercise. Numerous studies have shown that an increase in CK
  • intramuscular creatine levels with creatine supplementation is variable, with mammals falling into “responder” or “non-responder” groups. Much of this variability can lie within the regulation and activity of the creatine transporter. In one study the observation was that approximately 20% to 30% of participants following a creatine loading regime did not respond with an increase in intracellular creatine (Greenhaff et al. 1994 Amer. J. Physiol. 266 (5Pt 1): E725-30). Another study conducted a descriptive profile of the characteristics of individuals portraying Greenhaff s classification of responders versus non-responders.
  • creatine supplementation combined with PA may show a synergistic effect, not only in extending the benefits of creatine supplementation to creatine non-responders, but also to increase the creatine effect in responders. Therefore a composition of creatine with PA, PA-enriched lecithin is recommended or lyso-PA.
  • Creatine is available in several forms such as creatine salt, creatine ester, creatine ether, creatinol, creatinol ether, creatinol salt, all of which can be used with the compositions and methods described herein.
  • Various forms of creatine that may be used are also described in U.S. Patent Nos. 7,772,428 (Heuer et al.) and 7,476,749 (Heuer et al.)
  • hormones such as testosterone, human growth hormone, insulin, and insulin-like growth hormones can also play a role in promoting anabolism. These hormones may be especially efficacious for cachectic patients.
  • Other "micronutrients” such as chromium, vanadium and Coenzyme Q10 may also be added to the diet or the compositions described herein.
  • PA and lyso-PA are important in shifting the metabolism from the catabolic state to the anabolic state and improving nitrogen balance. The shift in metabolism from the catabolic state to the anabolic state can be readily measured by determining the nitrogen balance, the ratio between nitrogen consumed as protein and nitrogen excretion as urea.
  • the urinary excretion of creatinine may be analyzed to determine the nitrogen balance.
  • a positive nitrogen balance is critical for preventing, reducing, or inhibiting cachexia and other forms of muscle deterioration.
  • the term “about” can refer to a variation of ⁇ 5%, ⁇ 10%, ⁇ 20%, or ⁇ 25% of the value specified.
  • “about 50" percent can in some embodiments carry a variation from 45 to 55 percent.
  • the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percents, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.
  • a recited range includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as “up to”, “at least”, “greater than”, “less than”, “more than”, “or more”, and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above.
  • an “effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
  • an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated.
  • an “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a condition or disorder, or to treat the symptoms of the condition or disorder, in a host.
  • an “effective amount” generally means an amount that provides the desired effect.
  • an effective amount can refer to an amount effective for enhancing lean muscle stimulus, growth, strength and recovery, increasing nutrient delivery and/ or promoting increased vascular response, e.g., blood flow and circulation, in a subject, for example, when administered over a period of week(s).
  • An effective amount of the actives e.g., creatine, essentially pure phosphatidic acid, phosphatidic acid-enriched lecithin, lyso-phosphatidic acid, or phospho lipase D
  • an effective amount of the composition comprises from about 1 g to about 10 g of the nutritional composition per serving.
  • treating include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
  • the terms “treat”, “treatment”, and “treating” can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated.
  • treatment can include medical, therapeutic, and/or prophylactic administration, as appropriate.
  • Lecithin is the commercial term for a naturally occurring mixture of phospholipids (also called phosphatides or phosphoglycerides).
  • phospholipids also called phosphatides or phosphoglycerides.
  • the most common phospholipids in lecithin are phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylcholine (PC),
  • phosphatidylserine PS
  • PI phosphatidylinositol
  • the "head" of a phospholipid is hydrophilic, while the hydrophobic "tails" are repelled by water and form aggregates in aqueous compositions. As a result of this configuration, phospholipids form natural barriers, segregating or insulating structures.
  • the hydrophilic head contains the negatively charged phosphate group, and may contain other polar groups such as choline.
