Use of S-Nitrosothiol Signaling to Treat Disordered Control of Breathing

Abstract

The present invention is directed to a method of treating disordered control of breathing including the treatment of apnea and hypoventilation associated with congenital or acquired brain stem abnormalities. Specifically the invention is directed to treating disordered control of breathing by administering an S-nitrosylating agent selected from the group consisting of ethyl nitrite, glutathione, nitric oxide, S-nitrosocysteine, S-nitrosoglutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine and S-nitroso-N-acetyl cysteine. As shown in FIG. 1 C the ability of endogenous SNOs to increase V E in freely behaving, conscious rats using whole-body plethysmography revealed that CSNO, GSNO and CGSNO (1 nmol each) caused equivalent increases in V E , whereas D-CSNO had no effect (left bar graph is the control whereas the right bar represents administration of the respective SNO).

1 - 13 . (canceled) 
   
   
       14 . A method of treating disordered control of breathing, said method comprising the step of administering to an individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide. 
   
   
       15 . The method of  claim 14 , wherein the S-nitrosylating agent is administered parenterally. 
   
   
       16 . The method of  claim 14 , wherein the S-nitrosylating agent is administered intravenously. 
   
   
       17 . The method of  claim 14 , wherein the S-nitrosylating agent is administered subcutaneously. 
   
   
       18 . The method of  claim 14 , wherein the S-nitrosylating agent is administered intramuscularly. 
   
   
       19 . The method of  claim 14 , wherein the S-nitrosylating agent is administered transdermally. 
   
   
       20 . The method of  claim 14 , wherein the S-nitrosylating agent is administered by inhalation. 
   
   
       21 . The method of  claim 14 , wherein the S-nitrosylating agent is administered orally. 
   
   
       22 . The method of  claim 14 , wherein said disordered control of breathing is at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       23 . The method of  claim 14 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       24 . The method of  claim 14 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       25 . The method of  claim 14 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       26 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and wherein the S-nitrosylating agent is administered parenterally. 
   
   
       27 . The method of  claim 26 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       28 . The method of  claim 26 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       29 . The method of  claim 26 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       30 . The method of  claim 26 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       31 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and wherein the S-nitrosylating agent is administered intravenously. 
   
   
       32 . The method of  claim 31 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       33 . The method of  claim 31 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       34 . The method of  claim 31 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       35 . The method of  claim 31 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       36 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and wherein the S-nitrosylating agent is administered subcutaneously. 
   
   
       37 . The method of  claim 36 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       38 . The method of  claim 36 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       39 . The method of  claim 36 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       40 . The method of  claim 36 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       41 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and wherein the S-nitrosylating agent is administered intramuscularly. 
   
   
       42 . The method of  claim 41 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       43 . The method of  claim 41 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       44 . The method of  claim 41 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       45 . The method of  claim 41 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       46 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and wherein the S-nitrosylating agent is administered transdermally. 
   
   
       47 . The method of  claim 46 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       48 . The method of  claim 46 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       49 . The method of  claim 46 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       50 . The method of  claim 46 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       51 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is at least one of the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, and nitric oxide; and wherein the S-nitrosylating agent is administered by inhalation. 
   
   
       52 . The method of  claim 51 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       53 . The method of  claim 51 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       54 . The method of  claim 51 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       55 . The method of  claim 51 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       56 . A method of increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said method comprising the step of administering to said individual a composition comprising an S-nitrosylating agent, wherein the S-nitrosylating agent is at least one of the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine; and wherein the S-nitrosylating agent is administered orally. 
   
   
       57 . The method of  claim 56 , wherein said individual has at least one condition selected from the group consisting of: apnea, central apnea, obstructive sleep apnea, hypoventilation, central hypoventilation, congenital central hypoventilation syndrome, impaired control of peripheral respiratory drive, impending respiratory failure, impending respiratory failure, respiratory fatigue complicating obstructive lung disease, impaired respiratory drive, impaired respiratory drive associated with chronic obstructive pulmonary disease, impaired respiratory drive associated with emphysema, impaired respiratory drive associated with chronic bronchitis, impaired respiratory drive associated with cystic fibrosis, and impaired respiratory drive associated with a-1 antitrypsin deficiency. 
   
   
       58 . The method of  claim 56 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable carrier. 
   
   
       59 . The method of  claim 56 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable dilutent. 
   
   
       60 . The method of  claim 56 , wherein the S-nitrosylating agent is formulated with at least one pharmaceutically acceptable solubilizing agent. 
   
   
       61 . A kit for treating disordered control of breathing, said kit comprising an S-nitrosylating agent selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and reagents for detecting and monitoring the in vivo concentration of S-nitrosothiols; and instructional materials for use. 
   
   
       62 . A kit for increasing minute ventilation (V E ) at the level of the brainstem respiratory control centers in the nucleus tractus solitarius of an individual, said kit comprising an S-nitrosylating agent selected from the group consisting of ethyl nitrite, glutathione, S-nitroso-L-cysteinyl glycine, N-acetyl cysteine, S-nitroso-N-acetyl cysteine, and nitric oxide; and reagents for detecting and monitoring the in vivo concentration of S-nitrosothiols; and instructional materials for use.