Methods of increasing endogenous erythropoietin (EPO)

Abstract

The present invention relates to methods for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo. Methods for treating, pretreating or preconditioning, or preventing erythropoietin-associated conditions are also included. Compounds for use in these methods are provided, as are methods of identifying such compounds.

Description

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 60 / 349,659, filed on 16 Jan. 2002; U.S. Provisional Application Serial No. 60 / 386,488, filed on 5 Jun. 2002; U.S. Provisional Application Serial No. 60 / 337,082, filed on 6 Dec. 2001; and U.S. Provisional Application Serial No. 60 / 359,683, filed on 25 Feb. 2002; each of which is incorporated by reference herein in its entirety.[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.[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,...

AI Technical Summary

Benefits of technology

[0100] Additionally, the methods can be used to increase endogenous EPO levels in an anemic or non-anemic patient scheduled to undergo surgery to reduce the need for allogenic blood transfusions or to facilitate banking of blood prior to surgery. The small decreases in hematocrit that typically occur after presurgical autologous blood donation do not stimulate an increase in endogenous EPO or in compensatory erythropoiesis. However, preoperative stimulation of endogenous EPO would effectively increase erythrocyte mass and autologous donation volumes while maintaining higher hematocrit levels, and such methods are specifically contemplated herein. In some surgical populations, particularly those individuals who experience surgical blood losses in excess of 2 liters, the methods of the invention could be applied to reduce allogeneic blood exposure. (Crosby (2002) Amer J Therap 9:371-376.)

[0101] The methods of the invention can also be used to enhance athletic performance, improve exercise capacity, and facilitate or enhance aerobic conditioning. Such methods can be used, e.g., by athletes to facilitate training and by soldiers to improve, e.g., stamina and endurance.

[0102] The methods of the invention have been shown to increase endogenous erythropoietin levels in media from cultured cells treated in vitro and in blood plasma from animals treated in vivo. Although the kidney is the major source of erythropoietin in the body, other organs, including brain, liver, and bone marrow, can and do synthesize erythropoietin upon appropriate stimulation. Using the methods of the invention, endogenous erythropoietin expression can be increased in various organs of the body, including brain, kidney, and liver. Indeed, methods of the invention even increase endogenous erythropoietin levels in animals that have undergone bilateral nephrectomy.

[0104] Further, the methods of the invention increase the hematocrit and blood hemoglobin level in animals treated in vivo. The increases in plasma EPO, hematocrit, and blood hemoglobin in response to the compounds used in the methods of the invention are dose-sensitive; however, dosing regimes can be established which produce a constant, controlled level of response to the compounds of the invention. Further, treatment with compounds of the invention can correct anemia, for example, induced by a toxic compound such as the chemotherapeutic agent cisplatin, or due to blood loss, e.g., trauma, injury, parasites, or surgery.

[0184] For example, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable excipient, may be administered to an HIV-infected patient being treated with zidovudine or other reverse transcriptase inhibitors. In another example, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable excipient, may be administered to an anemic cancer patient receiving cyclic cisplatin-or non-cisplatin-containing chemotherapy. In yet another example, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable excipient, may be administered to an anemic or non-anemic patient scheduled to undergo surgery to reduce the need for allogenic blood transfusions.

[0185] Preferred routes of administration include oral and transdermal delivery mechanisms. Such mechanisms provide benefit over current EPO replacement therapies by allowing for, e.g., ease of administration, self-administration by patient, reduced cost, fewer physician visits, and reduced risks due to infection and immunogenic complications, minimizing the adverse reactions some patients develop in response to dosing with recombinant EPO.

Problems solved by technology

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.

Various conditions can cause the destruction of erythrocytes (hemolysis), thus leading to anemia.

In addition, there are unusual situations in which the body produces antibodies against its own erythrocytes, resulting in hemolysis.

Irradiation, disease, or various chemical agents can also cause bone marrow destruction, producing aplastic anemia.

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, anemia can result from defective or abnormal hemoglobin or erythrocytes, such as in disorders including microcytic anemia, hypochromic anemia, etc.

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