  • the hydrophobic tail consists of long fatty acid hydrocarbon chains.
  • Lecithin is found in many natural products including but not limited to soybeans, peanuts, eggs, grains, liver, fish, legumes, safflower, and milk.
  • a typical lecithin used in the compositions and methods described herein is soy lecithin.
  • Lecithin from any source may be isolated to an essentially pure phosphatidic acid (PA) (, for example, at least 98% pure) by enzymatic conversion, a method well known in the art.
  • PA phosphatidic acid
  • a suitable composition can be prepared from soy lecithin to contain at least about 40% PA to provide PA-enriched lecithin.
  • PA-enriched lecithin can be, for example, 5-15% phosphatidyl choline, 1-5% lyso-phosphatidylcholine, and/or 1 -5% N-acyl phosphatidylethanolamine. These components neither increase nor interfere with the PA content and activity.
  • Lecithin is meant to include chemically or enzymatically altered derivatives, such as DHA-soy lecithin.
  • enriched refers to a partially purified extract or composition from which undesirable impurities have been removed and/or by certain actions, the concentration of a particular component is increase.
  • the undesirable impurities may be a single compound or multiple compounds. In some embodiments, at least 25%, at least 50%, or at least 75%, of the undesirable impurities have been removed.
  • PA Phosphatidic acid
  • Cx is the alkyl or alkenyl moiety of a fatty acid.
  • an unsaturated fatty acid bonded to carbon-2 and a saturated fatty acid is bonded to carbon-3.
  • PA can also be used in the compositions described herein as its phosphate salt.
  • Essentially pure PA refers to a composition of phosphatidic acid (PA) that is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%, pure PA, by weight.
  • PA-enriched lecithin includes at least about 10%, at least 40%, at least 50%, at least 60%, or at least 70%, PA.
  • Lysophosphatidic acid (lyso-PA or LP A) is a phospholipid having the structure:
  • R 1 is the alkanoyl or alkenoyl moiety of a fatty acid and R 2 is H, or vice versa.
  • R is H, the compound is 1 -lyso-PA; when R is H, the compound is 2-lyso-PA.
  • lyso-PA fatty acid moieties e.g., OR 1 or OR 2
  • examples of lyso-PA fatty acid moieties include (Z)-octadec-9-enoate or octadecanoate.
  • fatty acids that can form esters with the glycerol backbone of PA or lyso-PA include, but are not limited to, decanoic acid (10:0), undecanoic acid (1 1 :0), 10-undecanoic acid (11 : 1), lauric acid (12:0), cz ' s-5-dodecanoic acid (12: 1), tridecanoic acid (13:0), myristic acid (14:0), myristoleic acid (cz ' s-9-tetradecenoic acid, 14: 1), pentadecanoic acid (15:0), palmitic acid (16:0), palmitoleic acid (cz ' s-9-hexadecenoic acid, 16: 1), heptadecanoic acid (17: 1), stearic acid (18:0), elaidic acid (irara-9-octadecenoic acid, 18: 1), oleic acid (cz ' s-9-oc
  • trans- ⁇ 0,cis- ⁇ 2 octadecadienoic acid cis- ⁇ 0,trans- ⁇ 2 octadecadienoic acid; cis-9 ,trans- ⁇ 1 octadecadienoic acid; trans-9, cis-l 1 octadecadienoic acid, as well as "omega-3 fatty acids" such as
  • EPA ⁇ -5, 8,1 1,14,17-eicosapentaenoic acid
  • DHA ⁇ -4,7,10,13,16,19-docosahexanoic acid
  • acyl residues of a fatty acid moiety can also be conjugated alkenes, hydroxylated, epoxidized, and/or hydroxyepoxidized acyl residues.
  • Lyso-PA can act as a signalling molecule. Lyso-PA can be used in the compositions described herein as its phosphate salt. Lyso-PA can be substituted for PA in any embodiment of this invention, or it can be added to a composition or method that uses PA to supplement the composition's activity.
