AU4575299A - Creación de Inventos y Patentes con Inteligencia Artificial

AU4575299A – Compositions for increasing energy (in vivo)
– Google Patents

AU4575299A – Compositions for increasing energy (in vivo)
– Google Patents
Compositions for increasing energy (in vivo)

Download PDF
Info

Publication number
AU4575299A

AU4575299A
AU45752/99A
AU4575299A
AU4575299A
AU 4575299 A
AU4575299 A
AU 4575299A
AU 45752/99 A
AU45752/99 A
AU 45752/99A
AU 4575299 A
AU4575299 A
AU 4575299A
AU 4575299 A
AU4575299 A
AU 4575299A
Authority
AU
Australia
Prior art keywords
ribose
pentose
atp
mammal
energy
Prior art date
1998-06-19
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Application number
AU45752/99A
Inventor
Clarence A. Johnson
John St. Cyr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Bioenergy Inc

Original Assignee
Bioenergy Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1998-06-19
Filing date
1999-06-17
Publication date
2000-01-05

1999-06-17
Application filed by Bioenergy Inc
filed
Critical
Bioenergy Inc

2000-01-05
Publication of AU4575299A
publication
Critical
patent/AU4575299A/en

Status
Abandoned
legal-status
Critical
Current

Links

Espacenet

Global Dossier

Discuss

Classifications

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES

A61K31/00—Medicinal preparations containing organic active ingredients

A61K31/70—Carbohydrates; Sugars; Derivatives thereof

A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES

A61K31/00—Medicinal preparations containing organic active ingredients

A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids

A61K31/19—Carboxylic acids, e.g. valproic acid

A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES

A61K31/00—Medicinal preparations containing organic active ingredients

A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids

A61K31/19—Carboxylic acids, e.g. valproic acid

A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES

A61K33/00—Medicinal preparations containing inorganic active ingredients

A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay

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

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P9/00—Drugs for disorders of the cardiovascular system

A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Abstract

Precursors of adenosine triphosphate are administered orally to increase intracellular ATP concentration as dietary supplements or for treatment of reduced energy availability resulting from strenuous physical activity, illness or trauma. Pentose sugars are administered individually, mixed into dry food or in solution. The preferred pentose is D-ribose, singly or combined with creatine, pyruvate, L-carnitine and/or vasodilating agents. Additionally, magnesium, electrolytes, fatty acids and hexose sugars can be used. The compositions and methods of this invention are especially beneficial to mammals having reduced energy availability or high energy demand.

