US20060105972A1 - Method to enhance delivery of glutathione and ATP levels in cells - Google Patents

Method to enhance delivery of glutathione and ATP levels in cells Download PDF

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Publication number
US20060105972A1
US20060105972A1 US10/990,933 US99093304A US2006105972A1 US 20060105972 A1 US20060105972 A1 US 20060105972A1 US 99093304 A US99093304 A US 99093304A US 2006105972 A1 US2006105972 A1 US 2006105972A1
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ribcys
tissue
mammal
gsh
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Herbert Nagasawa
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MAX INTERNATIONAL Inc
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Priority to US10/990,933 priority Critical patent/US20060105972A1/en
Assigned to BIOCEUTICALS, INC. reassignment BIOCEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NAGASAWA, HERBERT T.
Priority to CA2587616A priority patent/CA2587616C/en
Priority to EP05823154A priority patent/EP1824481B1/en
Priority to ES05823154T priority patent/ES2390228T3/es
Priority to CNA2005800393226A priority patent/CN101060840A/zh
Priority to DK05823154.9T priority patent/DK1824481T3/da
Priority to PCT/US2005/041458 priority patent/WO2006055597A1/en
Priority to MX2007005835A priority patent/MX2007005835A/es
Priority to EA200701017A priority patent/EA014076B1/ru
Priority to AU2005307885A priority patent/AU2005307885B2/en
Priority to PL05823154T priority patent/PL1824481T3/pl
Priority to BRPI0516814-7A priority patent/BRPI0516814A/pt
Priority to JP2007543186A priority patent/JP2008520681A/ja
Priority to KR1020077013535A priority patent/KR20070095900A/ko
Publication of US20060105972A1 publication Critical patent/US20060105972A1/en
Priority to US12/182,354 priority patent/US8501700B2/en
Assigned to MAX INTERNATIONAL, INC. reassignment MAX INTERNATIONAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CELLGEVITY, INC.
Assigned to CELLGEVITY, INC. reassignment CELLGEVITY, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: BIOCEUTICALS, INC.
Priority to US13/958,530 priority patent/US9144570B2/en
Priority to US14/838,274 priority patent/US20160082029A1/en
Assigned to EAST WEST BANK reassignment EAST WEST BANK INTELLECTUAL PROPERTY SECURITY AGREEMENT Assignors: MAX INTERNATIONAL, LLC
Abandoned legal-status Critical Current

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    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0331—Animal model for proliferative diseases
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells

