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Title:  Methods of treating intestinal ischemia using heparin-binding epidermal growth factor

United States Patent:  6,387,878

Inventors:  Besner; Gail E. (Dublin, OH); Pillai; Srikumar B. (Columbus, OH)

Assignee:  Children's Hospital Inc. (Columbus, OH)

Appl. No.:  518950

Filed:  March 6, 2000

Abstract

The present invention provides methods of treating pathologic conditions associated with intestinal ischemia. In the methods, patients at risk for or suffering from intestinal ischemia are treated with a heparin-binding epidermal growth factor product.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides methods of treating pathological conditions associated with intestinal ischemia by administering an HB-EGF product to patients.

As used herein, "BB-EGF product" includes HB-EGF proteins comprising about amino acid 63 to about amino acid 148 of SEQ ID NO: 2; HB-EGP proteins comprising about amino acid 73 to about amino acid 148 of SEQ ID NO: 2; HB-EGF proteins comprising about amino acid 74 to about amino acid 148 of SEQ ID NO: 2; HB-EGF proteins comprising about amino acid 77 to about amino acid 148 of SEQ ID NO: 2; HB-EGF proteins comprising about amino acid 82 to about amino acid 148 of SEQ ID NO: 2; HB-EGF proteins comprising a continuous series of amino acids of SEQ ID NO: 2 which exhibit less than 50% homology to EGF and which are efficacious in the rat model specified below; fusion proteins comprising the foregoing HB-EGF proteins; and the foregoing HB-EGF proteins including conservative amino acid substitutions. Conservative amino acid substitions are understood by those skilled in the art. The HB-EGF products may be isolated from natural sources known in the art [e.g., the U-937 cell line (ATCC CRL 1593)], chemically synthesized, or produced by recombinant techniques such as disclosed in WO92/06705, supra, the disclosure of which is hereby incorporated by reference. In order to obtain HB-EGF products of the invention, HB-EGF precursor proteins may be proteolytically processed in situ. The HB-EGF products may be post-translationally modified depending on the cell chosen as a source for the products.

The administration of HB-EGF products is preferably accomplished with a pharmaceutical composition comprising an HB-EGF product and a pharmaceutically acceptable carrier. The carrier may be in a wide variety of forms depending on the route of administration. The route of administration may be oral, rectal, parenteral, or through a nasogastric tube. Examples of parenteral routes of administration are intravenous, intraperitoneal, intramuscular, or subcutaneous injection. The presently preferred route of administration is the oral route as the present invention contemplates that the acid stability of HB-EGF is a unique factor as compared to, for example, EGF. The HB-EGF pharmaceutical composition may also include other ingrediants to aid solubility, or for buffering or preservation purposes. Pharmaceutical composition containing HB-EGF products comprises HB-EGF at a concentration of about 0.5 to 10 mg/ml and preferably at a concentration of 1 mg/ml in saline. Addition of other bioactive compounds [e.g., antibiotics, free radical scavenging or conversion materials (e.g., vitamin E, beta-carotene, BHT, ascorbic acid, and superoxide dimutase), fibrolynic agents (e.g., plasminogen activators), and slow-release polymers] to the HB-EGF compounds or separate administration of the other bioactive compounds is also contemplated.

As used herein, "pathological conditions associated with intestinal ischemia" includes conditions which directly or indirectly cause intestinal ischemia (e.g., premature birth; birth asphyxia; congenital heart disease; cardiac disease; polycythemia; hypoxia; exchange transfusions; low-flow states; atherosclerosis, embolisms or arterial spasms; ischemia resulting from vessel occlusions in other segments of the bowel; ischemic colitis; and intestinal torsion such as occurs in infants and particularly in animals) and conditions which are directly or indirectly caused by intestinal ischemia (e.g., necrotizing enterocolitis, shock, sepsis, and intestinal angina). Thus, the present invention contemplates administration of HB-EGF products to patients in need of such treatment including patients at risk for intestinal ischemia, patients suffering from intestinal ischemia, and patients recovering from intestinal ischemia. The administration of HB-EGF to patients is contemplated in both the pediatric and adult populations.

More particularly, the invention contemplates a method of reducing necrosis associated with intestinal ischemia comprising administering an HB-EGF product to a patient at risk for, suffering from, or recovering from intestinal ischemia. Also contemplated is a method of protecting intestinal epithelial cells from hypoxia comprising exposing the cells to an HB-EGF product. Administration of, or exposure to, HB-EGF products reduces lactate dehyrogenase efflux from intestinal epithelial cells, maintains F-actin structure in intestinal epithelial cells, increases ATP levels in intestinal epithelial cells, and induces proliferation of intestinal epithelial cells.

In view of the efficacy of HB-EGF in protecting intestinal tissue from ischemic events, it is contemplated that HB-EGF has a similar protective effect on myocardial, renal, spleen, lung, and liver tissue.

In another aspect, the invention provides a novel animal model of intestinal ischemia, designated herein a model of "segmental" intestinal ischemia, that is useful for evaluating the efficacy of putative therapeutics. Mammals, preferably rats, are subjected to reversible arterial occlusion, wherein a first order branch of the SMA and terminal collateral branches are occluded. Preferably, the first order branch of the SMA is selected from the group consisting of the middle ileum and the distal ilieum. Also preferably, six to seven terminal collateral branches are occluded. Reversible occlusion may be accomplished by means such as a micro-vascular clip or sutures.

Claim 1 of 1 Claim

We claim:

1. A method of treating intestinal cell necrosis associated with intestinal ischemia in a patient in need thereof comprising administering to said patients an effective amount of heparin-binding epidermal growth factor product, effective to reduce intestinal cell necrosis.


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