Description

WO 99/65476 PCT/US99/13720 COMPOSITIONS FOR INCREASING ENERGY IN VIVO FIED OF THE INVENTION The present invention relates to compositions and methods for increasing the energy available to mammals having reduced energy availability or expending high levels of energy. 5 Such mammals include humans with illnesses resulting in reduced intracellular adenosine triphosphate (ATP), humans engaged in heavy physical activity such as athletes or laborers, and humans desiring to increase their energy levels. Other mammals such as dogs and cats are also included in the present method. Administration of the compositions of the invention provides increased levels of blood and intracellular ATP, extends the time and intensity at 10 which a mammal can exercise, and increases the rate of oxygen utilization by the exercising subject. Non-exercising mammals and those that expend a higher than normal level of energy during recovery from physical insults such as trauma, burns and sepsis also benefit from administration of the compositions of the invention. BACKGROUND OF THE INVENTION 15 It is well known that the energy coinage of the cell is adenosine triphosphate (ATP). During anabolism, the energy derived from the metabolism of nutrients is transferred to high energy phosphate bonds of ATP. The energy in these bonds is expended during the energy consumption phase. An important and «costly» expenditure, in which ATP is rapidly cycled, is that required for muscular contraction. 20 The energy buildup steps occur within the muscle cell during two basic processes. Oxidative phosphorylation replenishes ATP by the breakdown of circulating fatty acids, glucose and intramuscular glycogen and triglycerides. Anaerobic phosphorylation provides ATP from creatine phosphate, circulating glucose and intramuscular glycogen via kinase reactions such as the myokinase reaction. 25 United States Patent Number 5,714,515 describes the administration of compositions containing pyruvate, an intermediate breakdown product of glucose, to enhance recovery from surgical or accidental trauma, shock, exhaustion due to prolonged physical effort and other indications. United States Patent Number 5,709,971 discloses the administration of other glucose metabolites, namely glyceraldehyde-3-phosphate, phosphoenolpyruvate and 3 30 phosphoglycerate, in combination with nicotineadeninedinucleotide, coenzyme A and acetyl coenzyme A. A different approach to increasing the substrates available for production of ATP that has been employed is the administration of the amino acid L-carnitine, which is thought to WO 99/65476 PCTIUS99/13720 2 enhance the transport and absorption of fatty acids into mitochondria, the site of oxidative phosphorylation. United States Patent No. 4,968,719 describes the use of L-camitine for the treatment of peripheral vascular diseases. Regardless of whether the high energy phosphate bonds of ATP are generated 5 oxidatively or anaerobically, and irrespective of the substrates used for its generation, ATP cannot be synthesized unless the precursors of the ATP molecule itself are available. The resynthesis of the ATP molecule can occur by de novo or salvage pathways. In the synthesis of ATP via the nucleotide salvage pathway, the nucleotide precursors that may be present in the tissue are converted to AMP and further phosphorylated to ATP. 10 Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP. Ribose is found in the normal diet only in very low amounts, and is synthesized within the body by the pentose phosphate pathway. In the de novo synthetic pathway, ribose is phosphorylated to PRPP, and condensed with adenine to form the intermediate adenosine monophosphate 15 (AMP.) AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP. Synthesis by the de novo pathway is slow. Normally, AMP synthesis is believed to occur mainly by the salvage pathway, however, following anoxia or ischemia, the activity of the de novo pathway is increased. 20 During energy consumption, ATP loses one high energy bond to form ADP, which can be hydrolyzed to AMP. AMP and its metabolites adenine, hypoxanthine and inosine are freely diffusible from the muscle cell and may not be available for resynthesis to ATP via the salvage pathway. In United States Patent No. 4,719,201, it is disclosed that when ATP is hydrolyzed to 25 AMP in cardiac muscle during ischemia, the AMP is further metabolized to adenosine, inosine and hypoxanthine, which are lost from the cell upon reperfusion. In the absence of AMP, rephosphorylation to ADP and ATP cannot take place. Since the precursors were washed from the cell, the nucleotide salvage pathway is not available to replenish ATP levels. It is disclosed that when ribose is administered via intravenous perfusion into a heart 30 recovering from ischemia, recovery of ATP levels is enhanced. Pliml, in German Patent No. 4,228,215, found that oral ribose was effective in treating cardiac insufficiency and hypovolemic shock in humans. The advantage of the administration of pentoses such as ribose or xylitol to prevent WO 99/65476 PCT/US99/13720 3 pain and stiffness of skeletal muscle in patients suffering from the autosomal recessive genetic disease myoadenylate deaminase (MAD) deficiency was shown by Z6llner et al. (Klinische Wochenshritt 64: 1281-1290, 1986.) This disease is characterized by permanent muscular hypotonia, excessive muscular weakness, fatigue, soreness, burning pain, stiffness 5 and cramps. These symptoms are considered to be consequences of the interruption of the ATP cycle. Dephosphorylation of ATP is inhibited by the accumulation of AMP, resulting in less available energy to effect muscle contraction and relaxation. However, even though symptoms of MAD-deficient patients were relieved by administration of ribose, the intracellular levels of adenine nucleotides remained abnormally high and normal volunteers 10 experienced no beneficial effect from ribose administration. (Gross, Reiter and Z5llner, Klinische Wochenshritt, 67:1205-1213, 1989.) Tullson et al. (Am. J. Physiol., 261 (Cell Physiol. 30) C343-347, 1991) cite references showing that high intensity exercise increases degradation and subsequent loss of AMP from isolated muscle. They further disclose that adding ribose to the perfusate in a rat hindquarter 15 preparation increases the de novo synthesis of AMP in sedentary muscle, but does not eliminate the decline in de novo synthesis seen in contracting muscle. Carniglia, et al, United States Patent No. 4,871,718, disclose that when a complex mixture comprising amino acids, metabolites, electrolytes and ribose or a precursor of ribose, was administered orally as a dietary supplement to race horses, increases in intracellular ATP 20 levels and physical performance result. The performance evaluation was anecdotal, however, based on the subject’s performance history. Thus, a continuing need exists for simple methods to enhance skeletal muscle performance in normal mammals; that is, mammals that are not at the time of application of the method experiencing ischemia, prior to or undergoing physical activity. A need also 25 exists for a method to increase the energy level of mammals to provide an increased feeling of well-being. SUMMARY OF THE INVENTION The present invention provides compositions and methods of increasing the energy level in a mammal. It is believed that the present compositions and methods function by 30 stimulating the synthesis of ATP in a mammal experiencing a less than optimal availability of ATP in order to support cellular function. Specifically, a pentose such as D-ribose is given orally before, during and after a period of high ATP demand, in amounts effective to enhance WO 99/65476 PCT/US99/13720 4 the energy of the mammal. Mammals given ribose are able to exercise longer, to achieve a higher intensity and subjectively have more energy than those not given ribose. It is proposed that the cellular concentration of PRPP is the limiting factor in recovery