Definitions

  • GSH glutathione
  • GSH glutathione
  • nucleotide precursors that may be present in the tissue are converted to AMP and further phosphorylated to ATP.
  • Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP.
  • PRPP 5-phosphoribosyl-1-pyrophosphate
  • 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 (AMP). AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP.
  • AMP adenosine diphosphate
  • ATP ATP loses one high energy bond to form ADP, which can be hydrolyzed to AMP.
  • AMP and its metabolites adenine, inosine and hypoxanthine are freely diffusible from the muscle cell and may not be available for resynthesis to ATP via the salvage pathway.
  • PRPP 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.
  • G6PDH glucose-6-phosphate dehydrogenase
  • Glucose is converted by enzymes such as G6PDH to ribose-5-phosphate and further phosphorylated to PRPP, which augments the de novo and salvage pathways, as well as the utilization of adenine.
  • hypoxia many conditions produce hypoxia. Such conditions include acute or chronic ischemia when blood flow to the tissue is reduced due to coronary artery disease or peripheral vascular disease where the artery is partially blocked by atherosclerotic plaques.
  • U.S. Pat. No. 4,719,201 it is disclosed that when ATP is hydrolyzed to 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 recovering from ischemia, recovery of ATP levels is enhanced.
  • Transient hypoxia frequency occurs in individuals undergoing anesthesia and/or surgical procedures in which blood flow to a tissue is temporarily interrupted. Peripheral vascular disease can be mimicked in intermittent claudication where temporary arterial spasm causes similar symptoms. Finally, persons undergoing intense physical exercise or encountering high altitudes may become hypoxic.
  • U.S. Pat. No. 6,218,366 discloses that tolerance to hypoxia can be increased by the administration of ribose prior to the hypoxic event.
  • GSH Hypoxia or ischemia can also deplete GSH.
  • strenuous aerobic exercise can also deplete antioxidants from the skeletal muscles, and sometimes also from the other organs.
  • Exercise increases the body's oxidative burden by calling on the tissues to generate more energy. Making more ATP requires using more oxygen, and this in turn results in greater production of oxygen free radicals.
  • GSH is depleted by exercise, and that for the habitual exerciser supplementation with GSH precursors may be effective in maintaining performance levels. See L. L. Ji, Free Rad. Biol. Med., 18, 1079 (1995).
  • Tissue injury as from burns, ischemia and reperfusion, surgery, septic shock, or trauma can also deplete tissue GSH.
  • K. Yagi Lipid Peroxides in Biology and Medicine, Academic Press, N.Y. (1982) at pages 223-242; A. Blaustein et al., Circulation, 80, 1449 (1989); H. B. Demopoulos, Pathology of Oxygen, A. P. autor, ed., Academic Press, N.Y. (1982) at pages 127-128; J. Vina et al., Brit. J. Nutr., 68, 421 (1992); C. D. Spies et al., Crit. Care Med., 22, 1738 (1994); B. M. Lomaestro et al., Annals. Pharmacother., 29, 1263 (1995) and P. M. Kidd, Alt. Med. Res., 2, 155 (1992).
  • L-2-Oxothiazolidine-4-carboxylate is converted to L-cysteine via the enzyme 5-oxo-L-prolinase.
  • the dissociation to yield L-cysteine necessarily releases an equimolar amount of the aldehyde (3), RCHO.
  • R is an aromatic or an alkyl residue
  • U.S. Pat. No. 4,868,114 discloses a method comprising stimulating the biosynthesis of glutathione in mammalian cells by contacting the cells with an effective amount of a compound of the formula (1): wherein R is a (CHOH) n CH 2 OH and wherein n is 1-5.
  • the compound wherein n is 3 is 2(R,S)-D-ribo-(1′, 2′, 3′, 4′-tetrahydroxybutyl)thiazolidone-4(R)-carboxylic acid (Ribose-Cysteine, RibCys).
  • RibCys releases cysteine by non-enzymatic hydrolysis.
  • RibCys has been demonstrated to be effective to protect against acetaminophen-induced hepatic and renal toxicity. A. M. Lucus, Toxicol. Pathol., 28, 697 (2000). RibCys can also protect the large and small bowel against radiation injury. See M. P. Caroll et al., Dis. Colon Rectum, 38, 716 (1995). These protective effects are believed to be due to the stimulation of GSH biosynthesis, which elevates intracellular GSH.
  • the present invention provides a method to treat a mammal threatened by, or afflicted with a hypoxic condition (hypoxia) comprising administering an effective amount of a compound of formula (Ia): (RibCys) or a pharmaceutically acceptable salt thereof, effective to counteract the effects of said hypoxia in the tissue(s) of said mammal.
  • a compound of formula (Ia): (RibCys) or a pharmaceutically acceptable salt thereof effective to counteract the effects of said hypoxia in the tissue(s) of said mammal.
  • GSH precursor such as cysteine
  • administration of effective amounts of RibCys can deliver amounts of ribose to ATP-depleted tissues that stimulate the in vivo synthesis of ATP and that also can stimulate the synthesis of NADPH (nicotinamide adenine dinucleotide phosphate, reduced).
  • compound (Ia) can be administered with an additional amount of free ribose.
  • administration will be by oral administration, particularly in prophylactic or pre-loading situations, but parenteral administration, as by injection or infusion, may be necessary in some situations.
  • FIG. 1 depicts the metabolic synthesis of glutathione (GSH) from L-glutanic acid.
  • FIG. 2 depicts the in vivo dissociation of a compound of formula I to yield cysteine and an aldehyde.
  • RibCys refers to 2(R,S)-D-ribo-(1′, 2′, 3′, 4′-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid, as well as the 2R or 2S enantiomers of (Ia), and its pharmaceutically acceptable salts.
  • Such salts include alkali metal salts of the carboxylic acid moiety as well as stable acid addition salts of the NH moiety, including salts of both inorganic and organic acids, such as citrate, malate, gluconate, glutamate, hydrochloride, hydrosulfate and the like.
  • hypoxia or “hypoxic condition” is defined to mean a condition in which oxygen in one or more tissues of a mammal is lowered below physiologic levels, e.g., to a less than optimal level.
  • Hypoxia also includes conditions in which oxygen levels are lowered in tissues due to stress such as aerobic exercise, physical weight pressure, anesthesia, surgery, anemia, acute respiratory distress syndrome, chronic illness, chronic fatigue syndrome, trauma, burns, skin ulcers, cachexia due to cancer and other catabolic states and the like.
