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Title:  Method of use of erythropoietin to treat ischemic acute renal failure

United States Patent:  6,784,154

Issued:  August 31, 2004

Inventors:  Westenfelder; Christof (Salt Lake City, UT)

Assignee:  University of Utah Research Foundation (Salt Lake City, UT)

Appl. No.:  003352

Filed:  November 1, 2001

Abstract

Recombinant erythropoietin is used in a method to prevent ischemic acute renal failure in patients at risk for developing ischemic acute renal failure and to treat fully-developed ischemic acute renal failure. The method is also used to prevent harmful cell apoptosis in renal tubular cells and to stimulate mitogenesis and motogenesis in renal tubular cells. The method comprises the administration of a composition of recombinant erythropoietin in a pharmacologically acceptable carrier to a patient for the purpose of preventing the development of ischemic acute renal failure, treating established acute renal failure, preventing harmful cell apoptosis in renal tubular cells.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method of preventing the onset of ischemic ARF in an individual by administration of a composition of EPO in a pharmaceutically acceptable carrier.

The present invention also provides a method for treating an individual suffering from ischemic ARF by administration of a composition of EPO in a pharmaceutically acceptable carrier.

The present invention also provides a method for preventing potentially harmful cell apoptosis in renal tubular cells by administration of a composition of EPO in a pharmaceutically acceptable carrier.

The present invention also provides a method for stimulating motogenesis and mitogenesis in renal tubular cells by administration of a composition of EPO in a pharmaceutically acceptable carrier.

Preferably, the EPO is recombinant or naturally-derived EPO, and the composition is administered systemically such that the EPO circulates through the body. The composition can further comprise other ingredients such as pharmaceutically acceptable solvents, diluents, excipients, emulsifiers, stabilizers, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention stems from the discovery that EPO is a multifunctional renotropic cytokine, the actions of which are diminished in cases of ischemic ARF. Ischemic ARF causes reduced expression of EPO which in turn slows cellular recovery. The administration of EPO at subpolycythemic levels, as described in the present invention, can enhance and speed recovery from ischemic ARF without certain harmful side effects such as polycythemia, hypertension and thromboembolism.

The present invention provides a method of treating and preventing ischemia-induced ARF, or ischemic ARF. The present invention also provides a method of preventing likely harmful cell apoptosis in renal tubular cells as well as a method of stimulating mitogenesis and motogenesis in renal tubular cells. The preferred method of the present invention comprises the administration of a composition of preferably 300 U/kg body weight EPO in a carrier to an individual with ischemic ARF. The dose is preferably administered 2-4 times over a time period of 2-4 days, giving one dose every 24 hours subcutaneously or intravenously.

Before the present methods of preventing and treating ischemic ARF, preventing likely harmful cell apoptosis in renal tubular cells, and stimulating motogenesis and mitogenesis in renal tubular cells are disclosed and described, it is to be understood that this invention is not limited to the particular configurations, process steps, and materials disclosed herein as such configurations, process steps, and materials may vary somewhat. It is also to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a carrier" includes reference to one or more of such carriers and reference to "an excipient" includes reference to a mixture of two or more excipients.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

The following abbreviations are used herein: ARF, acute renal failure; EPO, erythropoietin; EPOR, erythropoietin receptor; MCT, murine proximal tubular cells; HK-2, human proximal tubular cells; BSC-1, green monkey proximal tubular cells. The abbreviation "U" stands for "units of activity," and is defined by the supplier of the recombinant EPO. In this case, the recombinant EPO used was highly pure EPOGEN.TM. from Amgen. The sequence of the recombinant EPO is available in GenBank at accession number XM-- 011627 (National Center for Biotechnology Information, Bethesda, Md.).

As used herein, "pharmaceutically acceptable" means a component that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

As used herein, "therapeutically effective amount" means an amount of EPO that is nontoxic but sufficient to provide the desired effect and performance at a reasonable benefit/risk ratio attending any medical treatment.

As used herein, "administering" and similar terms mean delivering the composition to the individual being treated such that the composition is capable of being circulated systemically to the kidney where the EPO can bind its specific receptor in the kidney. Thus, the composition is preferably administered to the individual by systemic administration, typically by subcutaneous, intramuscular, or intravenous administration, or intraperitoneal administration. Injectables for such use can be prepared in conventional forms, either as a liquid solution or suspension or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion. Suitable carriers include, for example, water, saline, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances such as wetting or emulsifying agents, buffers, and the like can be added.

Ischemia is defined as a poor supply of blood to an organ. When the blood supply to the kidneys is cut off or reduced, ischemic ARF can develop. Ischemia has many causes such as multiple bodily injuries, infections invading the bloodstream (septicemia), internal or external hemorrhaging, loss of fluid from the body as a result of severe diarrhea or burns, reactions to transfusions, severe heart attacks, and kidney transplantations, as well as other surgical shock. In these situations, the blood flow to the kidneys may be reduced to dangerously low levels for a time period great enough to cause the development of ischemic ARF.

ARF occurs when renal function suddenly declines to levels so low that little or no urine is formed, and substances that the kidney usually eliminates remain in the body. Ischemia causes ARF by depressing the blood flow to the kidneys, which leads to inefficient excretion. The depressed blood flow also results in necrosis, or tissue death, in the kidney, damaging the renal tubular cells. Repair or prevention of this damage helps ameliorate ARF.