or increase of ATP levels via either the de novo or nucleotide salvage pathways and that the 5 administration of ribose can stimulate ATP synthesis, providing larger pools of ATP for energy expenditure. Mammals experiencing a less than optimal availability of ATP include normal, healthy subjects undergoing high energy demand such as athletes, and workers performing heavy labor. It is further proposed that normal subjects even in the resting state will experience a positive feeling of enhanced well-being after administration of effective 10 amounts of ribose. The availability of PRPP appears to control the activity of both the salvage and de novo pathways, as well as the direct conversion of adenine to ATP. Production of PRPP from glucose appears to be limited by the enzyme glucose-6-phosphate dehydrogenase (G6PDH). Glucose is converted by enzymes such as G6PDH to ribose-5-phosphate and further 15 phosphorylated to PRPP, which augments the de novo and salvage pathways, as well as the utilization of adenine. The addition of ribose bypasses this rate limiting enzymatic step. Also included in the group of subjects benefitting from the method of the invention are mammals having a chronic low energy level due to advanced age, trauma, sepsis, or such disease conditions as congestive heart failure and other chronic illnesses. 20 Compositions that enhance the pentose benefit are also provided. Such compositions preferably comprise at least one of magnesium, creatine, pyruvate, L-carnitine, pentose, other energy metabolites and optionally at least one vasodilating substance. Of these, creatine and magnesium are preferred for combination with ribose. Mammals undergoing high energy demand and loss of fluids also benefit from a composition that further comprises electrolytes 25 and an additional energy source such as carbohydrate. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the dose response of the adenine salvage pathway in normal adult rats to the administration of ribose. Figure 2 shows the mean power output per sprint session of normal adult humans, 30 following administration of ribose or placebo, as measured on an exercycle.
WO 99/65476 PCT/US99/13720 5 Figure 3 shows the peak power output per sprint session of normal adult humans, following administration of ribose or placebo, as measured on an exercycle. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of stimulating the synthesis of ATP by the 5 oral administration of a pentose and provides pentose-containing compositions that are especially beneficial to mammals undergoing high energy demands or those having chronic low energy levels. For the purpose of describing this invention, the following terms have the following meanings: 10 1. «Pentose» means a monosaccharide, including but not limited to, ribose, D-ribose, ribulose, xylitol, xylulose, and any 5-carbon precursor of ribose. 2. «Vasodilator» includes any substance that causes dilation of blood vessels, including adenine, hydralazine, arginine and nitroglycerine administered transdermally or orally. 3. «Intracellular ATP levels» means ATP concentrations measured directly by tissue 15 biopsy or nuclear magnetic resonance or indirectly by blood ATP concentration. 4. «Other energy metabolites and co-factors» means creatine, co-enzymes, intermediates of the tricarboxylic acid, pentose phosphate or glycolytic enzyme pathways, pyrimidine and purine nucleotides and minerals. The compositions preferably contain an energy-enhancing amount of pentose 20 dissolved or dispersed in an aqueous vehicle such as water, that may optionally contain minor but effective amounts of additives such as polyols, preservatives, flavorings, colorings and the like. Compositions containing pentoses adapted for oral administration also include solid dosage forms such as tablets, lozenges, capsules and the like. Pentoses may also be incorporated in solid nutriments such as bars, moist or dry dog food, powders or drink mixes. 25 Effective total dosages of ribose, which can be extrapolated to other pentoses, are disclosed hereinbelow. Because pentoses are naturally occurring sugars with a pleasant taste and virtually no WO 99/65476 PCT/US99/13720 6 toxicity, subjects may be encouraged to self-administer pentose in the form of tablets, lozenges, powders, suspensions, solutions, or mixed in with solid food. When the subject is canine or feline, pentose can be easily integrated into «senior diet» or «cardiac diet» and separate administration is not necessary. When the subject is human, pentose can be 5 included in drinks, bars, shakes or snack food. The preferred pentose is ribose or xylitol. The preferred dosage is 0.1 to 100 gm pentose per day, preferably 1 to 20 gm pentose per day. An average adult human may find that 4 to 8 gm pentose per day is sufficient to provide the benefits of the invention. The upper dose is limited only by the taste preference of the subject, although at very high doses, subjects may experience diarrhea. The dose may be 10 given once a day in a single unit dosage form, but preferably is given two or three times throughout the day, most conveniently during or following mealtime. During strenuous activity, individuals may sweat profusely, requiring replacement of body fluids and electrolytes. Subjects such as dogs, which do not sweat, lose copious amount of water through the lungs and also require fluid replacement. In addition to the advantages 15 provided by pentoses alone, with carnitine and or vasodilating agents, it is convenient to include other components within a replacement solution to be drunk during and following exercise. Rehydration solutions such as Gatorade @, Thirst Quencher, and Max@ drinks are among those popular with athletes. These sustained energy and anabolic formulas are generally made up of different 20 carbohydrates, including corn syrup, sucrose, fructose, and maltodextrin; proteins, including casein and other proteins from milk and soybean; and lipids, including corn, soy, safflower, and canola oils and medium chain triglycerides. Efforts at improving such «performance drinks» continue. United States Patent No. 5,292,538 describes an energy sustaining composition 25 containing fructose, glucose, hydrolyzed protein and magnesium liganded to an amino acid chelate. Other ingredients noted as especially advantageous include potassium, phosphorus, manganese, zinc, boron, copper, molybdenum, chromium, vanadium, vitamins B 1,2,5,6 and 12′ C, E and carnitine. United States Patent No. 5,114,723 describes hypotonic beverage compositions for 30 oral administration comprising electrolytes, minerals, carbohydrates and other ingredients. The compositions are adjusted to have an osmolarity between 100 and 270 mOs/l. Each of these rehydration drinks will be improved by the addition of from about 1 to 20% pentose, most preferably 10% by weight to volume. The amount of pentose to be added WO 99/65476 PCTIUS99/13720 7 will depend on the composition of other nutrients, to keep the osmolarity within the preferred limits. These drinks will be further improved by the addition of other energy metabolites and co-factors. The invention will be further described by reference to the following examples. 5 Example 1. Effect of D-ribose on nucleotide salvage in resting rat muscle. It has been theorized but not objectively shown that ribose, via PRPP synthesis, increases the rate of ATP synthesis via the nucleotide salvage pathway. However, nothing is known about the total adenine nucleotide (TAN) or ribose levels in the resting muscle and therefore, it is possible that the synthetic enzyme pathway is already saturated and that 10 administration of ribose does not increase ATP levels in normal, non-ischemic skeletal muscle. In order to demonstrate the effect of ribose on the pathway, plantaris complex muscles of healthy adult male Sprague-Dawley rats were surgically exposed and perfused with reconstituted blood perfusion medium containing amino acids, mM glucose and 100 pU of bovine insulin/ml. The muscle was perfused with reconstituted blood medium at ~ 40 15 ml/min, providing tissue perfusion of approximately 0.65 ml/min. Varying concentrations of D-ribose were added to the perfusate to bring the concentration to 0.156 mM, 0.5 mM, 1.58 mM, 5.0 mM and 15.0 mM. The muscle was perfused for 30 minutes. A minimum of two rats was used for analysis at each dose of ribose tested. Following perfusion, muscle sections were quickly dissected from the limb and 20 freeze-clamped with aluminum tongs chilled in liquid nitrogen. Muscle sections were lyophilized and reconstituted in distilled water for subsequent separation of adenine nucleotides by reverse-phase high pressure liquid chromatography. Results are expressed as salvage of adenine (i.e., formation of ATP) in nanomoles salvaged per gram wet weight of muscle per hour (nM/gm/hr).