  • Hypoxia also includes “ischemia” or “ischemic conditions” in which tissues are oxygen-deprived due to reduction in blood flow, as due to constriction in, or blockage of, a blood vessel.
  • Ischemia and/or ischemic conditions include those caused by coronary artery disease, cardiomyopathy, including alcoholic cardiomyopathy, angioplasty, stenting, heart surgery such as bypass surgery or heart repair surgery (“open-heart surgery” ), organ transplantation, prolonged weight pressure on tissues (pressure ulcers or bedsores), ischemia-reperfusion injury which can cause damage to transplanted organs or tissue, and the like.
  • the present invention is effective to treat the GSH and ATP depletion due to hypoxia and thus to increase a subject's energy level strength and well-being, even though the underlying cause of the hypoxic condition, such as viral or bacterial infection, exposure to bacterial or other toxins, low red-cell counts, aging, cancer or continued exercise, is not affected.
  • treating includes the effects of RibCys administration to both healthy and patients afflicted with chronic or acute illness and includes inducing protective affects as well as decreasing at least one symptom of a past or ongoing hypoxic condition.
  • RibCys Effective doses of RibCys will vary dependent upon the condition, age and weight of the patient to be treated, the condition to be treated and the mode of administration. Both cysteine, as released in vivo from RibCys in animal models, and ribose, as administered directly to human subjects, have been found to be essentially non-toxic over wide dosage ranges. For example, ribose has been reported to increase exercise capacity in healthy human subjects when taken orally at dosages of 8-10 g per day by an adult. See U.S. Pat. No. 6,534,480. RibCys administered to mice at 8 mmol/kg i.p., increased glutathione levels in numerous organs, including heart (1.5 ⁇ ) and muscle tissue (2.5 ⁇ ). See, J. C.
  • RibCys at 8 mmol/kg has been found to deliver effective protective amounts of cysteine to mice exposed to cyclophosphamide. This dose can deliver about 70-80 g of ribose and about 60-70 g of cysteine to an adult human. See J. C. Roberts, Anticancer Res., 14, 383 (1994). Doses of 2 g/kg RibCys were reported to protect mice against acetaminophen hepatic and renal toxicity by A. M. Lucas et al., Toxicol. Pathol., 20, 697 (2000).
  • these compounds, and the pharmaceutically acceptable salts thereof can be administered in the form of a pharmaceutical unit dosage form comprising the active ingredient in combination with a pharmaceutically acceptable carrier, which can be a solid, semi-solid, or liquid diluent.
  • a pharmaceutically acceptable carrier which can be a solid, semi-solid, or liquid diluent.
  • a unit dosage of the compound can also be administered without a carrier material.
  • pharmaceutical preparations include, but are not limited to, tablets, powders, capsules, aqueous solutions, suspensions including concentrates, liposomes, and other slow-releasing formulations, as well as transdermal delivery forms.
  • the unit dosage form includes about 0.001-99% of the active substance.
  • the compounds can be delivered by any suitable means, e.g., topically, orally, parenterally.
  • the delivery form is liquid or a solid such as a powder that can be stirred into an ingestible liquid.
  • Standard pharmaceutical carriers for topical, oral, or parenteral compositions may be used, many of which are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.
  • suitable pharmaceutical carriers or diluents can include mannitol, lactose, starch, magnesium stearate, talcum, glucose, and magnesium carbonate.
  • Oral compositions can be in the form of tablets, capsules, powders, solutions, suspensions, sustained release formulations, and the like.
  • a typical tablet or capsule can contain 40-99% lactose, 1-2% magnesium stearate, and 10-20% cornstarch, along with the active substance (preferably about 0.001-20%).
  • An aqueous solution can contain up to the saturation level of RibCys or its salt, preferably with an amount of ribose added that is effective to prevent or inhibit premature in vitro dissociation.
  • suitable pharmaceutical carriers can include water, saline, dextrose, Hank's solution, Ringer's solution, glycerol, and the like.
  • Parenteral compositions can be in the form of suspensions, solutions, emulsions, and the like. Parenteral administration is usually by injection or infusion which can be subcutaneous, intramuscular, or intravenous.
  • Rat hepatocytes were isolated following the methods of P. O. Seglen, Exper. Cell Res., 74, 450 (1972). After final plating, the hepatocytes were maintained in culture for 24 hr prior to use. Only primary cultures were used throughout the studies. The hepatocytes were incubated with cysteine prodrugs NAC and (Ia) for a 4-hr period, and after removal of media by aspiration, the cells were rinsed with cold phosphate-buffered saline and deproteinized with 5% sulfosalicylic acid.
  • Total GSH content was determined by a modification of the DTNB [5,5′-dithiobis(2-nitrobenzoic acid)] glutathione reductase recycling method of F. Tietze, Anal. Biochem., 27, 502 (1969).
  • the GSH concentration in the sample was quantified by determining the cycling rate ( ⁇ OD at 412 nm/min) of the sample.
  • the cells were pre-exposed to BSO (0.20 mM) before treatment with the L-cysteine prodrugs.
  • N-Acetyl-L-cysteine the drug presently used for the clinical treatment of acetaminophen overdoses, also raised GSH levels by 30% in this system, but required 2.5 times the concentration of the thiazolidine prodrugs for comparable elevation.
  • BSO buthionine sulfoxime
  • GSH glutathione
  • cysteine/ribose pro-drug RibCys is also expected to be applicable to any tissue or organ that has suffered hypoxia, such as an ischemic insult where antioxidant augmentation and ATP recovery would be helpful.
  • these situations include but are not limited to: myocardial infarction, stroke, organ transplant with organ preservation, neonatal support, multi-organ system failures, shock and trauma resulting in compromised circulation, and the like.
  • the present invention provides a method whereby hypoxic tissue can be treated so as to quickly regain and maintain normal ATP levels, both to improve tissue survival and to hasten general bodily recovery.