  • Phospholipase D is an enzyme that catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid (PA), releasing the soluble choline headgroup into the cytosol. PLD is often located in the plasma membrane of cells. The two mammalian isoforms of phospholipase D are PLD1 and PLD2.
  • PLD Phospholipase D
  • One specific example of PLD is autotaxin, also known as ecto nucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2).
  • E-NPP 2 ecto nucleotide pyrophosphatase/phosphodiesterase family member 2
  • PLD can be substituted for PA in any embodiment of this invention, or it can be added to a composition or method that uses PA to supplement the composition's activity.
  • the amount of PLD used can be about 50 mg to about 1 gram, about 100 mg to about 800 mg, about 200 mg to about 750 mg, about 100 mg to about 400 mg, about 400 mg to about 800 mg, or 200 mg, 400 mg, 500 mg, 750 mg, or 1 gram.
  • Creatine refers to the chemical compound N-methyl-N-guanyl glycine (CAS Registry No. 57-00-1), also known as (oc-methyl guanido)acetic acid, N-(aminoiminomethyl)-N-glycine, methylglycocyamine, methylguanidoacetic acid, andN-methyl-N-guanylglycine, whose chemical structure and zwitterionic form are shown below.
  • creatine also includes derivatives of creatine such as esters, and amides, and salts, as well as other derivatives, including derivatives that become active upon metabolism. Creatinol (CAS Registry No. 6903-79-3), also known as creatine-O-phosphate,
  • 2-(carbamimidoyl-methyl-amino)ethoxyphosphonic acid is also a creatine derivative that can be used in the compositions and methods described herein.
  • Creatine and creatine derivatives are widely available from a number of commercial sources.
  • Commercially available creatine derivatives include creatine phosphate, creatine citrate, magnesium creatine, alkaline creatine, creatine pyruvate, creatine hydrates (including, but not limited to creatine monohydrate), and creatine malate.
  • Glycocyamine an in vivo precursor of creatine, is also commercially available and suitable in the practice of the invention described herein.
  • the compositions include creatine malate or creatine monohydrate.
  • anabolic window or the “metabolic window” refers to the first 90 minutes following vigorous exercise, when the body is typically in a catabolic state as a result of the exercise.
  • the compounds and active agents described herein can be used to prepare therapeutic compositions.
  • the compounds may be added to the compositions in the form of a salt or solvate.
  • administration of the compounds as salts may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, oc-ketoglutarate, and oc-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound.
  • a sufficiently basic compound such as an amine
  • a suitable acid for example, a sufficiently basic compound such as an amine
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.
  • the actives described herein can be formulated as therapeutic compositions and administered to a mammalian host, such as a human patient, in a variety of forms.
  • the forms can be specifically adapted to a chosen route of administration, e.g., oral or or subcutaneous routes.
  • the actives may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • compounds can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet.
  • compositions and preparations typically contain at least 1% of active compound. In some embodiments, the percentage of the
  • compositions and preparations can vary and may conveniently be from about 2% to about 90% of the weight of a given unit dosage form.
  • the amount of active in such therapeutically useful compositions is such that an effective dosage level can be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate.
  • a sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active may be incorporated into sustained-release preparations and devices.
  • the active may also be administered as a solution or dispersion.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may optionally contain a preservative to prevent the growth of microorganisms.
  • Useful dosages of the actives described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent
  • the amount of an active, an active salt or derivative thereof, or a combination of actives can vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and can be ultimately at the discretion of an attendant physician, clinician, nutritional advisor.
  • the dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more doses or sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced
  • a dosage of 0.1 grams to about 40 grams of PA-enriched lecithin can be administered to a mammal orally one to three times daily, preferably 90 minutes before to 90 minutes after exercise, e.g., during the anabolic window.
  • a mammal is a human
  • 0.5 to four grams is a recommended single dosage.