WO 99/65476 PCT/US99/13720 8 TABLE I Ribose Skeletal Muscle Dose-Response Kinetics Saturation Kinetics mM Ribose Observed with Base 0.000 48.6 5 0.158 113.0 85.82 0.500 110.0 118.68 1.000 154.12 1.580 188.5 183.51 2.000 199.74 10 2.500 215.29 3.000 227.85 5.000 250.0 260.68 15.000 315.5 310.37 As is shown in Figure 1 and Table I, adenine salvage at zero millimolar (mM) ribose 15 is less than 50 nM/gm/hr and doubles with administration of 0.158 mM ribose. At 5 mM ribose, the rate of ATP synthesis reaches 250 nM/gm/hr. These results show that normal, healthy muscle has low baseline levels of ribose and nucleotide salvage capability, which can be increased by the administration of ribose. Example . Increased exercise capacity in normal subjects. 20 Four healthy, fit subjects in the age range 24 to 26 years of age were tested. The group was selected to be homogeneous regarding fitness level, gender and mean age with no known metabolic, neuronal, endocrine or cardiopulmonary disorders. All were capable of or had experience with cycling. The study protocol included four phases: (1) an initial baseline phase consisting of no exercise session; (2) a loading phase including three days of 25 administration of either D-ribose or placebo (glucose) three times per day; (3) a training phase of three days employing exercise sessions characterized by serial (N=6) bouts of short (10 second) high-intensity cycle sprints at 7% body mass resistance with 50 second rest periods between sprints twice per day (morning and afternoon), and (4) a recovery phase for a WO 99/65476 PCT/US99/13720 9 period of 48 hours after the final training session. Figure 1 is a diagram of a single cycle sprint bout. Muscle biopsies (MB) were performed on the vastis lateralis muscle using both legs in order to evenly distribute and minimize sampling and possible muscle soreness per leg due to 5 the biopsy itself. The first MB was collected at rest at the beginning of the study to establish a baseline and immediately after the first training session of day 0 or the first phase. During the loading phase, no MB was taken. Muscle Biposies were taken following the final training session and after 48 hours of recovery. Two subjects were randomly selected for inclusion into the placebo or ribose group. 10 Ribose or glucose was administered orally in a 250 ml iso-osmotic solution containing 10.0 grams of either ribose or placebo three times per day for three days preceding training (loading phase) and for three days during training (training phase). One-half liter isotonic electrolyte solution was given immediately post exercise and again 30 minutes later to avoid dehydration. 15 The concentration of the following analytes was determined in the MB samples: ATP, ADP, AMP, IMP (inosine monophosphate), TAN (total adenine nucleotides), creatine phosphate and creatine.
WO 99/65476 PCT/US99/13720 10 TABLE II Ribose Athlete Study Mean Power Per Kilogram (Watts) Subject 1 2 31 4 5 Ayrage 5 1P 6.0 6.7 7.3 7.4 7.3 7.5 7.0 2R 6.9 7.5 7.8 7.6 7.9 7.4 7.5 3R 8.7 9.2 9.1 9.0 8.5 8.2 8.8 4P 7.5 8.0 7.7 8.7 8.0 7.6 7.9 Placebo 6.8 7.4 7.5 8.0 7.6 7.5 7.5 100.0% 10 Ribose 7.8 8.4 8.5 8.3 8.2 7.8 8.2 109.0% TABLE III Ribose Athlete Study Peak Power Per Kilogram (Watts) Subject 1 2 3 4 5 6 Aemge 15 1P 6.8 7.9 8.6 8.6 8.3 9.0 8.2 2R 7.9 8.8 9.2 9.0 9.4 8.7 8.8 3R 9.8 10.6 10.7 10.7 10.1 9.9 10.3 4P 7.7 8.6 8.7 9.4 8.8 9.0 8.7 Placebo 7.7 8.6 8.7 9.4 8.8 9.0 8.7 100.0% 20 Ribose 8.9 9.7 10.0 9.9 9.8 9.3 9.6 109.9% WO 99/65476 PCT/US99/13720 11 TABLE IV Ribose Athlete Study Total Power Per Kilogram Subject 1 2 3. 4 5 -i Ayerag 5 IP 59.1 67.0 72.7 73.3 72.5 74.2 69.8 2R 71.9 74.7 77.1 75.6 78.1 73.4 75.1 3R 86.8 91.9 91.3 90.0 85.4 82.5 88.0 4P 74.5 80.3 76.8 87.4 80.0 76.4 79.2 Placebo 66.8 73.6 74.8 80.4 76.3 75.3 74.5 100.0% 10 Ribose 79.3 83.3 84.2 82.8 81.8 77.9 81.6 109.5% As can be seen from Tables II to IV and Figures 2 and 3, administration of ribose increased performance by 9%. The improvement in performance is reflected in the ATP levels in the muscle biopsies. As shown in Table V, the subjects preloading with ribose for three days began the training 15 phase with higher levels of ATP, which declined significantly more than that of the placebo group after the sprint bouts, indicating that ATP was being utilized more efficiently. Recovery of the ribose group at 48 hours was 82% of the initial level, compared to 78% in the placebo group. TABLE V 20 Mean ATP Values (mmol/kg dw) Group Pre Post Recovery Recovery Change Change _____I__ _I_% of Pre Pre-Post Post-Rec Placebo 23.60 20.05 18.30 78% -3.55 -1.75 Ribose 25.33 13.90 20.80 82% -11.43 6.90 Example 3. Increased stamina and feeling of well-being in normal, untrained subjects. 25 D-ribose, given immediately before and during exercise, can provide a benefit to those subjects who have not been previously trained. Four healthy, normal male volunteers will be tested for sprint power output on an exercycle, as for Example 2 above. Each subject will serve as his own control. Between the sprint bouts, the subjects will cycle slowly and continuously. Total test time will be one hour, with four sprint bouts during the test.
WO 99/65476 PCT/US99/13720 12 Following the initial baseline test and following each sprint bout, the subjects will be given 5 grams of D-ribose in 200 ml. of water or a similar tasting placebo (glucose). Sprint power output will be tested 15 minutes after each ingesting of the test solutions. Each subject will undergo two sessions, one week apart, one with ribose and one with placebo, in randomized 5 order. The placebo will be sweetened with glucose in order to be indistinguishable from the ribose solution. It is expected that the subjects will show higher power output after ribose administration following sustained mild exercise than they showed after placebo administration. It is further expected that the subjects will have a subjectively higher feeling of well being. 10 Exaple 4. Relief of exercise induced angina. A sixty-eight year old male patient with a history of coronary artery disease, status post triple coronary artery bypass, experienced exercise induced angina. His present medications are: enalapril (an angiotensin converting enzyme inhibitor), carvedilol (a p blocking agent), nitroglycerine patch and nitroglycerine tablets sublingual as needed. The 15 most recent coronary angiogram revealed advancement of his coronary artery disease with total occlusion of one of the bypass grafts. The patient performed poorly on two stress tests. His exercise regimen consisted of a daily walk. Due to the development of angina, the patient was able to walk less than one mile per day, at which point he took sublingual nitroglycerine. The patient was given oral D-ribose 20 dissolved in about 250 cc. of water. Over a six-month period, the patient received intermittent doses of 5-10 grams per day of D-ribose. Post ribose administration, the patient was able to increase his exercise tolerance to two miles per day without any supplementation of oral nitroglycerine. When the ribose was discontinued, his pre-ribose, anginal-inducing exercise state recurred, which necessitated the use of supplemental oral nitroglycerine. 