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Methods of increasing endogenous erythropoietin (epo)Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 2 Peptide Repeating Units In Known Peptide ChainMethods of increasing endogenous erythropoietin (epo) description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060178316, Methods of increasing endogenous erythropoietin (epo). Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of U.S. application Ser. No. 10/313,643, filed 6 Dec. 2002, U.S. Provisional Application Ser. No. 60/349,659, filed on 16 Jan. 2002; U.S. Provisional Application Ser. No. 60/386,488, filed on 5 Jun. 2002; U.S. Provisional Application Ser. No. 60/337,082, filed on 6 Dec. 2001; and U.S. Provisional Application Ser. No. 60/359,683, filed on 25 Feb. 2002; each of which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to methods for increasing endogenous erythropoietin, ex vivo and in vivo, and to compounds that can be used in the methods. BACKGROUND OF THE INVENTION [0003] Erythropoietin (EPO), a naturally occurring hormone, stimulates the production of red blood cells (erythrocytes), which carry oxygen throughout the body. EPO is normally secreted by the kidneys, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by the blood's reduced capacity to carry oxygen, and thus are associated with similar signs and symptoms, including pallor of the skin and mucous membranes, weakness, dizziness, easy fatigability, and drowsiness, leading to a decrease in quality of life. Subjects with severe cases of anemia show difficulty in breathing and heart abnormalities. Anemia is typically associated with a condition in which the blood is deficient in red blood cells or in hemoglobin. [0004] Common causes of anemia include deficiencies of iron, vitamin B.sub.12, and folic acid. Anemia can also develop in association with chronic diseases, e.g., in inflammatory disorders, including disorders with consequent inflammatory suppression of marrow, etc. Anemia may be caused by loss of blood, for example, due to accidents, surgery, or gastrointestinal bleeding caused by medications such as aspirin and ibuprofen. Excessive blood loss can also be seen in women with heavy menstrual periods, and in people with stomach ulcers, duodenal ulcers, hemorrhoids, or cancer of the stomach or large intestine, etc. [0005] Various conditions can cause the destruction of erythrocytes (hemolysis), thus leading to anemia. For example, allergic-type reactions to bacterial toxins and various chemical agents such as sulfonamides and benzene can cause hemolysis. Hemolytic anemia is often caused by chemical poisoning, parasites, infection, or sickle-cell anemia. In addition, there are unusual situations in which the body produces antibodies against its own erythrocytes, resulting in hemolysis. Any disease or injury to the bone marrow can cause anemia, since that tissue is the site of erythropoiesis, i.e. erythrocyte synthesis. Irradiation, disease, or various chemical agents can also cause bone marrow destruction, producing aplastic anemia. Cancer patients undergoing chemotherapy often have aplastic anemia. [0006] Anemia is also associated with renal dysfunction, the severity of the anemia correlating highly with the extent of the dysfunction. Most patients with renal failure undergoing dialysis suffer from chronic anemia. [0007] In addition to being produced in the kidney, erythropoietin is produced by astrocytes and neurons in the central nervous system (CNS), and EPO and EPO receptors are expressed at capillaries of the brain-periphery interface. Furthermore, systemically administered EPO crosses the blood-brain barrier and reduces neuronal cell loss in response to cerebral and spinal chord ischemia, mechanical trauma, epilepsy, excitotoxins, and neuroinflammation. (Sakanaka (1998) Proc Natl Acad Sci USA 95:4635-4640; Celik et al. (2002) Proc Natl Acad Sci USA 99:2258-2263; Brines et al. (2000) Proc Natl Acad Sci USA 97:10526-10531; Calapai et al. (2000) Eur J Pharmacol 401:349-356; and Siren et al. (2001) Proc Natl Acad Sci USA 98:4044-404.) [0008] In the late 1980s, Amgen introduced a genetically engineered EPO for the treatment of anemia in chronic renal failure patients. EPO is also administered to cancer patients undergoing radiation and/or chemotherapy, decreasing the need for blood transfusions. EPO is used to treat anemia associated with HIV infection or azidothymidine (AZT) therapy. Although the market for EPO therapy is increasing, future sales are adversely affected by the high cost of the product. In addition, recombinant EPO therapy requires intravenous administration of EPO one to three times per week for up to twelve weeks, a treatment regimen that limits self-administration and is inconvenient for the patient. Further, human serum EPO shows size heterogeneity due to extensive and varied glycosylation not reproduced in any recombinant human EPO. [0009] Due to deficiencies in current production and use of recombinant EPO, there remains a need for methods and compounds effective in the treatment of erythropoietin-associated conditions such as anemia, including anemia associated with diabetes, ulcers, kidney failure, cancer, infection, dialysis, surgery, and chemotherapy. Specifically, there is a need in the art for methods and compounds that increase endogenous erythropoietin. SUMMARY OF THE INVENTION [0010] The present invention relates generally to methods for increasing endogenous erythropoietin. In one aspect, the present invention provides a method of increasing endogenous erythropoietin (EPO) in a subject, the method comprising stabilizing the alpha subunit of hypoxia inducible factor (HIF.alpha.). In another aspect, the present invention provides a method of increasing endogenous EPO in a subject, the method comprising inhibiting hydroxylation of HIF.alpha.. In yet another aspect, a method of increasing endogenous EPO in a subject, the method comprising inhibiting 2-oxoglutarate dioxygenase enzyme activity, is provided. The present invention provides in a further aspect a method of increasing endogenous EPO levels in a subject, the method comprising inhibiting HIF prolyl hydroxylase enzyme activity. [0011] The subject can be, in various embodiments, an