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Title:  Intraperitoneal administration of adenosine for the treatment of prevention of gastrointestinal of systemic diseases

United States Patent:  6,566,371

Issued:  May 20, 2003

Inventors:  Jackson; Edwin K. (Pittsburgh, PA)

Assignee:  University of Pittsburgh (Pittsburgh, PA)

Appl. No.:  844255

Filed:  April 30, 2001

Abstract

A method for preventing or treating gastrointestinal or systemic diseases in a mammalian subject, comprising: the step of administering a therapeutically effective amount of a composition comprising adenosine or a prodrug thereof into the peritoneal cavity of said subject at a dose that does not achieve pharmacologically active levels in the aortic arterial plasma of said subject.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the present invention to provide a method of peritoneal lavage with adenosine which provides therapeutically effective levels of adenosine in the intestines of a subject without substantially elevating adenosine levels in the systemic circulation of the subject.

Another object of the present invention is to provide a method of peritoneal lavage with an adenosine-releasing "prodrug", i.e., a compound metabolized to adenosine, to provide pharmacological levels of adenosine in the intestines of a subject without elevating adenosine levels in the systemic circulation of the subject.

Still another object of the present invention is to provide a method of peritoneal lavage with adenosine -5'-monophosphate ("AMP"), an adenosine-releasing prodrug, to provide pharmacological levels of adenosine in the intestines of a subject without elevating adenosine levels in the systemic circulation of the subject.

Another object of the present invention is to provide a method of intraperitoneal administration of adenosine which confers therapeutic benefits, both locally and systemically, in a subject such as improved renal function, improved metabolic status, and improved survival in hemorrhagic shock.

These and other objects of the of the present invention are achieved by one or more of the following embodiments.

In one aspect, the invention features a method for preventing or treating gastrointestinal or systemic diseases in a mammalian subject, comprising:

the step of administering a therapeutically effective amount of a composition comprising adenosine or a prodrug thereof into the peritoneal cavity of the subject at a dose that does not achieve pharmacologically active levels in the aortic arterial plasma of the subject.

In preferred embodiments the phosphate ester of adenosine is selected from the group consisting of adenosine-5'-monophosphate, adenosine-5'-diphosphate, adenosine-5'-triphosphate, and adenosine 3':5'-cyclic monophosphate.

In another aspect, the invention features a pharmaceutical composition for treating gastrointestinal or inflammatory diseases in a mammalian subject, wherein the composition comprises adenosine or a prodrug thereof and a pharmaceutically acceptable carrier, and wherein the composition is administered into the peritoneal cavity of the subject at a therapeutically effective dose that does not achieve pharmacologically active levels in the aortic arterial plasma of the subject.

In yet another preferred embodiment, the phosphate ester of adenosine is selected from the group consisting of adenosine-5'-monophosphate, adenosine-5'-diphosphate, adenosine-5'-triphosphate, and adenosine 3':5'-cyclic monophosphate.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiment, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term "peritoneal lavage" means placement of a solution into the peritoneal cavity of a subject. Peritoneal lavage may be carried out once, continuously, or intermittently, in accordance with the present invention.

"Mesenteric blood flow" refers to the volume of blood per unit time passing through the mesenteric artery.

"Mean arterial blood pressure" is the average (arithmetic mean) arterial blood pressure over a defined period of time.

A "prodrug of adenosine" means a compound that is metabolized or converted to adenosine such as, for example, adenosine-5'-monophosphate ("AMP"), adenosine-5'-diphosphate, adenosine-5'-triphosphate, and adenosine 3':5'-cyclic monophosphate.

"Pharmacologically active" refers to the level of adenosine that activates adenosine receptors in a subject.

"Splanchnic circulation" refers to circulation to the abdominal viscera of a subject.