  • the mammal is a horse
  • 10 to 40 grams is a recommended dosage.
  • the mammal is a whippet
  • 0.1 to 0.3 grams is a recommended dosage.
  • the mammal is a greyhound
  • 0.2 to 0.4 grams is a recommended dosage.
  • a gastric acid secretion inhibitory coating may be applied to the dose in a manner that protects the PA from degradation by gastric juices.
  • enteric coatings include polymers such as cellulose.
  • Enteric coated PA can be incorporated in the manufacture of foods, drugs, and dietary supplements of complex formulations and various dosage forms including capsules, tablets, caplets, lozenges, liquids, solid foods, powders and other dosage forms that may be developed, without the need to impart enteric protection to the entire mixture, any other part of the mixture, or finished products.
  • a variety of methods for delivery and/or administration of PA can be carried out, for example and not by way of limitation, by tablet, capsule, powder, granule, microgranule, pellet, soft gel, controlled release form, liquid, solution, elixir, syrup, suspension, emulsion, magma, gel, cream ointment, lotion, transdermal, sublingual, ophthalmic, nasal, otic, aerosol, inhalation, spray, parenteral, suppository and the like.
  • PA may be administered by intravenous or intraarterial infusion.
  • Compositions of the invention may also be administered in nutraceutical or functional foods.
  • the effective amount of PA may be combined with amino acids, botanicals, functional foods, herbals, nucleotides, nutraceuticals, pharmaceuticals, proteins, minerals, and/or vitamins in an effort to enhance the targeted activity.
  • Vitamins, amino acids, and other additives are described by, for example, Remington: The Science and Practice of Pharmacy, 22 th edition (Lippincott Williams & Wilkins, 2000).
  • a double-blinded study was planned to test the effect of PA on muscle strength.
  • the inclusion criteria were: participation in a resistance training program on a regular basis at recreational level or higher; no physical limitations as determined by health and activity questionnaire; between the ages of 18 and 29.
  • Subjects were excluded if they had allergy to soy, dairy, egg and wheat ingredients, peanuts, seeds and tree nuts. Those taking any other nutritional supplement or performance enhancing drugs were excluded.
  • subjects were excluded if it was determined they were unable or unwilling to perform the physical exercise to be performed for the study.
  • Example 2 Recommended supplements Essentially pure PA and PA-enriched lecithin were prepared from soy lecithin by enzymatic conversion.
  • the PA-enriched lecithin product produced by Chemi Nutra, Inc. (White Bear Lake, MN) contains 50-60% phosphatidic acid, 5-15% phosphatidylcholine, 1-5% lyso-phosphatidylcholine and 1-5% N-acyl phosphatidyl ethanolamine.
  • the PA-enriched lecithin was given in four 400 milligram capsules to provide 1.6 grams of PA-enriched lecithin.
  • the placebo was rice flour in a capsule identical in weight and color to the PA-enriched lecithin capsule.
  • the protein used was partially hydro lyzed and termed "collagen protein" having the components described in Table 1.
  • Proline and hydroxyproline comprised about one quarter of the amino acids and the leucine content was low.
  • Collagen protein with low leucine content was chosen because leucine can have an effect on muscle and for clarity, that effect was minimized by choice of protein.
  • the subjects were randomly divided into two groups, the test group and the control group.
  • the test group received 4 capsules of 400 mg equaling 1.6 grams per day of PA-enriched lecithin (Mediator ® , Chemi Nutra, Inc., White Bear Lake, MN).
  • the control subjects received 4 capsules of 400 mg equalling 1.6 grams per day of rice flour.
  • Subjects consumed either the test supplement or the placebo 15 minutes prior to workout.
  • subjects were provided with a collagen protein drink consisting of 36 grams of collagen peptides mixed with 500 mL of water.
  • subjects consumed the respective capsules at approximately the same time of day that they worked out. During these non-workout days, subjects did not receive the protein drink.