25 Resumption of oral ribose allowed the patient to walk two miles per day, without angina or the need for nitroglycerine. His subjective evaluation of the ribose treatment is there is «much less angina pain. I feel better, have more energy and can be more active without pain or pills [nitrogycerine].» Example 5. Improved treadmill test performance. 30 A sixty-year old male patient with stable coronary artery disease was observed to show a greater than fifty percent occlusion of more than one epicardial coronary artery and WO 99/65476 PCT/US99/13720 13 stable angina. The patient was tested for treadmill performance. After two baseline treadmill tests, following the Bruce protocol, he received orally administered D-ribose (40 gm in three divided doses daily) for three days and completed a third treadmill test. At each time, the test was to be stopped when a) the patient exhibited ST segment depression of 1 mm or more in 5 the ECG tracing; b) when the patient complained of angina or c) when the patient stopped due to dyspnea or fatigue. In each test, this patient concluded the test due to shortness of breath, but experienced no angina. As can be seen from Table VI, the administration of D-ribose for three days before the final treadmill test increased energy and heart function as measured by decrease in rate 10 pressure product at each stage of testing, including rest (zero time). It is generally accepted that the product of heart rate and systemic pressure is a measure of myocardial function and energy level, with lower numbers indicating better myocardial function. As a result of the administration of ribose, average tolerated time on the treadmill increased. In addition to the objective measure of efficacy, the patient subjectively reported feeling more energetic during 15 ribose administration. TABLE VI Rate-pressure product as beats per minute times systolic blood pressure mm Hg Time Baseline 1 Baseline 2 Average Test %change 0 (rest) 11,088 9,272 10,180 9,177 -9.55% 20 3 minutes 17,574 13,468 15,521 15,272 -1.60% 6 minutes 26,500 22,344 24,422 20,592 -15.68% 9 minutes 33,396 29,526 31,461 25,356 -9.87% Tolerated time, sec. 483.00 545.00 514.00 540.00 5.06% 25 In the Bruce protocol, the treadmill speed in increased in three minute increments from 1.7 to 6.0 miles per hour, while the slope is increased from 10 to 22 %. Example. Self administration of ribose. Patients with chronic illnesses, including but not limited to coronary artery disease, AIDS, intermittent claudication, tuberculosis and chronic fatigue syndrome, that are 30 characterized by low energy levels, and even those subjects free of overt disease but having low energy due to advanced age, trauma, bums, and recovery from illness or surgery, are WO 99/65476 PCT/US99/13720 14 benefitted by being able to raise their energy levels without continual medical intervention. Many individuals with relatively stable disease live a day to day existence by conforming to an altered life style, coupled with pharmaceutical supplementation. Often, such subjects are inhibited from undertaking a regimen of moderate physical activity from fear of inducing 5 unpleasant effects, such as angina, breathlessness, muscle soreness, cramping or a feeling of exhaustion. Such avoidance lowers the quality of life of the subject and engenders an ever present background anxiety. In addition, the benefits of moderate exercise, which include improved digestion, sleep and a more relaxed and positive state of mind, are denied to such subjects. Even subjects free of disease and considered healthy may be dissatisfied with their 10 subjective feeling of energy level and well being. An example of a subject having no overt disease who benefitted from self administered ribose is a fifty-five year old male. He had adhered to a strict weekly exercise regimen most of his life until sustaining a systemic bacterial infection, which required admission to the intensive care unit for one month and rehabilitation for an additional month. 15 His cardiovascular and pulmonary systems were predominantly affected during and following his illness and function had not recovered to its previous levels, or to his satisfaction, after one year. Following convalescence, he has attempted to resume an exercise regimen, which involves running on a treadmill four days a week and lifting weights for two days a week. 20 The runs were restricted to short intervals. Following the daily exercises, he has continuously experienced fatigue to the point of exhaustion and has required frequent naps. The patient began self-administering oral D-ribose at two doses per day, 4-5 grams per dose. Within seven days, he testified that his «pep» and exercise tolerance has increased. For the first time since his illness, he is able to run as long as 30 minutes on the treadmill. He still experiences 25 a degree of fatigue, but has been able to discontinue the naps after exercise. He continues on the daily oral doses of ribose, along with his scheduled exercises and feels a continuing improvement in his energy level after four weeks of ribose administration. He has experienced no adverse effects from the ribose. Example 7. Effect of ribose with arginine and/or carnitine on subjects with chronic 30 conditions. As shown in Example 6, subjects experiencing low energy levels are predicted to benefit by the self-administration of pentoses. It is further predicted that ingestion of a orally WO 99/65476 PCTIUS99/13720 15 acceptable vasodilator such as L-arginine will have an additional beneficial effect on such subjects. It is still further predicted that ingestion of L- camitine to transport fatty acids into the mitochondria will provide an additional beneficial effect to such subjects. It is still further predicted that the addition of other energy metabolites and co-factors will provide additional 5 beneficial effects to such subjects. Arginine is known to be a precursor of the endothelium-relaxing factor nitric oxide. In vitro analyses have determined that under normal circumstances, an excess of L-arginine is available to endothelial cells. However, in vitro studies have also shown that endothelium dependent vasodilatation is improved with the addition of L-arginine, when L-arginine stores 10 are depleted or if L-glutamine, an antagonist of L-arginine, is present. It was not known, prior to this invention, if oral arginine can enhance cardiac perfusion and thus the distribution of ribose to muscle tissue. The test group chosen will be human patients with low energy levels due to cardiac disease, which is an available and well-studied group. The results are expected to apply equally to other subjects having low energy levels, such as subjects with 15 debilitating diseases and elderly human and canines. Thirty adult (45-70 years of age) subjects with known stable coronary artery disease, but without resting ischemia, will be randomized into three separate groups. Each patient will be subjected to a serial exercise treadmill testing to initially qualify for admission into this protocol. A final treadmill test will be performed after a three day course of either L-arginine, 20 D-ribose, L-carnitine or a combination of L-arginine, D-ribose and L-carnitine. The end points of this study will investigate time to development of angina pectoris and/or electrocardiographic changes during treadmill exercise. It is expected that these test subjects will show even more improvement than the 10% decrease in rate-pressure and 5% increase in tolerated time as shown in Example 2. 25 All publications and patents cited herein are incorporated by reference as though fully set forth. This invention has been described with respect to various specific and preferred embodiments. However, it should be understood that many variations or modifications may be made while remaining within the spirit and scope of the invention.

