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Title:  Intestinal function using leptin

United States Patent:  6,630,444

Issued:  October 7, 2003

Inventors:  Schwartz; Marshall (Bryn Mawr, PA); O'Connor; Darlise (Newark, DE)

Assignee:  The Nemours Foundation (Wilmington, DE)

Appl. No.:  693864

Filed:  October 23, 2000

Abstract

A method for treating a patient that has inadequate intestinal function is described. Administering leptin to a subject increases the intestinal function beyond that for a normal intestine and beyond that of a normal adaptive response. Further, administering leptin to a subject results in an increase in amino acid absorption, sugar absorption, mucosal mass, transport mechanisms for amino acids, or transport mechanisms for sugars. The method may be used for treating subjects have conditions such as short bowel syndrome, inflammation of the bowel, necrotizing enterocolitis, intestinal atresia, midgut volvulus, severe acute gastroenteritis, chronic gastroenteritis, cholera, chronic infections of the bowel, immunologic disorders affecting the small intestine, and inflammatory bowel disease such as, chronic ulcerative colitis and Crohn's Disease.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an alternative method for management for short bowel syndrome and other disorders of the intestine.

Accordingly, the present invention includes a method for treating a patient comprising the step of administering leptin to a subject having a condition resulting from inadequate intestinal function. Leptin may be administered in an amount ranging from about 1 .mu.g/kg body weight/day to about 50 .mu.g/kg body weight/day. In another embodiment leptin may be administered in an amount ranging from about 2 .mu.g/kg body weight/day to about 20 .mu.g/kg body weight/day. The patient may have a condition selected from the group consisting of short bowel syndrome, inflammation of the bowel, inflammatory bowel disease (such as, chronic ulcerative colitis and Crohn's Disease), necrotizing enterocolitis, intestinal atresia, midgut volvulus, severe acute gastroenteritis, chronic gastroenteritis, cholera, chronic infections of the bowel, and immunologic disorders affecting the small intestine.

In accordance with one embodiment of the present invention leptin may be administered systemically. In another embodiment leptin may be administered lumenally.

Further, leptin may be administered with nutritional supplements or with growth factors that increase the function of the intestine. In a preferred embodiment, the growth factors may be selected from the group consisting of HGF, EGF, IGF-1, IL-11, and GLP-2.

The present invention includes a method for supplying nutrients to a subject comprising the steps of providing nutrients to the subject and administering leptin to the subject in an amount effective to increase the absorption of the nutrients in the intestine of the subject. Leptin may be administered in an amount ranging from about 1 .mu.g/kg body weight/day to about 50 .mu.g/kg body weight/day. In another embodiment, leptin may be administered in an amount ranging from about 2 .mu.g/kg body weight/day to about 20 .mu.g/kg body weight/day. The subject may have a condition selected from the group consisting of short bowel syndrome, inflammation of the bowel, inflammatory bowel disease (such as, chronic ulcerative colitis and Crohn's Disease), necrotizing enterocolitis, intestinal atresia, midgut volvulus, severe acute gastroenteritis, chronic gastroenteritis, cholera, chronic infections of the bowel, and immunologic disorders affecting the small intestine. Leptin may be administered systemically or luminally.

Still further, the present invention includes a method for treating the intestine in a subject comprising the step of administering leptin to the subject in an amount effective to increase the intestinal function of the intestine. Still further, the method includes an amount of leptin that is effective to increase sugar absorption. The method may include an amount of leptin that is effective to increase amino acid absorption. Further, the method may include an amount of leptin that is effective to increase mucosal mass of the intestine. The amount of leptin ranges from 1 .mu.g/kg body weight/day to about 50 .mu.g/kg body weight/day. In another embodiment, leptin may be administered in an amount ranging from about 2 .mu.g/kg body weight/day to about 20 .mu.g/kg body weight/day. The subject may have a condition selected from the group consisting of short bowel syndrome, inflammation of the bowel, inflammatory bowel disease (such as, chronic ulcerative colitis and Crohn's Disease), necrotizing enterocolitis, intestinal atresia, midgut volvulus, severe acute gastroenteritis, chronic gastroenteritis, cholera, chronic infections of the bowel, and immunologic disorders affecting the small intestine. The leptin may be administered systemically or lumenally.

Leptin may be administered with nutritional supplements or with growth factors that increase the function of the intestine. In a preferred embodiment, the growth factors may be selected from the group consisting of HGF, EGF, IGF-1, IL-11, and GLP-2.

The method also includes increasing intestinal function beyond the function of the normal intestine. The method also includes increasing intestinal function beyond the normal adaptive response.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Leptin, a 167 amino acid (16 kD) cytokine, is a peptide product of the obesity (ob) gene and is expressed in a wide variety of tissues, including adipocytes, the human placenta, the gastric epithelium, and the mammary gland. Leptin regulates appetite and metabolic activity in mice by acting through the long form of the leptin receptor (OB-Rb) in the hypothalamus. Recently, leptin has been demonstrated to have angiogenic activity in vivo and in vitro. The receptor for leptin is a single transmembrane protein most closely related to the gp 130 signal-transduction component of class I cytokine receptors, such as IL-6, IL-11, G-CSF and LIF.

