Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis

Abstract

Pyrimidine nucleotide precursors including acyl derivatives of cytidine, uridine, and orotate, and uridine phosphorylase inhibitors, and their use in enhancing resistance to sepsis or systemic inflammation are disclosed.

What is claimed is:  
     
         1 . A method for treating or preventing tissue damage due to systemic inflammatory response syndrome comprising administering to an animal a therapeutically effective amount of a pyrimidine nucleotide precursor.  
     
     
         2 . A method for treating or preventing sepsis comprising administering to an animal a therapeutically effective amount of a pyrimidine nucleotide precursor.  
     
     
         3 . A method as in  claim 2  wherein said pyrimidine nucleotide precursor is uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . A method as in  claim 3  wherein said acyl derivative of uridine is triacetyluridine.  
     
     
         5 . A method as in  claim 2  further comprising administering an inhibitor of uridine phosphorylase.  
     
     
         6 . A method for treating or preventing sepsis comprising administering to an animal a therapeutically effective amount of an inhibitor of uridine phosphorylase.  
     
     
         7 . A method for reducing toxicity of a therapeutic cytokine or inflammatory stimulus comprising administering to an animal a therapeutically effective amount of a pyrimidine nucleotide precursor prior to, during, or after administration of said cytokine or said stimulus.  
     
     
         8 . A method as in  claim 7  wherein said pyrimidine nucleotide precursor is uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A method as in  claim 8  wherein said acyl derivative of uridine is triacetyluridine.  
     
     
         10 . A method as in  claim 7  wherein said cytokine or said stimulus is selected from the group consisting of interleukin 1, interleukin-2, interleukin 6, tumor necrosis factor, endotoxin, fungal polysaccharides, and double-stranded RNA.  
     
     
         11 . A method as in  claim 7  further comprising the step of administering an inhibitor of uridine phosphorylase.  
     
     
         12 . A method for reducing toxicity of a therapeutic cytokine or inflammatory stimulus comprising administering to an animal a therapeutically effective amount of an inhibitor of uridine phosphorylase prior to, during, or after administering said cytokine or said stimulus.  
     
     
         13 . A method as in  claim 12  wherein said cytokine or said stimulus is selected from the group consisting of interleukin 1, interleukin-2, interleukin 6, tumor necrosis factor, endotoxin, fungal polysaccharides, and double-stranded RNA.  
     
     
         14 . A method for treating cancer comprising administering to an animal a therapeutically effective amount of a therapeutic cytokine or inflammatory stimulus and a therapeutically effective amount of a pyrimidine nucleotide precursor prior to, during, or after administration of said cytokine or said stimulus.  
     
     
         15 . A method as in  claim 14  wherein said pyrimidine nucleotide precursor is uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         16 . A method as in  claim 15  wherein said acyl derivative of uridine is triacetyluridine.  
     
     
         17 . A method as in  claim 14  wherein said cytokine or said stimulus is selected from the group consisting of interleukin 1, interleukin-2, interleukin 6, tumor necrosis factor, endotoxin, fungal polysaccharides, and double-stranded RNA.  
     
     
         18 . A method as in  claim 14  further comprising the step of administering an inhibitor of uridine phosphorylase.  
     
     
         19 . A method for treating cancer comprising administering to an animal a therapeutically effective amount of a therapeutic cytokine or inflammatory stimulus and a therapeutically effective amount of an inhibitor of uridine phosphorylase prior to, during, or after administering said cytokine or said stimulus.  
     
     
         20 . A method as in  claim 19  wherein said cytokine or said stimulus is selected from the group consisting of interleukin 1, interleukin-2, interleukin 6, tumor necrosis factor, endotoxin, fungal polysaccharides, and double-stranded RNA.  
     
     
         21 . A method for treating or preventing inflammatory hepatitis comprising administering to an animal a therapeutically effective amount of an acyl derivative of uridine, cytidine or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         22 . A method as in  claim 21  wherein said inflammatory hepatitis is due to viral infection.  
     
     
         23 . A method as in  claim 21  wherein said inflammatory hepatitis is due to autoimmune processes.  
     
     
         24 . A method as in  claim 21  wherein said inflammatory hepatitis is due to alcohol consumption.  
     
     
         25 . A method as in  claim 21  wherein said acyl derivative of uridine is triacetyluridine.  
     
     
         26 . A method as in  claim 21  including the further step of administering an inhibitor of uridine phosphorylase.  
     