Claims (16)

1. A method for increasing the energy levels of a mammal which comprises the oral administration of an effective amount of a pentose to said mammal.

2. The method according to claim 1 wherein the pentose is ribose.

3. The method according to claim 1 wherein the mammal has reduced availability of ATP.

4. The method according to claim 1 wherein the mammal has increased energy demand.

5. The method according to claim 3 wherein the mammal has coronary artery disease.

6 The method according to claim 4 wherein the mammal is recovering from infection, trauma or bum.

7. The method according to claim 4 wherein the mammal is exercising strenuously.

8. The method according to claim 4 wherein the mammal has not been subjected to ischemic insult.

9. A composition to be administered to increase energy levels in mammals which comprises an effective amount of a pentose.

10. A composition according to claim 9 wherein the pentose is ribose.

11. A composition according to claim 9 which further comprises magnesium, and creatine. WO 99/65476 PCTIUS99/13720 17

12. A unit dosage form comprising about 0.1 to 50 gm pentose in combination with a pharmaceutically acceptable vehicle, adapted for oral ingestion.

13. The unit dosage form of claim 12, wherein the pentose is ribose.

14. The unit dosage form of claim 12 wherein the vehicle is a liquid.

15. The unit dosage form of claim 14 wherein the liquid is an aqueous liquid.

16. The unit dosage form of claim 12 wherein the vehicle is a solid or semi-solid edible vehicle.

AU45752/99A
1998-06-19
1999-06-17
Compositions for increasing energy (in vivo)

Abandoned

AU4575299A
(en)

Applications Claiming Priority (5)

Application Number
Priority Date
Filing Date
Title

US9000198P

1998-06-19
1998-06-19

US60090001

1998-06-19

US09/290,789

US6159942A
(en)

1998-06-19
1999-04-12
Compositions for increasing energy in vivo

US09290789

1999-04-12

PCT/US1999/013720

WO1999065476A2
(en)

1998-06-19
1999-06-17
COMPOSITIONS FOR INCREASING ENERGY $i(IN VIVO)

Publications (1)

Publication Number
Publication Date

AU4575299A
true

AU4575299A
(en)

2000-01-05

Family
ID=26781174
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

AU45752/99A
Abandoned

AU4575299A
(en)

1998-06-19
1999-06-17
Compositions for increasing energy (in vivo)

Country Status (10)

Country
Link

US
(1)

US6159942A
(en)

EP
(1)

EP1087779B1
(en)

JP
(5)

JP2002518321A
(en)

CN
(1)

CN1306431A
(en)

AT
(1)

ATE534393T1
(en)

AU
(1)

AU4575299A
(en)

CA
(1)

CA2334415C
(en)

ES
(1)

ES2374260T3
(en)

NZ
(1)

NZ508478A
(en)

WO
(1)

WO1999065476A2
(en)

Families Citing this family (59)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US20020119933A1
(en)

2000-07-28
2002-08-29
Butler Terri L.
Compositions and methods for improving cardiovascular function

US6339716B1
(en)

1999-09-24
2002-01-15
Bioenergy Inc.
Method for determining viability of a myocardial segment

US6159943A
(en)

1999-09-24
2000-12-12
Bioenergy, Inc.
Use of ribose to prevent cramping and soreness in muscles

US6511964B2
(en)

1999-09-24
2003-01-28
Bioenergy, Inc.
Method for treating acute mountain sickness

GB2353217B
(en)

1999-10-27
2001-07-18
Bioenergy Inc
Use of ribose to treat fibromyalgia

US6703370B1
(en)

1999-10-27
2004-03-09
Bioenergy, Inc.
Use of ribose to treat fibromyalgia

WO2001035953A2
(en)

1999-11-17
2001-05-25
Kuhrts Eric H
Exercise and muscle enhancement formulations

AU2594001A
(en)

1999-12-21
2001-07-03
Bioenergy Inc.
Compositions for the storage of platelets

GB2364642B
(en)

2000-01-07
2004-10-27
Bioenergy Inc
Compositions for enhancing the immune response

AU2001229672A1
(en)

2000-01-20
2001-07-31
Bioenergy Inc.
Use of ribose supplementation for increasing muscle mass and decreasing body fatin humans

US6553254B1
(en)

2000-04-07
2003-04-22
Keith E. Kenyon
Combination of non-living-source physical energy and living-source chemical energy to maximize the salvage of ATP

US6835750B1
(en)

2000-05-01
2004-12-28
Accera, Inc.
Use of medium chain triglycerides for the treatment and prevention of alzheimer’s disease and other diseases resulting from reduced neuronal metabolism II

US6420342B1
(en)

2000-05-08
2002-07-16
N.V. Nutricia
Nutritional preparation comprising ribose and medical use thereof

IT1317043B1
(en)

2000-06-14
2003-05-26
Sigma Tau Healthscience Spa

FOOD SUPPLEMENT ENHANCING THE ENERGETIC-MUSCULAR METABOLISM, INCLUDING AN ALCANOIL L-CARNITINE AND RIBOSE.

DE60125191T2
(en)

2000-07-28
2007-10-25
Bioenergy Inc., Ham Lake

COMPOSITIONS AND METHODS FOR IMPROVING CARDIOVASCULAR FUNCTION

US6855727B2
(en)

2000-12-04
2005-02-15
Yaizu Suisankagaku Industry Co., Ltd.
Muscular fatigue-controlling composition and method for providing muscular fatigue-controlling effect

EP1247525A1
(en)

2001-04-02
2002-10-09
Bioenergy Inc.
Use of a monosaccharide in the manufacture of a medicament against acute mountain sickness

US7629329B2
(en)

2001-06-04
2009-12-08
Tsi Health Sciences, Inc.
Method for increasing muscle mass and strength through administration of adenosine triphosphate

GB2381451A
(en)

2001-11-01
2003-05-07
New Technology Res Ltd
Pharmaco-dietary preparation having nutrition-supplementing and nutrition-enhancing effect

DE10215007A1
(en)

2002-04-05
2003-10-16
Degussa Bioactives Deutschland

Use of creatine pyruvate to increase endurance during high-intensity physical interval workouts

US7547450B2
(en)

2002-10-24
2009-06-16
Nestec Ltd.
Senior feline food

US6838562B2
(en)

2003-04-01
2005-01-04
Sal Abraham
Process for preparing a creatine heterocyclic acid salt and method of use

US7687468B2
(en)

2003-05-14
2010-03-30
Viacell, LLC.
Rejuvenation of stored blood

US8759315B2
(en)