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US10/990,933 2004-11-17 2004-11-17 Method to enhance delivery of glutathione and ATP levels in cells Abandoned US20060105972A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
US10/990,933 US20060105972A1 (en) 2004-11-17 2004-11-17 Method to enhance delivery of glutathione and ATP levels in cells
KR1020077013535A KR20070095900A (ko) 2004-11-17 2005-11-16 세포 내 글루타티온 및 ａｔｐ의 전달 향상을 통하여저산소증을 치료하기 위한 리보스-시스테인의 용도
PL05823154T PL1824481T3 (pl) 2004-11-17 2005-11-16 Zastosowanie rybozo-cysteiny do leczenia niedotlenienia przez zwiększenie dostarczania glutationu i poziomów ATP w komórkach
JP2007543186A JP2008520681A (ja) 2004-11-17 2005-11-16 細胞におけるグルタチオンの送達およびａｔｐレベルを増強することによって低酸素症を処置するためのリボース−システインの使用
ES05823154T ES2390228T3 (es) 2004-11-17 2005-11-16 Uso de ribosa-cesteína para tratar la hipoxia mejorando el aporte de glutatión y los niveles de ATP en células
CNA2005800393226A CN101060840A (zh) 2004-11-17 2005-11-16 核糖－半胱氨酸通过提高细胞内谷胱甘肽的送递和atp的水平以治疗缺氧的用途
DK05823154.9T DK1824481T3 (da) 2004-11-17 2005-11-16 Anvendelse af ribose-cystein til behandling af hypoxia ved forhøjelse af tilførslen af glutathion og atp-koncentrationerne i celler
PCT/US2005/041458 WO2006055597A1 (en) 2004-11-17 2005-11-16 Use of ribose-cysteine to treat hypoxia by enhancing delivery of glutathione and atp levels in cells
MX2007005835A MX2007005835A (es) 2004-11-17 2005-11-16 Uso de ribosa-cisteina para tratar hipoxia mejorando el suministro de glutationa y los niveles de atp en las celulas.
EA200701017A EA014076B1 (ru) 2004-11-17 2005-11-16 Применение рибозы-цистеина для лечения гипоксии
AU2005307885A AU2005307885B2 (en) 2004-11-17 2005-11-16 Use of ribose-cysteine to treat hypoxia by enhancing delivery of glutathione and ATP levels in cells
CA2587616A CA2587616C (en) 2004-11-17 2005-11-16 Use of ribose-cysteine to treat hypoxia by enhancing delivery of glutathione and atp levels in cells
BRPI0516814-7A BRPI0516814A (pt) 2004-11-17 2005-11-16 usos do ácido 2(r,s)-d-ribo-(1',2',3',4'-tetrahidroxibutil)tiazolidina-4( r)-carboxilìco(ribcys) e métodos terapêuticos
EP05823154A EP1824481B1 (en) 2004-11-17 2005-11-16 Use of ribose-cysteine to treat hypoxia by enhancing delivery of glutathione and atp levels in cells
US12/182,354 US8501700B2 (en) 2004-11-17 2008-07-30 Method to enhance delivery of glutathione and ATP levels in cells
US13/958,530 US9144570B2 (en) 2004-11-17 2013-08-02 Method to enhance delivery of glutathione and ATP levels in cells
US14/838,274 US20160082029A1 (en) 2004-11-17 2015-08-27 Method to enhance delivery of glutathione and atp levels in cells