animal, a mammal, a human, a cell, a tissue, an organ, etc. [0012] In one aspect, the invention provides a method of increasing endogenous EPO, the method comprising stabilizing HIF.alpha., wherein the stabilizing takes place in vivo. A method of increasing endogenous EPO, the method comprising stabilizing HIF.alpha., wherein the stabilizing takes place in vitro, is also contemplated. [0013] In particular embodiments of the invention in which methods of stabilizing endogenous HIF.alpha. are contemplated, the HIF.alpha. is selected from the group consisting of HIF-1.alpha., HIF-2.alpha., HIF-3.alpha., and any fragment thereof. In one embodiment, the HIF.alpha. is endogenous to the subject. [0014] In methods of the invention relating to inhibition of 2-oxoglutarate dioxygenase enzyme activity, various embodiments are provided in which the 2-oxoglutarate dioxygenase enzyme is selected from the group consisting of EGLN1, EGLN2, EGLN3, procollagen prolyl 4-hydroxylase, procollagen prolyl 3-hydroxylase, procollagen lysyl hydroxylase, PHD4, FIH-1, and any subunit or fragment thereof. With respect to methods for increasing endogenous EPO which comprise inhibiting HIF prolyl hydroxylase enzyme activity, embodiments in which the HIF prolyl hydroxylase enzyme is selected from the group consisting of EGLN1, EGLN2, EGLN3, and any subunit or fragment thereof are contemplated. [0015] A preferred method for increasing endogenous EPO according to the present invention comprises administering to the subject a compound that increases endogenous EPO. In one aspect, the compound stabilizes HIF.alpha.. In another aspect, the compound inhibits hydroxylation of HIF.alpha.. In a further aspect, the compound inhibits 2-oxoglutarate dioxygenase enzyme activity. In a particular aspect, the compound inhibits HIF prolyl hydroxylase enzyme activity. [0016] In certain embodiments, the present invention provides a method for increasing endogenous EPO in a subject, the method comprising administering to the subject a compound selected from the group consisting of heterocyclic carboxamides, phenanthrolines, hydroxamates, and physiologically active salts and prodrugs derived therefrom. In a particular embodiment, the compound is a heterocyclic carboxamide selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides. In a preferred embodiment, the compound is delivered to the subject in the form of an oral formulation. In another preferred embodiment, the compound is delivered in a transdermal formulation. [0017] Various methods for treating, preventing, or pretreating an EPO-associated disorder in a subject are provided. In one aspect, the present invention provides a method for treating, preventing, or pretreating an EPO-associated disorder, the method comprising increasing endogenous EPO. In another aspect, a method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising stabilizing HIF.alpha., is provided. In another method according to the present invention, a method of treating, preventing, or pretreating an EPO-associated disorder in a subject comprises inhibiting hydroxylation of HIF.alpha.. In yet another aspect, the invention provides a method of treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising inhibiting 2-oxoglutarate dioxygenase enzyme activity. In a preferred aspect of the present invention, a method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising inhibiting HIF prolyl hydroxylase enzyme activity, is contemplated. [0018] The present invention specifically relates to methods for treating, preventing, or pretreating anemia in a subject. In one embodiment, the method comprises increasing endogenous EPO, including, in various embodiments, stabilizing HIF.alpha., inhibiting 2-oxoglutarate dioxygenase enzyme activity, inhibiting HIF prolyl hydroxylase enzyme activity, etc. [0019] In one aspect, the invention provides methods for treatment, prevention, and pretreatment/preconditioning of anemia, wherein the anemia is associated with abnormal hemoglobin or erythrocytes. In a further aspect, the anemia is associated with a condition selected from the group consisting of diabetes, cancer, ulcers, kidney disease, immunosuppressive disease, infection, and inflammation. In yet another aspect, the anemia is associated with a procedure or treatment selected from the group consisting of radiation therapy, chemotherapy, dialysis, and surgery. In another aspect, methods for treatment, prevention, and pretreatment/preconditioning of anemia, wherein the anemia is associated with blood loss, are provided. In various aspects, the blood less is associated with bleeding disorders, trauma, injury, surgery, etc. It is contemplated in specific embodiments that the anemia can be associated with defects in iron transport, processing, or utilization. Methods of pretreating/preconditioning, preventing, or treating anemia, the methods comprising increasing endogenous EPO, and further comprising administering to the subject a compound selected from the group consisting of, e.g., an iron supplement, vitamin B.sub.12, folic acid, exogenous erythropoietin, and granulocyte-colony stimulating factor, etc., are also contemplated. [0020] The present invention further relates to a method of treating, preventing, or pretreating a neurological disorder in a subject, the method comprising increasing endogenous EPO. In various aspects, the method comprises stabilizing HIF.alpha., inhibiting 2-oxoglutarate dioxygenase enzyme activity, and inhibiting HIF prolyl hydroxylase enzyme activity. The invention contemplates in certain aspects that the neurological disorder is associated with a condition selected from the group consisting of stroke, trauma, epilepsy, and neurodegenerative disease. [0021] In one embodiment, the present invention includes a method of enhancing oxygen consumption in a subject, the method comprising increasing endogenous EPO. Continue reading about Methods of increasing endogenous erythropoietin (epo)... Full patent description for Methods of increasing endogenous erythropoietin (epo) Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods of increasing endogenous erythropoietin (epo) patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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