2003-05-14
2014-06-24
Viacell, Llc
Methods for rejuvenating

US20040229205A1
(en)

2003-05-16
2004-11-18
Ericson Daniel G.
Compositions for the storage of platelets

CN1909912B
(en)

2004-01-14
2011-05-11
生物能公司
Use of ribose in recovery from anaesthesia

JP4754484B2
(en)

2004-03-18
2011-08-24
田辺三菱製薬株式会社

Depressive symptom improving agent

JP2005336176A
(en)

2004-04-28
2005-12-08
Tanabe Seiyaku Co Ltd
Body fatigue restorer

WO2005107768A2
(en)

2004-04-29
2005-11-17
Bioenergy, Inc.
Method for improving ventilatory efficiency

US20100099630A1
(en)

2004-04-29
2010-04-22
Maccarter Dean J
Method for improving ventilatory efficiency

US7968138B2
(en)

2004-07-23
2011-06-28
Arnold Nerenberg
Food sweetener

US20060029644A1
(en)

2004-08-06
2006-02-09
Kenyon Keith E
In vitro biochemical reactions with free anhydrous D-ribose

US20070135376A1
(en)

2005-06-20
2007-06-14
Accera, Inc.
Method to reduce oxidative damage and improve mitochondrial efficiency

US7566463B2
(en)

2006-05-03
2009-07-28
C. B. Fleet Company
Oral rehydration compositions

US20080146579A1
(en)

2006-12-15
2008-06-19
N.V. Nutricia
Treatment of patients with chronic pulmonary diseases and nutritional compositions therefore

ES2352154T3
(en)

2007-01-23
2011-02-16
Bioenergy Inc.

USE OF D-RIBOSE TO TREAT CARDIAC ARRITMIAS.

US20090197819A1
(en)

2007-03-20
2009-08-06
Clarence Albert Johnson
Compositions for improving and repairing skin

US20080312169A1
(en)

2007-03-20
2008-12-18
Clarence Albert Johnson
Cosmetic use of D-ribose

CN101356971B
(en)

2007-07-30
2012-11-07
石药集团中奇制药技术（石家庄）有限公司
Anti-fatigue anti-hypoxia health food composition

PT2179284T
(en)

2007-07-31
2016-12-30
Accera Inc
Use of genomic testing and ketogenic compounds for treatment of reduced cognitive function

US20090061016A1
(en)

2007-09-05
2009-03-05
Selzer Jonathan A
Seawater Based Dietary Supplement Product for Energy and Electrolyte Replacement

US20090232750A1
(en)

2008-03-13
2009-09-17
St Cyr John A
Compositions for indoor tanning

CN106138071A
(en)

2008-04-02
2016-11-23
生物能公司
Ribose is for the purposes in the first reaction of acute myocardial infarction

EP2285386B1
(en)

2008-05-16
2013-07-10
RiboCor, Inc.
Use of ribose in the treatment of restless legs syndrome

EP2303036A1
(en)

2008-07-03
2011-04-06
Accera, Inc.
Monoglyceride of acetoacetate and derivatives for the treatment of neurological disorders

CN102215846A
(en)

2008-08-20
2011-10-12
生物能公司
St cyr john a [us]; maccarter dean a

IT1391588B1
(en)

2008-10-15
2012-01-11
Giellepi Chemicals S P A

SYNERGIC COMPOSITION FOR THE RECOVERY AND REDUCTION OF LIEVE ISCHEMIC DAMAGE

US8255453B2
(en)

2009-09-14
2012-08-28
International Business Machines Corporation
Public BOT management in private networks

US8765432B2
(en)

2009-12-18
2014-07-01
Oligasis, Llc
Targeted drug phosphorylcholine polymer conjugates

WO2011103177A1
(en)

2010-02-16
2011-08-25
Viacell, Llc
Nucleoside-containing compositions and methods for treating red blood cells

CA2789709C
(en)

2010-02-16
2018-03-20
Viacell, Llc
Arginine-containing compositions and methods for treating red blood cells

CN102058045B
(en)

2010-10-26
2012-09-19
开平牵牛生化制药有限公司
Beverage for supplementing human body energy and recovering people from fatigue

JP6463361B2
(en)

2013-09-08
2019-01-30
コディアックサイエンシーズインコーポレイテッドＫｏｄｉａｋＳｃｉｅｎｃｅｓＩｎｃ．

Factor VIII zwitterionic polymer conjugate

CA2951567C
(en)

2014-06-12
2023-10-31
Lonza, Inc.
Method for decreasing skeletal muscle damage and/or oxidative stress in mammals

KR20170082568A
(en)

2014-11-03
2017-07-14
바이오에너지 라이프 사이언스, 인코포레이티드
Use of d-ribose to enhance adaptation to physical stress

WO2017106687A1
(en)

2015-12-18
2017-06-22
Lonza Inc.
Method and composition for increasing muscle protein synthesis and/or functional strength in mammals as well as method of producing a composition

US10821123B2
(en)

2016-02-01
2020-11-03
Bioenergy Life Science, Inc.
Use of ribose for treatment of subjects having congestive heart failure

CN108433106A
(en)

2017-11-07
2018-08-24
付少才
A kind of Oxygen-deficient endurance fructose powder (liquid) composition

WO2023135827A1
(en)

2022-01-13
2023-07-20
ＮｅＳＡ合同会社
Agent for protecting against and decelerating progression of neurodegenerative disease

Family Cites Families (32)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

JPS6049764A
(en)

1983-08-29
1985-03-19
Ajinomoto Co Inc
Food composition

JPS6094075A
(en)

1983-10-31
1985-05-27
Ajinomoto Co Inc
Fruit juice drink composition

US4605644A
(en)

1985-02-07
1986-08-12
Regents Of The University Of Minnesota
Method for stimulating recovery from ischemia employing ribose and adenine

US4719201A
(en)

1985-02-07
1988-01-12
Regents Of The University Of Minnesota
Method for stimulating recovery from ischemia

US4824660A
(en)

1985-06-06
1989-04-25
Paul S. Angello
Method of determining the viability of tissue in an organism

JPS6232860A
(en)

1985-08-06
1987-02-12
Riichiro Yamazaki
Healthy food

US4920098A
(en)

