Combination therapy to treat urea cycle disorders

Abstract

Embodiments of the disclosure include certain formulations for methods of treating urea cycle disorders. The methods encompass compositions that comprise benzoate and phenylbutyrate that may be at certain doses and have certain ratios of the components. The benzoate and phenylbutyrate may act synergistically in treatment of the urea cycle disorders, in particular embodiments.

What is claimed is: 
     
         1 . A method of treating an individual for one or more urea cycle disorders, comprising:
 administering a therapeutically effective amount of sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate,   wherein, the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate are each administered at no more than 200 mg/kg/day.   
     
     
         2 . The method of  claim 1 , wherein the urea cycle disorder encompasses one or more of the following diseases:
 N-acetylglutamate synthase deficiency (NAGS deficiency),   Carbamoyl-phosphate synthase 1 deficiency (CPS1 deficiency),   Ornithine transcarbamylase deficiency (OTC deficiency),   Ornithine translocase (ORNT1) deficiency,   Citrullinemia type I (ASS1 deficiency),   Argininosuccinic aciduria (ASL deficiency),   Arginase deficiency (hyperargininemia, ARG1 deficiency), and/or Citrin deficiency.   
     
     
         3 . The method of  claim 1  or  2 , wherein the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate is administered to the individual orally. 
     
     
         4 . The method of  claim 1 ,  2 , or  3 , wherein the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate are administered to the individual daily, weekly, multiple times in a week, bi-weekly, or monthly. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate are administered to the individual with or without food and/or drink. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the sodium benzoate is administered in a dosage of 20-200 mg/kg/day. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the sodium phenylbutyrate or glycerol phenylbutyrate is administered in a dosage of 20-200 mg/kg/day. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the amount of sodium phenylbutyrate or glycerol phenylbutyrate administered is greater on a mole:mole basis than the amount of sodium benzoate administered. 
     
     
         9 . The method of any one of  claims 1 - 8 , wherein the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate is administered as a single composition comprising both sodium benzoate and sodium phenylbutyrate. 
     
     
         10 . The method of any one of  claims 1 - 8 , wherein the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate are administered as separate compositions. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein the ratio of sodium phenylbutyrate or glycerol phenylbutyrate to sodium benzoate in the composition is 1:1 or greater on a mole:mole basis. 
     
     
         12 . The method of any one of  claims 1 - 10 , wherein the amount of sodium phenylbutyrate or glycerol phenylbutyrate administered is less on a mole:mole basis than the amount of sodium benzoate administered. 
     
     
         13 . The method of any one of  claims 1 - 10 , wherein the ratio of sodium phenylbutyrate or glycerol phenylbutyrate to sodium benzoate in the composition is 1:1 or less on a mole:mole basis. 
     
     
         14 . A method of treating an individual with a medical disorder or drug side effect associated with nitrogen retention, comprising:
 administering a therapeutically effective amount of sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate,   wherein, the sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate are each administered at no more than 200 mg/kg/day.   
     
     
         15 . The method of  claim 14 , wherein the disorder in the individual comprises hepatic encephalopathy (HE), metabolic disorders, vascular bypass of the liver, biliary atresia, and/or acute liver failure. 
     
     
         16 . The method of  claim 15 , wherein the metabolic disorder in the individual comprises hepatic disorders. 
     
     
         17 . The method of  claim 14 , wherein the drug associated with nitrogen retention in the individual is valproic acid, cyclophosphamide, and/or 5-pentanoic acid. 
     
     
         18 . The method of  claim 1  or  14 , wherein the individual is treated with an additional drug or therapy. 
     
     
         19 . The method of  claim 18 , wherein the additional drug comprises PAA precursors, supplementation of a deficient amino acid, carbamyl glutamate, and/or arginine hydrochloride. 
     
     
         20 . The method of  claim 19 , wherein the deficient amino acid is arginine, and/or citrulline. 
     
     
         21 . The method of  claim 18 , wherein the therapy comprises pump-driven extra corporeal membrane oxygenation (ECMO) hemodialysis, intermittent hemofiltration, intermittent hemodialysis, continuous renal replacement therapy, and/or peritoneal dialysis. 
     
     
         22 . The method of  claim 1  or  14 , wherein the disorder in the individual is identified by family history, physical examination, biochemical assay, and/or molecular genetic testing. 
     
     
         23 . The method of  claim 22 , wherein the biochemical assay comprises plasma ammonia concentration determination, quantitative plasma amino acid analysis, urinary orotic acid concentration determination, and/or urine amino acid analysis. 
     
     
         24 . The method of  claim 23 , wherein the quantitative plasma amino acid analysis is of citrulline, arginine, and/or ornithine. 
     
     
         25 . The method of  claim 22 , wherein the genetic testing comprises serial single-gene testing, a multi-gene panel, exome sequencing and/or genome sequencing. 
     
     
         26 . A method of treating an individual for one or more urea cycle disorders, comprising:
 administering a therapeutically effective amount of sodium benzoate and sodium phenylbutyrate,   wherein, the sodium benzoate and sodium phenylbutyrate are each administered at no more than 400 mg/kg/day.   
     
     
         27 . A composition comprising sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate. 
     
     
         28 . The composition of  claim 27 , wherein the amount of sodium benzoate and sodium phenylbutyrate or glycerol phenylbutyrate is each at least 2 g. 
     
     
         29 . The composition of  claim 27  or  28 , wherein the composition is a solid, liquid, or gel. 
     
     
         30 . The composition of  claim 27 ,  28 , or  29 , wherein the composition is in the form of a solution, suspension, emulsion, tablet, pill, capsule, film, sustained release formulation, buccal composition, troche, elixir, syrup, wafer, or combination thereof. 
     
     
         31 . The composition of any one of  claims 27 - 30 , wherein the ratio of sodium phenylbutyrate or glycerol phenylbutyrate to sodium benzoate in the composition is 1:1 or greater on a mole:mole basis. 
     
     
         32 . The composition of any one of  claims 27 - 30 , wherein the ratio of sodium phenylbutyrate or glycerol phenylbutyrate to sodium benzoate in the composition is 1:1 or less on a mole:mole basis. 
     
     
         33 . A kit, comprising the composition of any one of  claims 27 - 32 . 
     
     
         34 . A kit comprising (a) a composition comprising sodim phenylbutyrate or glycerol phenylbutyrate and (b) a composition comprising sodium benzoate.