Treatment of portal hypertension and restoration of liver function using l-ornithine phenylacetate

Abstract

Disclosed herein are methods of treating and/or preventing portal hypertension and/or restoring liver function using L-ornithine phenylacetate.

1 . A method of treating a condition in a subject, comprising administering to the subject L-ornithine in combination with at least one of phenylacetate and phenylbutyrate, thereby relieving the condition, wherein the condition is portal hypertension, variceal bleeding, or ascites. 
     
     
         2 . The method of  claim 1 , wherein the subject is suffering from liver disease. 
     
     
         3 . The method of  claim 2 , wherein the liver disease is a chronic liver disease or an acute liver failure. 
     
     
         4 . The method of  claim 3 , wherein the chronic liver disease is cirrhosis. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the treatment of the condition is achieved by reducing the level of proinflammatory cytokines or increasing endothelial nitric oxide synthase activity in the subject. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein said L-ornithine and phenylacetate is administered as L-ornithine phenyl acetate. 
     
     
         9 . The method of  claim 1 , wherein separate physiologically acceptable salts of said L-ornithine and at least one of phenylacetate and phenylbutyrate are administered to the subject. 
     
     
         10 . The method of  claim 1 , wherein said L-ornithine is present administered as a free monomeric amino acid or physiologically acceptable salt thereof. 
     
     
         11 . The method of  claim 1 , wherein at least one of phenylacetate and phenylbutyrate is administered as a sodium phenylacetate or sodium phenylbutyrate. 
     
     
         12 . The method of  claim 1 , wherein said administration is oral, intravenous, intraperitoneal, intragastric, or intravascular administration. 
     
     
         13 . The method of  claim 12 , wherein said administration is intravenous administration. 
     
     
         14 . The method of  claim 12 , wherein said administration is oral administration. 
     
     
         15 . The method of  claim 1 , wherein the dose of the L-ornithine and the phenylacetate or phenylbutyrate administered is between 20 g and 40 g. 
     
     
         16 . A method of delaying or reducing the likelihood of onset of portal hypertension in a subject, comprising administering to the subject L-ornithine in combination with at least one of phenylacetate and phenylbutyrate, thereby delaying or reducing the likelihood of onset of portal hypertension. 
     
     
         17 . The method of  claim 16 , wherein the subject is suffering from liver disease. 
     
     
         18 . The method of  claim 17 , wherein the liver disease is a chronic liver disease or an acute liver failure. 
     
     
         19 . The method of  claim 18 , wherein the chronic liver disease is cirrhosis. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 16 , wherein the delay or reduction in the likelihood of onset of portal hypertension is achieved by reducing the level of proinflammatory cytokines or increasing endothelial nitric oxide synthase activity in the subject. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 16 , wherein said L-ornithine and phenylacetate is administered as L-ornithine phenyl acetate. 
     
     
         24 . The method of  claim 16 , wherein separate physiologically acceptable salts of said L-ornithine and at least one of phenylacetate and phenylbutyrate are administered to the subject. 
     
     
         25 . The method of  claim 16 , wherein said L-ornithine is administered as a free monomeric amino acid or physiologically acceptable salt thereof. 
     
     
         26 . The method of  claim 16 , wherein at least one of phenylacetate and phenylbutyrate is administered as a sodium phenylacetate or sodium phenylbutyrate. 
     
     
         27 . The method of  claim 16 , wherein said administration is oral, intravenous, intraperitoneal, intragastric, or intravascular administration. 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 16 , wherein the dose of the L-ornithine and the phenylacetate or phenylbutyrate administered is between 20 g and 40 g. 
     
     
         31 . A method of restoring liver function in a subject having poor liver function, comprising administering to the subject L-ornithine in combination with at least one of phenylacetate and phenylbutyrate to said subject and thereby improving liver function. 
     
     
         32 . The method of  claim 31 , wherein the subject is suffering from portal hypertension. 
     
     
         33 . The method of  claim 32 , wherein improving liver function reduces the portal hypertension. 
     
     
         34 . The method of  claim 31 , wherein improving liver function comprises increasing liver perfusion. 
     
     
         35 . The method of  claim 31 , wherein said restoration of liver function is achieved by reducing the level of proinflammatory cytokines or increasing endothelial nitric oxide synthase activity in the subject. 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 31 , wherein said L-ornithine and phenylacetate is administered as L-ornithine phenyl acetate. 
     
     
         38 . The method of  claim 31 , wherein separate physiologically acceptable salts of said L-ornithine and at least one of phenylacetate and phenylbutyrate are administered to the subject. 
     
     
         39 . The method of  claim 31 , wherein said L-ornithine is present administered as a free monomeric amino acid or physiologically acceptable salt thereof. 
     
     
         40 . The method of  claim 31 , wherein at least one of phenylacetate and phenylbutyrate is administered as a sodium phenylacetate or sodium phenylbutyrate. 
     
     
         41 . The method of  claim 31 , wherein said administration is oral, intravenous, intraperitoneal, intragastric, or intravascular administration. 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 31 , wherein the dose of the L-ornithine and the phenylacetate or phenylbutyrate administered is between 20 g and 40 g. 
     
     
         45 .- 66 . (canceled) 
     
     
         67 . A method of protecting against brain injury in a patient with acute liver failure or acute liver decompensation, the method comprising:
 identifying a patient as suffering from acute liver failure or acute liver decompensation; and   administering to the patient L-ornithine in combination with at least one of phenylacetate and phenylbutyrate, thereby reducing the likelihood that the patient will develop brain injury.   
     
     
         68 . The method of  claim 67 , wherein said administering occurs immediately after said identifying. 
     
     
         69 . The method of  claim 67 , further comprising treating the acute liver failure or acute liver decompensation. 
     
     
         70 . The method of  claim 69 , wherein said treating comprises liver transplantation. 
     
     
         71 . The method of  claim 67 , further comprising treating a complication caused by the acute liver failure or acute liver decompensation. 
     
     
         72 . The method of  claim 71 , wherein said complication comprises variceal bleeding. 
     
     
         73 . The method of  claim 67 , wherein the dose of the L-ornithine and the phenylacetate or phenylbutyrate administered is between 20 g and 40 g.