1986-09-17
1990-04-24
Baxter International Inc.
Nutritional support or therapy for individuals at risk or under treatment for atherosclerotic vascular, cardiovascular, and/or thrombotic diseases

AU2228888A
(en)

1987-10-14
1989-05-25
Takeda Chemical Industries Ltd.
Aqueous pharmaceutical preparation for oral administration

JPH02212A
(en)

1987-10-14
1990-01-05
Takeda Chem Ind Ltd
Aqueous drug preparation for oral administration

US4871718A
(en)

1987-12-29
1989-10-03
Raymond A. Roncari
Composition of matter for increasing intracellular ATP levels and physical performance levels and for increasing the rate of wound repair

US4981687A
(en)

1988-07-29
1991-01-01
University Of Florida
Compositions and methods for achieving improved physiological response to exercise

US4968719A
(en)

1989-04-03
1990-11-06
Sigma Tau, Industrie Farmaceutiche Riunite Spa
Method for treating vascular disease

US5114723A
(en)

1990-02-27
1992-05-19
University Of Texas System Board Of Regents
Beverage compositions for human consumption

FR2668039B1
(en)

1990-10-18
1993-06-25
Pernod Ricard

DIETETIC DRINK INTENDED TO SUPPORT EFFORT.

IT1247125B
(en)

1991-03-01
1994-12-12
Depha Team Srl

DIETETIC OR PHARMACEUTICAL COMPOSITIONS FOR THE RESTORATION OF THE CELL CONTENT OF NUCLEOTID ADENINS IN THE SKELETAL AND CARDIAC MUSCLE.

US5292538A
(en)

1992-07-22
1994-03-08
Metagenics, Inc.
Improved sustained energy and anabolic composition and method of making

GB9215746D0
(en)

1992-07-24
1992-09-09
Hultman Eric
A method of increasing creatine supply depot

DE4228215A1
(en)

1992-08-25
1994-03-03
Pliml Wolfgang

Use of ribose for the manufacture of a medicament for the treatment of poor performance of the body, in particular organ deficiency

US5852058A
(en)

1993-06-11
1998-12-22
The Board Of Trustees Of The Leland Stanford Junior University
Intramural delivery of nitric oxide enhancer for inhibiting lesion formation after vascular injury

JPH07233070A
(en)

1994-02-23
1995-09-05
Taisho Pharmaceut Co Ltd
Fatigue improver

JP3213666B2
(en)

1994-02-28
2001-10-02
治彦末岡

Method for producing creatine beverage

AU1780395A
(en)

1994-05-02
1995-11-09
Omeara (Proprietary) Limited
Amino acid, carnitine and magnesium supplementation

US5536751A
(en)

1994-05-09
1996-07-16
The United States Of America As Represented By The Secretary Of The Army
Pharmaceutical alpha-keto carboxylic acid compositions method of making and use thereof

JPH07330584A
(en)

1994-06-08
1995-12-19
Taisho Pharmaceut Co Ltd
Fatigue ameliorant

GB9517443D0
(en)

1994-12-17
1995-10-25
Univ Nottingham
Increasing creatine and glycogen concentration in muscle

JP3595373B2
(en)

1995-02-20
2004-12-02
治彦末岡

Creatine beverage

US5707971A
(en)

1995-06-07
1998-01-13
Life Resuscitation Technologies, Inc.
Modulation of glycolytic ATP production

US5709971A
(en)

1995-06-20
1998-01-20
Eastman Kodak Company
Dye imbibition printing blanks with antistatic layer

GB9611356D0
(en)

1996-05-31
1996-08-07
Howard Alan N
Improvements in or relating to compositions containing Creatine, and other ergogenic compounds

JP3563892B2
(en)

1996-10-08
2004-09-08
伊藤ハム株式会社

Physical Strength Enhancement / Fatigue Recovery Agent and Food Using It

DE19650755A1
(en)

1996-12-06
1998-06-10
Wolfgang Dr Pliml
Use of ribose to increase physical performance of living organisms,

GB9715340D0
(en)

1997-07-22
1997-09-24
Cerestar Holding Bv
Beverages for enhanced physical performance

1999

1999-04-12
US
US09/290,789
patent/US6159942A/en
not_active
Expired – Lifetime

1999-06-17
CA
CA002334415A
patent/CA2334415C/en
not_active
Expired – Lifetime

1999-06-17
CN
CN99807560A
patent/CN1306431A/en
active
Pending

1999-06-17
NZ
NZ508478A
patent/NZ508478A/en
unknown

1999-06-17
ES
ES99928759T
patent/ES2374260T3/en
not_active
Expired – Lifetime

1999-06-17
AT
AT99928759T
patent/ATE534393T1/en
active

1999-06-17
WO
PCT/US1999/013720
patent/WO1999065476A2/en
active
Application Filing

1999-06-17
JP
JP2000554356A
patent/JP2002518321A/en
active
Pending

1999-06-17
EP
EP99928759A
patent/EP1087779B1/en
not_active
Expired – Lifetime

1999-06-17
AU
AU45752/99A
patent/AU4575299A/en
not_active
Abandoned

2010

2010-04-08
JP
JP2010089732A
patent/JP2010168394A/en
active
Pending

2013

2013-08-05
JP
JP2013162441A
patent/JP2013237697A/en
active
Pending

2013-11-05
JP
JP2013229436A
patent/JP2014043453A/en
active
Pending

2016

2016-04-27
JP
JP2016089312A
patent/JP2016153421A/en
active
Pending

Also Published As

Publication number
Publication date

JP2016153421A
(en)

2016-08-25

CA2334415C
(en)

2004-08-24

WO1999065476A2
(en)

1999-12-23

EP1087779A2
(en)

2001-04-04

ATE534393T1
(en)

2011-12-15

JP2013237697A
(en)

2013-11-28

NZ508478A
(en)

2003-10-31

CN1306431A
(en)

2001-08-01

EP1087779B1
(en)

2011-11-23

CA2334415A1
(en)

1999-12-23

JP2002518321A
(en)

2002-06-25

JP2010168394A
(en)

2010-08-05

JP2014043453A
(en)

2014-03-13

WO1999065476A3
(en)

2000-04-06

US6159942A
(en)

2000-12-12

ES2374260T3
(en)

2012-02-15

Información de contacto