It has been discovered that administering leptin to a patient results in an increase in intestinal function when compared to the function of the normal intestine. Intestinal function as used herein, means amino acid absorption, sugar absorption, mucosal mass, transport mechanisms for amino acids, or transport mechanisms for sugars. Specifically, it has been found that the administration of leptin to a subject increases amino acid absorption, increases sugar absorption, increases in mucosal mass, and increases the transport mechanisms for the transportation of amino acids and sugars into the mucosa of the small intestine.

After massive small bowel resection, the remaining intestine spontaneously undergoes an adaptive response in which the bowel wall thickens and the absorptive surface of the villi increases. The adaptive response increases the absorptive capacity of the mucosa per unit area. Despite this naturally occurring phenomenon, the adaptation frequently is not enough to maintain adequate absorption of nutrients needed to sustain growth. When the adaptive response is insufficient to meet the nutritional needs of the patient, short bowel syndrome ("SBS")is the result. This is particularly devastating to children, who have increased caloric requirements in order to support normal growth and development. There is a high mortality rate in the pediatric age group from complications such as liver failure, sepsis, and malnutrition. Treatments for SBS are parentally administered nutrients ("TPN"), surgically elongating the bowel, and small bowel transplantation which is usually accompanied by a liver transplant all of which have serious complications.

Importantly, it has been discovered that leptin not only increases the intestinal function of the intestine when compared to the function of the normal intestine, but also increases intestinal function beyond the normal adaptive response of the small bowel. Administering leptin to a subject increases the response of the small intestine epithelium during intestinal adaptation induced by massive bowel resection. Specifically, the administration of leptin increases carbohydrate absorption beyond the normal adaptive response.

Leptin may be administered in recombinant form or from natural sources. Leptin may be administered to patients at effective doses and for effective periods of time by the intestinal intralumenal route either by catheter or sustained release preparations or by systemic routes, including but not limited to intravenous administration. Suitable carriers for leptin may be found in Remington's Pharmaceutical Sciences, 18th ed., 1990, Mack Publishing Co., Easton, Pa. Further, leptin may be administered intravenously, intramuscularly, intraperitoneal, and through other parenteral routes.

As used herein, an "effective dose" of leptin is that amount of leptin administered to a subject sufficient to increase intestinal function of the intestine of the subject. An effective dose of leptin ranges from about 1 .mu.g/kg body weight/day to about 50 .mu.g/kg body weight/day. Preferably, the effective dose of leptin ranges from about 2 .mu.g/kg body weight/day to about 20 .mu.g/kg body weight/day. The number of days leptin may be administered to the subject may vary depending on the condition. However, leptin should be administered for a long enough period to increase the intestinal function of the intestine. Leptin doses should be provided at intervals sufficient to maintain the increase in intestinal function of the intestine. The length of administration and the intervals may vary depending on the age, size and condition of the subject. Subjects or patients include, but are not limited to, mammals, rats, infants, children, adults, and seniors.

It will be appreciated that nutritional supplements, medications, and growth factors may be administered with an effective dose of leptin. Nutritional supplements or nutrients may include enteral formulas and glutamine. The nutritional supplements may be administered along with the leptin or alternatively the nutritional supplements may be provided separately by the same or different administration routes. For example, the administration of leptin may occur intravenously while the nutritional supplements are taken orally. Medications may include antibiotics, anti-diarrheal and inti-inflammatory drugs and may be provided with the leptin or administered separately. Growth factors such as Hepatocyte Growth Factor ("HGF"), epidermal growth factor ("EGF"), Interleukin-11 ("IL-11"), glucagon-like peptide ("GLP-2"), and insulin-like growth factors such as insulin-like growth factor-1 (IGF-1) may also be included with the administration of leptin or provided separately.

Leptin may be useful for treating patients suffering from inadequate intestinal function. As used herein, "inadequate intestinal function" means absorption levels of amino acids and sugars below that for a normal intestine. Conditions that may be treated with leptin include, but are not limited to, short bowel syndrome and processes producing inflammation of the bowel which includes, but is not limited to, necrotizing enterocolitis, intestinal atresia, midgut volvulus, severe acute gastroenteritis, chronic gastroenteritis, cholera, inflammatory bowel disease ("IBD") such as, Chronic Ulcerative Colitis ("CUC") and Crohn's Disease ("CD"), and other chronic infections of the bowel, and any condition that will benefit from an increase in intestinal function.

It will be appreciated that the present invention will also have application for treating intestinal disorders in subjects having immunologic disorders and immunodeficiency syndromes such as HIV and the like.

Claim 1 of 9 Claims

What is claimed is:

1. A method for increasing intestinal function comprising administering leptin in an amount effective to increase intestinal absorption of amino acids and sugars in a patient having inadequate amino acid and sugar absorption that results in malnutrition.




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