Methods and Results

According to the present invention methods are provided for the treatment of diseases of the gastrointestinal tract as well as many systemic diseases. Specifically provided are methods for administering adenosine or a prodrug thereof to treat or prevent gastrointestinal or systemic diseases. According to the present invention, the adverse effects of adenosine that result from systemic administration (intravenous or intraarterial administration) are circumvented by administering adenosine or a prodrug thereof via single application or intermittent or continuous peritoneal lavage which induce beneficial effects on the intestines of a subject. This approach can achieve pharmacologically active levels of adenosine in the intestinal wall of a mammalian or human without producing significant levels of adenosine in the systemic circulation of the subject. However, there was a possibility that the metabolic barrier to adenosine absorption by the gastrointestinal tract, i.e., intestinal adenosine deaminase (see, Geiger, J. D., et al., Adenosine and Adenine Nucleotides as Regulators of Cellular Function, Phillis, J. W., Ed. CRC Press (1991), the disclosure of which is incorporated herein by reference), would be so effective in limiting the bioavailability of peritoneally administered adenosine that active levels of adenosine in the gastrointestinal tract could only be achieved with concentrations of adenosine in the peritoneal cavity so high that absorption at other sites in the peritoneal cavity would result in overwhelming systemic levels of adenosine. It was found that according to the present invention, however, that adenosine when administered to a subject by peritoneal lavage dilates the splanchnic circulation and increases adenosine levels in the mesenteric vein, without affecting systemic hemodynamics or increasing adenosine levels in the arterial circulation. The present invention therefore establishes that therapeutically effective levels of adenosine can be achieved in the peritoneal cavity in a subject without attaining pharmacologically active levels in the subject's systemic circulation.

The methods of the present invention are illustrated in more detail below. In one study, rats received an intramesenteric artery infusion of angiotensin II (30 .mu.g/min) plus methoxamine (3 .mu.g/min) to reduce mesenteric blood flow by approximately 60%, and adenosine solutions were instilled into the abdominal cavity. In a second study, microdialysis probes were placed in the mesenteric vein and aortic arch of rats, and the peritoneal cavity was continuously ravaged with adenosine or AMP solutions. In a third study, rats were subjected to hemorrhagic shock (2.75 ml of blood removed per 100 grams of body weight over a 15 minute period) for two hours, followed by volume resuscitation for one hour and observation for 72 hours. Rats received peritoneal lavage with adenosine or vehicle (0.9% saline) beginning 20 minutes after blood withdrawal and continuing through the one hour resuscitation period.

As will be seen, peritoneal lavage with adenosine normalized mesenteric blood flow (p<0.05) without affecting blood pressure or heart rate. Peritoneal administration of adenosine or AMP induced micromolar levels of adenosine and inosine in the mesenteric vein (p<0.05), without affecting adenosine or inosine levels in the aorta. Peritoneal lavage with adenosine increased survival in hemorrhagic shock (9 of 10 animals in the group treated with intraperitoneal adenosine survived for 72 hours, whereas only 4 of 10 animals in the group treated with vehicle survived for 72 hours; p<0.05). In rats subjected to hemorrhagic shock, intraperitoneal administration of adenosine significantly (p<0.05) improved metabolic parameters (reduced elevated plasma potassium and plasma lactate and increased arterial plasma pH) and improved renal function (reduced elevated blood urea nitrogen levels, an index of glomerular filtration rate). Therefore, according to the present invention, peritoneal lavage with adenosine or one of its prodrugs, AMP, provides pharmacological levels of adenosine in the gastrointestinal tract without systemic side effects. Peritoneal lavage with adenosine improves survival, metabolic status and renal function in hemorrhagic shock.

