Formulation of amino acids and riboflavin useful to reduce toxic effects of cytotoxic chemotherapy

Abstract

Pharmaceutical compositions effective in alleviating or reducing the effects of fatigue and weakness associated with cancer and cytotoxic cancer chemotherapy are disclosed. The pharmaceutical compositions of the present invention comprise riboflavin, effectors of the urea cycle in free form or pharmacologically acceptable salts thereof, and amino acids selected from the groups of essential and non-essential amino acids, in free form or pharmaceutically acceptable salts thereof, suitably combined with appropriate carriers, diluents, or excipients. Also disclosed are methods of alleviating or reducing the effects of fatigue and weakness associated with cancer and cytotoxic cancer chemotherapy by administration of pharmaceutical compositions of the present invention.

What is claimed is:  
     
         1 . A method for alleviating or reducing the toxic, nutritional and metabolic disturbances associated with cancer and cancer chemotherapy comprising: administering to a patient a composition comprising an effective amount of riboflavin, an effector of the urea cycle, and the amino acids alanine, glycine, serine, taurine, threonine and valine.  
     
     
         2 . A method according to  claim 1  wherein the effector of the urea cycle is arginine, omithine or citrulline.  
     
     
         3 . The method of  claim 1  wherein the amino acids are in free form or pharmacologically acceptable salts.  
     
     
         4 . The method of  claim 1 , wherein the concentration of riboflavin is about 5 to about 300 mg/L.  
     
     
         5 . The method of  claim 1 , wherein the concentration of the effector of the urea cycle is about 2 to about 120 mg/L.  
     
     
         6 . The method of  claim 1 , wherein the concentration of alanine is about 1 to about 90 mg/L, the concentration of glycine is about 1 to about 75 mg/L, the concentration of serine is about 1 to about 75 mg/L, the concentration of taurine is about 0.5 to about 30 mg/L, the concentration of threonine is about 1 to about 90 mg/L and the concentration of valine is about 1 to about 50 mg/L.  
     
     
         7 . The method of  claim 1 , wherein said composition is administered enterally or parenterally.  
     
     
         8 . The method of  claim 1 , wherein composition is administered intravenously.  
     
     
         9 . The method of  claim 1 , wherein said composition further comprises at least one pharmaceutically-acceptable carrier, diluent, or excipient.  
     
     
         10 . The method of  claim 1 , wherein the composition consists of riboflavin, arginine, alanine, glycine, serine, taurine, threonine, valine and a pharmaceutically-acceptable carrier or diluent.  
     
     
         11 . The method of  claim 10 , wherein the concentration of riboflavin is about 5 to about 300 mg/L, the concentration of arginine is about 2 to about 120 mg/L, the concentration of alanine is about 1 to about 90 mg/L, the concentration of glycine is about 1 to about 75 mg/L, the concentration of serine is about 1 to about 75 mg/L, the concentration of taurine is about 0.5 to about 30 mg/L, the concentration of threonine is about 1 to about 90 mg/L and the concentration of valine is about 1 to about 50 mg/L.  
     
     
         12 . The method of  claim 1 , wherein the composition consists of riboflavin, ornithine, alanine, glycine, serine, taurine, threonine, valine and a pharmaceutically-acceptable carrier or diluent.  
     
     
         13 . The method of  claim 12 , wherein the concentration of riboflavin is about 5 to about 300 mg/L, the concentration of ornithine is about 2 to about 120 mg/L, the concentration of alanine is about 1 to about 90 mg/L, the concentration of glycine is about 1 to about 75 mg/L, the concentration of serine is about 1 to about 75 mg/L, the concentration of taurine is about 0.5 to about 30 mg/L, the concentration of threonine is about 1 to about 90 mg/L and the concentration of valine is about 1 to about 50 mg/L.  
     
     
         14 . A pharmaceutical composition for alleviating or reducing the toxic, nutritional and metabolic disturbances associated with cancer and cancer chemotherapy comprising: an effective amount of riboflavin, an effector of the urea cycle, and the amino acids alanine, glycine, serine, taurine, threonine, and valine.  
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the effector of the urea cycle is selected from arginine, omithine or citrulline, wherein the effector is in free form or a pharmacologically acceptable salt.  
     