     
         27 . A method for treating or preventing inflammatory hepatitis comprising administering to an animal a therapeutically effective amount of an inhibitor of uridine phosphorylase.  
     
     
         28 . A method for treating or preventing inflammatory hepatitis comprising administering to an animal a therapeutically effective amount of uridine or cytidine.  
     
     
         29 . A method as in  claim 28  wherein from 2 to 40 grams of uridine or cytidine are administered per day.  
     
     
         30 . A method for treating or preventing hepatic damage in an animal receiving parenteral nutrition comprising administering intravenously to said animal a therapeutically effective amount of a pyrimidine nucleotide precursor.  
     
     
         31 . A method as in  claim 30  wherein said hepatic damage is due to said animal receiving parenteral nutrition.  
     
     
         32 . A method as in  claim 30  wherein said pyrimidine nucleotide precursor is uridine; cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         33 . A method as in  claim 30  wherein from 2 to 40 grams of said pyrimidine nucleotide precursor are administered per day.  
     
     
         34 . A method as in  claim 30  including the further step of administering an inhibitor of uridine phosphorylase.  
     
     
         35 . A method for treating or preventing hepatic damage in an animal receiving total parenteral nutrition comprising administering to said animal an inhibitor of uridine phosphorylase.  
     
     
         36 . A method for treating or preventing hepatic damage in an animal receiving a liver transplant comprising administering to said animal a therapeutically effective amount of a pyrimidine nucleotide precursor.  
     
     
         37 . A method as in  claim 36  wherein said pyrimidine nucleotide precursor is uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         38 . A method as in  claim 36  wherein from 2 to 40 grams of said pyrimidine nucleotide precursor are administered per day.  
     
     
         39 . A method as in  claim 36  including the further step of administering an inhibitor of uridine phosphorylase.  
     
     
         40 . A method for treating or preventing hepatic damage in an animal receiving a liver transplant comprising administering to said animal an inhibitor of uridine phosphorylase.  
     
     
         41 . A composition comprising: 
 a) an acyl derivative of a pyrimidine nucleotide precursor and;    b) an inhibitor of uridine phosphorylase    
     
     
         42 . A composition comprising: 
 a) an acyl derivative of a pyrimidine nucleotide precursor and;    b) a purine nucleotide precursor.    
     
     
         43 . A composition as in  claim 42  where said pyrimidine nucleotide precursor is uridine, cytidine, or orotate.  
     
     
         44 . A composition as in  claim 42  where said purine nucleotide precursor is inosine, adenosine, or an acyl derivative of inosine or adenosine.  
     
     
         45 . A composition comprising a parenteral nutrition formula and 2 to 40 grams of a pyrimidine nucleotide precursor per daily portion  
     
     
         46 . A composition as in  claim 45  wherein said pyrimidine nucleotide precursor is uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine; or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         47 . A method of providing nutrition to a mammal receiving nutrition intravenously comprising administering to said mammal the composition of  claim 45 .  
     
     
         48 . A composition comprising 
 a) glucose, and    b) a pyrimidine nucleotide precursor.    
     
     
         49 . A composition as in  claim 48  wherein said composition is an aqueous solution containing 1 to 10% glucose.  
     
     
         50 . A composition as in  claim 48  wherein said composition is an aqueous solution containing 5% glucose.  
     
     
         51 . A composition as in  claim 48  wherein said pyrimidine nucleotide precursor is uridine or cytidine.  
     
     
         52 . A method of treating a mammal during or after liver transplantation comprising administering the composition of  claim 48 .  
     
     
         53 . A method for reducing the effects of ethanol intoxication comprising administering to a mammal in need of such treatment uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         54 . A method of treating ethanol intoxication comprising administering to an intoxicated mammal uridine, cytidine, orotic acid, or an acyl derivative of uridine, cytidine, or orotic acid, or a pharmaceutically acceptable salt thereof.  
     
     
         55 . A method as in  claim 54  wherein said administering step comprises administering triacetyluridine.  
     
     
         56 . A method as in  claim 54  wherein said administering step comprises administering uridine or cytidine.  
     
     
         57 . A method of reducing inflammatory liver injury in an animal in need of such treatment comprising administering to said animal a therapeutically effective amount of an acyl derivative of uridine, cytidine or orotic acid, or a pharmaceutically acceptable salt thereof.