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US12/182,354 Active 2027-03-03 US8501700B2 (en) 2004-11-17 2008-07-30 Method to enhance delivery of glutathione and ATP levels in cells
US13/958,530 Expired - Lifetime US9144570B2 (en) 2004-11-17 2013-08-02 Method to enhance delivery of glutathione and ATP levels in cells
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US14/838,274 Abandoned US20160082029A1 (en) 2004-11-17 2015-08-27 Method to enhance delivery of glutathione and atp levels in cells

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US (4) US20060105972A1 (enrdf_load_stackoverflow)
EP (1) EP1824481B1 (enrdf_load_stackoverflow)
JP (1) JP2008520681A (enrdf_load_stackoverflow)
KR (1) KR20070095900A (enrdf_load_stackoverflow)
CN (1) CN101060840A (enrdf_load_stackoverflow)
AU (1) AU2005307885B2 (enrdf_load_stackoverflow)
BR (1) BRPI0516814A (enrdf_load_stackoverflow)
CA (1) CA2587616C (enrdf_load_stackoverflow)
DK (1) DK1824481T3 (enrdf_load_stackoverflow)
EA (1) EA014076B1 (enrdf_load_stackoverflow)
ES (1) ES2390228T3 (enrdf_load_stackoverflow)
MX (1) MX2007005835A (enrdf_load_stackoverflow)
PL (1) PL1824481T3 (enrdf_load_stackoverflow)
WO (1) WO2006055597A1 (enrdf_load_stackoverflow)

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AU2005307885A1 (en) 2006-05-26
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