     
         16 . The pharmaceutical composition of  claim 14  wherein the amino acids are in free form or pharmacologically acceptable salts.  
     
     
         17 . The pharmaceutical composition of  claim 14 , wherein the concentration of riboflavin is about 5 to about 300 mg/L.  
     
     
         18 . The pharmaceutical composition of  claim 14 , wherein the concentration of the effector of the urea cycle is about 2 to about 120 mg/L.  
     
     
         19 . The pharmaceutical composition of  claim 14 , wherein the concentration of alanine is about 1 to about 90 mg/L, the concentration of glycine is about 1 to about 75 mg/L, the concentration of serine is about 1 to about 75 mg/L, the concentration of taurine is about 0.5 to about 30 mg/L, the concentration of threonine is about 1 to about 90 mg/L and the concentration of valine is about 1 to about 50 mg/L.  
     
     
         20 . The pharmaceutical composition of  claim 14 , having a pH of about 6.0 to about 7.0.  
     
     
         21 . The pharmaceutical composition of  claim 14 , further comprising at least one pharmaceutically-acceptable carrier, diluent, or excipient.  
     
     
         22 . The pharmaceutical composition of  claim 14 , consisting of riboflavin, arginine, alanine, glycine, serine, taurine, threonine, valine and a pharmaceutically-acceptable carrier or diluent.  
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the concentration of riboflavin is about 5 to about 300 mg/L, the concentration of arginine is about 2 to about 120 mg/L, the concentration of alanine is about 1 to about 90 mg/L, the concentration of glycine is about 1 to about 75 mg/L, the concentration of serine is about 1 to about 75 mg/L, the concentration of taurine is about 0.5 to about 30 mg/L, the concentration of threonine is about 1 to about 90 mg/L and the concentration of valine is about 1 to about 50 mg/L.  
     
     
         24 . The pharmaceutical composition of  claim 14 , consisting of riboflavin, ornithine, alanine, glycine, serine, taurine, threonine, valine and a pharmaceutically-acceptable carrier or diluent.  
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the concentration of riboflavin is about 5 to about 300 mg/L, the concentration of omithine is about 2 to about 120 mg/L, the concentration of alanine is about 1 to about 90 mg/L, the concentration of glycine is about 1 to about 75 mg/L, the concentration of serine is about 1 to about 75 mg/L, the concentration of taurine is about 0.5 to about 30 mg/L, the concentration of threonine is about 1 to about 90 mg/L and the concentration of valine is about 1 to about 50 mg/L.  
     
     
         26 . A method for alleviating or reducing the toxic, nutritional and metabolic disturbances associated with cancer and cancer chemotherapy comprising: administering to a patient a composition comprising an effective amount of riboflavin, an effector of the urea cycle comprising arginine and omithine, and the amino acids alanine, glycine, serine, threonine and valine.  
     
     
         27 . The method of  claim 26 , wherein the composition further comprises 3-phenylacetylamino-2,6-piperidinedione.  
     
     
         28 . The method of  claim 26 , wherein the composition consists of 0.01-10 wt % riboflavin, 1-15 wt % arginine, and 1-15 wt % ornithine, 1-15 wt % alanine, 1-15 wt % glycine, 1-15 wt serine, 1-15 wt % threonine 1-15 wt % valine, and 25-75 wt % 3-phenylacetylamino-2,6-piperidinedione.  
     
     
         29 . A pharmaceutical composition for alleviating or reducing the toxic, nutritional and metabolic disturbances associated with cancer and cancer chemotherapy comprising: an effective amount of riboflavin, an effector of the urea cycle comprising arginine and omithine, and the amino acids alanine, glycine, serine, threonine and valine.  
     
     
         30 . The pharmaceutical composition of  claim 29 , further comprising 3-phenylacetylamino-2,6-piperidinedione.  
     
     
         31 . The pharmaceutical composition of  claim 29 , consisting of 0.01-10 % riboflavin, 1-15 % arginine, and 1-15 wt % ornithine, 1-15 wt % alanine, 1-15 wt % glycine, 1-15 wt % serine, 1-15 wt % threonine 1-15 wt % valine, and 25-75 wt % 3-phenylacetylamino-2,6-piperidinedione.