  • PA supplementation resulted in an increase in strength in the bench press of 10.5% and an increase in strength in the squat of 21 %.
  • Supplementation with the placebo resulted in no increase in strength in either exercise.
  • the two subjects performed the same 6-week training program, consisting of a 2 day per week lower body resistance program (squats, lunge/front squat, leg curl, knee extension, calf raises, seated row, EZ bar curls, dumbbell curls.) There was a 90 second rest period between each set. The addition of any additional sets or exercises was prohibited as it would change the training volume.
  • PA supplementation resulted in an increase of 13% in training volume (pre: 49,640; post: 56,000), whereas placebo had no effect on training volume (pre: 92,800; post: 92,800). PA supplementation also resulted in a greater increase in muscle thickness compared to the placebo. In summary, PA supplementation resulted in greater increase in muscle mass, as demonstrated in this study, resulting in an increase of 9% more between a PA supplemented subject and a non-supplemented subject. In addition, PA supplementation resulted in greater increase in training volumes (13%).
  • creatine is a known muscle building substance, but about 30% of any population does not respond to creatine administration.
  • the lower body exercise included seven different exercises: seated leg press, leg curls, standing calf raises, leg extensions, inclined leg lift, inverted sit-ups (back extension) and 45° inclined sit-ups .
  • the upper body exercise consisted of seven different exercises: bench press, latissimus pulldown, triceps pulldown, inclined dumbbell curls, seated preacher curls, seated rows, and CyBec Pec Fly.
  • Total upper body weight and lower body weight lifted were calculated as the average weight lifted during the last three sets multiplied by the average repetition in each set. Total strength was determined as the combined lower and upper total weight lifted. Total body weight was determined after day 8 and day 15. Strength was measured on days 1 and 15.
  • B. MP a 43-year old male, 185 cm tall, also a known non-responder to creatine supplementation, followed a three-week strength training program while testing whether supplementation with PA-enriched-lecithin improves creatine response.
  • Total starting total body weight and strength were measured on day one, followed by the training program, consisting of concentric and eccentric isotonic lifting exercises that worked the upper and lower body muscle groups with either free weights or weight machines used once or twice weekly.
  • Strength training was performed three times per week with at least one day of rest between sessions, which alternated between lower and upper body exercises. During the three-week period, a total of 10 training sessions (five upper body and five lower body) were performed. Each exercise included two sets of ten repetitions at 40% and 65% IRM, followed by two sets of 3 to 5 repetitions at 90% IRM.
  • the lower body exercise included seven different exercises: seated leg press, leg curls, standing calf raises, leg extension, inclined leg lift, inverted sit-ups (back extension) and 45° inclined sit-ups
  • the upper body exercise consisted of seven different exercises: bench press, latissimus pull-down, triceps pull-down, inclined dumbbell curls, seated preacher curls, seated rows, and CyBec Pec Fly.
  • Total upper body and lower body weight lifted were calculated as the average weight lifted during the last three sets multiplied by the average repetition in each set.
  • Total strength was determined as the combined lower and upper total weight lifted.
  • Total body weight was determined after day 8 and day 22. Strength was measured on days 1 and 22.
  • creatine loading alone was not effective in preventing a slight weight loss
  • creatine plus PA-enriched lecithin reversed the weight loss and allowed a slight weight gain, presumably due to an increased muscular creatine concentration with concomitant muscle weight gain, as expected from the known non-responder status of MP.
  • total strength substantiated this theory: during the two-week baseline period, strength increased 5%, the same as during the creatine supplement period, which showed a similar 5% strength increase, verifying that MP was a creatine non-responder.
  • the supplementation with both creatine and PA-enriched lecithin showed a gain in strength of 1 1.5%, more than double that of exercise alone or supplementation with creatine plus exercise.