Peritoneal lavage with adenosine or adenosine prodrugs according to the present invention is useful for the treatment of a number of gastrointestinal and systemic diseases without the adverse effects associated with systemic administration of such drugs. Because adenosine increases gastrointestinal blood flow, peritoneal lavage with adenosine is useful to treat or prevent gastrointestinal diseases associated with inadequate blood flow to the intestines. Examples of such diseases are occlusion of mesenteric arterial or venous blood vessels caused by, for example, thrombosis or embolism of the mesenteric arteries or veins, atherosclerosis of the mesenteric arterial blood vessels, necrotizing enterocolitis, intestinal transplantation, traumatic injury to the intestines, or intestinal hypoperfusion due to hemorrhagic shock. Because adenosine is an antiinflammatory substance, peritoneal lavage with adenosine is useful to treat or prevent gastrointestinal diseases associated with inflammation of the bowel. Examples of such diseases include Crohn's disease, ulcerative colitis and reperfusion of the bowel following bowel ischemia for any reason and necrotizing enterocolitis. Because adenosine inhibits the proliferation of fibroblasts and the production of collagen by fibroblasts, peritoneal lavage with adenosine is useful to treat or prevent the formation of adhesions in the peritoneal cavity following abdominal surgery. Because adenosine inhibits the activity of various cells in the blood including platelets and neutrophils and because these blood cells circulate to the intestines, peritoneal lavage with adenosine is useful to treat or prevent systemic diseases in which activation of blood cells, particularly platelets and neutrophils, participate in the pathophysiology of the systemic disease. In this regard, adenosine in the intestinal circulation inhibits blood cells as they pass through the intestinal vasculature. Even though the adenosine is removed from the intestinal circulation as the blood draining the intestines passes through the intestines, liver and lungs, the inhibited blood cells remains inhibited for a period of time. Examples of diseases treatable or preventable by inhibiting blood cells with peritoneal adenosine include hemorrhagic shock, myocardial infarction and stroke.

Although this invention in its preferred embodiments is primarily addressed to use in humans, veterinary use is also anticipated and is encompassed by the present invention. In this regard, adenosine or a prodrug thereof may be administered intraperitoneally to dogs, cats, horses, cattle and sheep for gastrointestinal diseases such as, for example, preventing the formation of adhesions in the peritoneal cavity following surgery.

Adenosine or a prodrug thereof may be admixed with any pharmaceutically acceptable carrier or carriers, such as water, saline, physiological salt solutions, Ringer's solution, or any other carrier customarily used for intraperitoneal administration to the subject in question.

In that the method of the present invention involves administration of adenosine or a prodrug thereof intraperitoneally, the drug may be subject to destruction by adenosine deaminase or other enzymes. Therefore adenosine or a prodrug thereof accordingly must be administered in a larger concentration so that the amount is sufficient to achieve the desired therapeutic effect. The optimal therapeutic concentration of adenosine or adenosine prodrug in the peritoneal lavage solution will vary from species to species, individual to individual, and prodrug to prodrug depending on such factors as rate of uptake and metabolism of adenosine. For example, the rate of adenosine uptake is much higher in humans compared with rat red blood cells (Van Belle, H., Biochim. Biophys. Acta 192:124 (1969) and Jarvis, S. M., et al., Biochem. J. 208:83 (1982), the disclosures of which are incorporated herein by reference), and this may necessitate the use of even higher concentrations of adenosine or adenosine prodrugs in the peritoneal lavage solution to produce pharmacologically active concentrations of adenosine in the intestinal circulation in humans. On the other hand, some individuals may require less adenosine to deliver therapeutic amounts to the intestinal circulation and some prodrugs may be more or less efficient than adenosine in delivering appropriate amounts of adenosine to the intestinal circulation. It is within the skill of those in the art to determine the appropriate concentration of adenosine or prodrug thereof to be instilled into the peritoneal cavity of a subject.

Claim 1 of 7 Claims

I claim:

1. A method for preventing or treating gastrointestinal or systemic diseases in a mammalian subject, comprising:

the step of administering a therapeutically effective amount of a composition comprising adenosine or a prodrug thereof into the peritoneal cavity of said subject at a dose that does not achieve pharmacologically active levels in the aortic arterial plasma of said subject.
 


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