The regeneration of renal tubular cells likely depends, at least in part, on the intrinsic actions of EPO, but in ischemic ARF, the levels of EPO are also reduced, compounding the injury and preventing the regeneration of renal tubular cells. The disclosed methods provide levels of EPO high enough to aid in the regeneration of renal tubular cells, but not so high as to cause renal vasoconstriction and other unwanted side effects, such as hypertension and thromboembolism.

The present method also helps prevent likely harmful apoptosis, or programmed cell death of tubular cells. Apoptosis of renal tubular cells is increasingly recognized as a significant mechanism that contributes to the deterioration of renal function in ARF. The administration of EPO reduces the levels of harmful apoptosis of renal tubular cells during the development and later stages of ARF. The present method of administration of EPO to patients at risk of developing ischemic ARF or with ischemic ARF also stimulates mitogenesis and motogenesis in renal tubular cells. Mitogenesis is the production of cells and motogenesis is the movement of cells to specific locations in the body. These effects result in the proliferation of new renal tubular cells and the functional recovery of an ARF-damaged kidney.

The preferred method of the present invention is ideal for the management of patients with ischemic ARF. The effects of EPO when administered according to the preferred method help ameliorate ischemic ARF and facilitate renal tubular cell repair. EPO, with its extremely high safety profile, is of particular utility in the prevention of ischemic ARF in the large number of patients who are at risk for this complication. This includes patients with diabetes mellitus, patients with underlying renal insufficiency or with nephrotic syndrome, old age, patients with atherosclerotic disease, patients who are given nephrotoxic agents (radio contrast media, aminoglycosides, cis-platinum, cyclosporin A, FK506) or patients who are septic, hypotensive, hypoxic, who undergo surgery (aortic aneurysm, cardiac repair), or who have myoglobinuria-hematuria, pregnancy associated ARF, or significant liver disease, and so forth.

The preferred embodiment of the claimed methods comprises the administration of a pharmaceutical composition containing recombinant EPO to a patient at risk for or with fully-developed ischemic ARF. The preferred pharmaceutical composition contains recombinant EPO and a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration [24]. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. Except when a conventional media or agent is incompatible with an active compound, use of these compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical composition is formulated to be compatible with the intended route of administration, including intravenous, intraperitoneal, intradermal, subcutaneous, transdermal (i.e., topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR EL.TM. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid so as to be administered using a syringe. Such compositions should be stable during manufacture and storage and must be preserved against contamination from microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by using surfactants. Various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal, can control microorganism contamination. Isotonic agents, such as sugars, polyalcohols such as manitol, sorbitol, and sodium chloride can be included in the composition. Compositions that delay absorption include agents such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in an appropriate solvent with one or a combination of ingredients, followed by sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium, and any other required ingredients. Sterile powders for the preparation of sterile injectable solutions methods of preparation include vacuum drying and freeze-drying that yield a powder containing the active ingredient and any desired ingredient from a sterile solution.

Systemic administration can also be transmucosal or transdermal. For transmucosal or transdermal administration, penetrants that can permeate the target barrier(s) are selected. Transmucosal penetrants include, detergents, bile salts, and fusidic acid derivatives. Nasal sprays or suppositories can be used for transmucosal administration. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams.

The preferred dosage of the pharmaceutical composition of the present invention comprises the administration of a subpolycythemic dose of EPO administered subcutaneously to patients at risk for, or exhibiting the symptoms of, ischemic ARF. A subpolycythemic dose is about 250-350 U/kg body weight, preferably 300 U/kg body weight. The preferred dosage of EPO prevents the development of polycythemia, a condition where there are too many red blood cells present. Polycythemia formally exists when the hemoglobin level, red blood cell count, and total red blood cell volume are all above normal, resulting in a high hematocrit level. Polycythemia results in thickened blood and retarded blood flow, and increases the danger of blood clot formation within the circulatory system. Administration of EPO at greater than subpolycythemic doses causes polycythemia as well as other negative reactions, such as renal vasoconstriction, hypertension and thromboembolism.

By utilizing a subpolycythemic dosage of EPO, such as 300 U/kg body weight, such renal vasoconstriction can be avoided and EPO's numerous renoprotective effects can occur. The recommended short-term treatment of patients with established ischemic ARF or who are at risk for developing ischemic ARF is a course of 2-4 doses at subpolycythemic concentrations. This protocol avoids adverse side effects such as thromboembolism, hypertension, and polycythemia.

In patients at risk for developing ischemic ARF, such as patients entering surgery, the preferred treatment protocol includes administering a dose of between 250-350 U/kg body weight of EPO in a pharmacological composition up to six hours prior to the ischemic ARF-inducing event. Thereafter, the preferred protocol includes administering a dose of between 250-350 U/kg body weight of EPO in a pharmacological composition 24 hours after the first dose, and thereafter every 24 hours for up to three additional daily doses. The total number of doses should not exceed four.

In patients with established ischemic ARF, the preferred treatment protocol includes administering a dose of between 250-350 U/kg body weight of EPO in a pharmacological composition. This dose is preferably repeated every 24 hours for no more than four doses.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and depends upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Claim 1 of 21 Claims

I claim:

1. A method of renoprotection in an individual at risk for developing ischemic acute renal failure comprising administering a composition prior to the individual developing ischemic acute renal failure, said composition comprising a therapeutically effective amount of erythropoietin and a pharmaceutically acceptable carrier, for a time and under conditions effective for renoprotection.



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