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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
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  • 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
• the first reaction in which L- cysteine is required i.e., the synthesis of ⁇ -L-glutamyl-L-cysteine
• the rate- limiting step of glutathione biosynthesis is the rate- limiting step of glutathione biosynthesis.
• the availability of intracellular L-cysteine is a critical factor in the overall biosynthesis of GSH, are sufficient stores of ATP.
• 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-l- pyrophosphate (PRPP) and then converted to AMP.
• PRPP 5-phosphoribosyl-l- 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 hydro lyzed 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.
• 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. In U.S.
• 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. Hypoxia or ischemia can also deplete GSH. For example, 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.
• 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); CD. Spies et al., Crit. Care Med.. 22, 1738 (1994); B.M. Lomaestro et al., Annals. Pharmacomer.. 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 ) :
• 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-(l ⁇ 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.. Pis. 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):
• the present invention also provides the use of a compound of formula I(a) or a salt thereof to prepare a medicament useful to treat a mammal, such as a human, threatened by or afflicted with a hypoxic condition (hypoxia).
• compound (Ia) can be administered with an additional amount of free ribose.
• a medicament containing compound I(a) can contain 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.
• Figure 1 depicts the metabolic synthesis of glutathione (GSH) from L- glutanic acid.
• Figure 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-(l',2',3',4'- tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid, as well as the 2R or 2 S 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.
• the term "treating" or "treatment” as used herein 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 (1.5x) and muscle tissue (2.5x). 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 pha ⁇ naceutical 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.
• 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 (GSH+GSSG) was determined by a modification of the DTNB [5,5'-dithiobis(2-nitrobenzoic acid)] glutathione reductase recycling method of F. Tietze, Anal. Biochem..
• 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 is a specific inhibitor of gamma-glutamyl cysteine synthetase, the enzyme responsible for catalyzing the first step in GSH biosynthesis.
• Table 2 The data summarized on Table 2, below, demonstrate that GSH levels were decreased by this inhibitor even in the presence of RibCys, thus providing evidence that the increased levels of GSH observed were indeed due to de novo GSH biosynthesis from the L-cysteine provided by the thiazolidine prodrugs.
• GSH glutathione
• 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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