  • Creatinine is the metabolite of creatine, as noted above, an important compound in muscle. Creatinine is excreted without reabsorption from the kidney tubules and can be determined as an estimate of renal function. Creatinine recovery varies greatly from patient to patient and is affected by such things as degree of hydration.
  • the patients will be given 0.5 to four grams of PA-enriched lecithin three times a day. While oral administration is preferred, for those patients unable to ingest or who are on intravenous or intraarterial therapies, PA or PA-enriched lecithin may be infused. The results will show an improvement in nitrogen balance.
  • compositions and methods of this invention will improve the muscle mass and strength of older subjects. It is especially recommended to combine ingestion of about 5 grams of creatine and 3 grams of an amino acid such as leucine or glutamine, taken 1 to 3 times daily in their exercise regimen.
  • PA Phosphatidic acid
  • lecithin is a natural phospholipid compound derived from lecithin, which is commonly found in egg yolk, grains, fish, soybeans, peanuts and yeast. PA is involved in several intracellular processes associated with muscle hypertrophy. Specifically, PA has been reported to activate protein synthesis through the mammalian target of rapamycin (mTOR) signalling pathway and thereby can enhance the anabolic effects of resistance training. To our knowledge, no one has examined the effect of PA supplementation in humans while undergoing a progressive resistance training program.
  • mTOR mammalian target of rapamycin
  • This example examined the effect of PA supplementation on lean soft tissue mass (LM) and strength after 8 weeks of resistance training.
  • PA supplementation was determined to beneficial at improving SQ and LM over PL by 26% and 64%, respectively.
  • the strong relationship between changes in total training volume and LM in the PA group suggest that greater training volume can lead to the greater changes in LM. No such relationship was found with PL group.
  • the PA group resulted in a 42% greater increase in strength over PL, although the effect is still under evaluation. While more research is needed to elucidate the mechanism of action, the current findings suggest that in experienced resistance trained men, supplementing 750 mg PA per day for 8 weeks provides greater changes in muscle mass and strength compared with resistance training alone.
  • Example 8 Lyso-phosphatidic acid supplement increases lean body mass, muscle hypertrophy, power and strength comparable to whey protein following resistance exercise
  • Lyso-phosphatidic acid activates protein synthesis through the mTOR signaling pathway. Supplementing with LP A along with resistance training enhances lean body mass. Three highly resistance trained subjects with an average lean body mass of 66.9 ⁇ 3.6 kg trained for 4 weeks as a part of a daily undulating periodized resistance-training program centered around the following standard compound movements: the squat, the deadlift and the bench press. Subjects were supplemented with a 500 mg LPA formulation administered prior to their workouts and again after their exercise. Dual X-ray absorptiometry was used to determine changes in lean body mass. All 3 subjects increased in lean body mass an average of 3.1 kg. Individual subject data and average changes are illustrated in Figure 1.
  • the assays were performed as follows (see Figure 2).
  • Chemi Nutra PA 300 ⁇ Stimulate with 300 ⁇ Chemi Nutra PA using 100 ⁇ L of solution.
  • make 125 ⁇ , of solution thus use 0.75 ⁇ of PA in 125 ⁇ , of PBS.
  • Chemi Nutra PA 100 ⁇ Stimulate with 100 ⁇ Chemi Nutra PA using 100 ⁇ L of solution.
  • Make 125 ⁇ , of solution thus use 0.25 ⁇ of PA in 125 ⁇ , of PBS.
  • Chemi Nutra PA 30 ⁇ Stimulate with 30 ⁇ Chemi Nutra PA using 1 ⁇ of solution.
  • make 125 ⁇ ⁇ of solution thus prepare 0.075 ⁇ of PA in 125 ⁇ ⁇ of PBS.
  • Egg PA 300 ⁇ Stimulate with 300 ⁇ MEgg PA using ⁇ of solution.
  • C8 PA Stimulate with 30 ⁇ C8 PA using ⁇ of solution.
  • make 125 ⁇ ⁇ of solution thus prepare 0.075 ⁇ of PA in 125 ⁇ ⁇ of PBS.
  • G3P -Glycerophosphate
  • Prepare stock solution with 6 mmol/L 6 ⁇ /mL.
  • Adding 0.1 mL of the 6 mM stock solution to the media is equivalent to adding 0.6 ⁇ .
  • G3P 100 ⁇ Stimulate with 100 ,MM G3P using ⁇ of solution.
  • Prepare stock solution with 6 mmol/L 6 ⁇ mol/mL. Dilute the stock solution to 2 mM by combining 333 uL of 6mM solution plus 667 uL of PBS. Adding 0.1 mL of the 2 mM stock solution to the media is equivalent to adding 0.2 ⁇ .
  • FIG. 3 CHEMI Nutra PA activates mTOR signaling.
  • C2C12 myoblasts were stimulated with various dose of glucose-3-phosphoate (G3P), CHEMI Nutra PA (CN PA) or the vehicle (control) for 20 minutes as described on the previous slides. Stimulations with C8 PA or Egg PA were used as positive controls.
  • G3P glucose-3-phosphoate
  • CN PA CHEMI Nutra PA
  • A. Western blot of p70 phosphorylated on the threonine 389 residue [P- p70(389)] was compared to total p70 and used as a marker of mTOR signaling.
  • B Graphical representation of the P-p70(389) to total p70 ratio expressed as a percent of the control values. * P ⁇ 0.05 compared to control.
  • compositions illustrate representative dosage forms that may be used for the therapeutic or prophylactic administration of a compound (e.g., PA) described herein, a compound or composition specifically disclosed herein (e.g., a composition that includes some type of PA), or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Composition
  • compositions may be varied according to well-known techniques to accommodate differing amounts and types of active ingredient 'Composition X' (e.g., PA and/or other actives described herein).
  • Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest.

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Abstract

Selon l'invention, de l'acide phosphatidique, de l'acide lysophosphatidique, du glycérol-3-phosphate et/ou de la phospholipase D peuvent être administrés à des mammifères à l'entraînement pour augmenter la masse musculaire et la force. Ces principes actifs peuvent être administrés par voie orale à des patients vieillissants, alités ou cachectiques pour améliorer le bilan azoté. La lécithine enrichie en acide phosphatidique est une forme hautement appropriée d'acide phosphatidique pour administration. De la créatine peut être co-administrée par voie orale pour augmenter les effets de développement des muscles et d'augmentation de la force. D'autres additifs peuvent comprendre des suppléments nutritifs et d'origine végétale, des micronutriments et des hormones.
PCT/IB2013/054137 2012-05-21 2013-05-20 Compositions et procédés pour l'augmentation de la force et de la masse musculaire WO2013175386A1 (fr)

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GB2532200A (en) * 2014-11-05 2016-05-18 Dodson & Horrell Ltd Composition for horses
EP3003319A4 (fr) * 2013-05-31 2017-01-25 Sports Nutrition Research Ltd. Procédé pour accroître la masse et la force musculaires, et compositions associées
US10674746B2 (en) 2015-10-27 2020-06-09 Cytozyme Animal Nutrition, Inc. Animal nutrition compositions and related methods
US10869843B2 (en) 2010-11-23 2020-12-22 Chemi Nutra Method for increasing muscle mass and strength
US11297851B2 (en) 2015-10-27 2022-04-12 Cytozyme Laboratories, Inc. Animal nutrition compositions and related methods

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EP3003319A4 (fr) * 2013-05-31 2017-01-25 Sports Nutrition Research Ltd. Procédé pour accroître la masse et la force musculaires, et compositions associées
GB2532200A (en) * 2014-11-05 2016-05-18 Dodson & Horrell Ltd Composition for horses
GB2532200B (en) * 2014-11-05 2021-10-20 Dodson & Horrell Ltd Composition for horses
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