Treating asthma by preventing and/or accomodating for S-nitrosothiol breakdown

Abstract

Asthma is ameliorated, and mild or moderate asthma is prevented from progressing to more severe asthma by administering agents which prevent and/or accommodate for S-nitrosothiol breakdown. The method reduces requirements for systemic corticosteroids for the treatment of severe asthma.

What is claimed is:  
     
         1 . A method for treating a patient with asthma to ameliorate symptoms thereof comprising administering to said patient (a) a therapeutically effective amount of an inhibitor of S-nitrosothiol breakdown except for aurothioglucose, gold sodium thiomalate and Auranofin or (b) therapeutically effective amounts of an NO donor and of an inhibitor of S-nitrosothiol breakdown, or (c) a therapeutically effective amount of an NO donor which is itself an S-nitrosothiol or which generates an S-nitrosothiol in vivo which is resistant to breakdown by catalysts which cause S-nitrosothiol breakdown.  
     
     
         2 . The method of  claim 1 , wherein administration is of a therapeutically effective amount of an inhibitor of S-nitrosothiol breakdown.  
     
     
         3 . The method of  claim 2 , wherein the inhibitor of S-nitrosothiol breakdown is an inhibitor of gamma-glutamyltranspeptidase.  
     
     
         4 . The method of  claim 3 , wherein the inhibitor of gamma-glutamyltranspeptidase is selected from the group consisting of L-gamma-glutamyl-(o-carboxy)phenylhydrazide, D-gamma-glutamyl-(o-carboxy)phenylhydrazide, acivicin and the combination of L-serine and borate.  
     
     
         5 . The method of  claim 2 , wherein the inhibitor of S-nitrosothiol breakdown is an inhibitor of xanthine oxidase.  
     
     
         6 . The method of  claim 2 , wherein the inhibitor of S-nitrosothiol breakdown is a chelator of copper and/or heme or non-heme iron.  
     
     
         7 . The method of  claim 1 , wherein the inhibitor of S-nitrosothiol breakdown is an inhibitor of an enzyme or a non-enzymatic protein containing a thiol group and/or selenothiol group, which inhibitor is not a gold-containing compound.  
     
     
         8 . The method of  claim 1 , wherein administration is of therapeutically effective amounts of an NO donor and of an inhibitor of S-nitrosothiol breakdown.  
     
     
         9 . The method of  claim 8 , wherein the NO donor is an S-nitrosothiol which is subject to breakdown by catalysts which cause S-nitrosothiol breakdown in asthma.  
     
     
         10 . The method of  claim 9 , wherein the S-nitrosothiol has a molecular weight less than 150.  
     
     
         11 . The method of  claim 8 , wherein the inhibitor of S-nitrosothiol breakdown is selected from the group consisting of inhibitors of gamma-glutamyl transpeptidase, inhibitors of xanthine oxidase, chelators of copper and/or heme iron, and inhibitors of enzymes and non-enzymatic proteins containing thiol groups and/or selenothiol groups.  
     
     
         12 . The method of  claim 11 , wherein the inhibitors of enzymes and non-enzymatic proteins containing thiol groups and/or selenothiol groups are selected from the group consisting of aurothioglucose, gold sodium thiomalate, and (1-thio-beta-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold.  
     
     
         13 . The method of  claim 1 , wherein administration is of a therapeutically effective amount of an NO donor which is itself an S-nitrosothiol or which generates an S-nitrosothiol in vivo which is resistant to breakdown by catalysts which cause S-nitrosothiol breakdown.  
     
     
         14 . The method of  claim 13 , wherein the NO donor is an NO x  derivative of an asthma drug selected from the group consisting of β 2 -adrenergic agonists, cromolyn, theophylline and atrovent, where x ranges from 1 to 2.  
     
     
         15 . The method of  claim 14 , wherein the NO donor is an S-nitrosothiol derivative of an asthma drug selected from the group consisting of β 2 -adrenergic agonists, cromolyn, theophylline and atrovent.  
     
     
         16 . The method of  claim 1  which is for treating a patient with severe asthma which additionally comprises administering systemic corticosteroid in a dosage of 10 to 80% of that utilized without the administration of (a), (b) or (c).  
     
     
         17 . A method for treating patients with mild or moderate asthma to inhibit progression to more severe asthma comprising administering to said patient (a) a therapeutically effective amount of an inhibitor of S-nitrosothiol breakdown except for aurothioglucose, gold sodium thiomalate and Auranofin or (b) therapeutically effective amounts of an NO donor and of an inhibitor of S-nitrosothiol breakdown or (c) a therapeutically effective amount of an NO donor which is itself an S-nitrosothiol or which generates S-nitrosothiol in vivo which is resistant to breakdown by catalysts which cause S-nitrosothiol breakdown.  
     
     
         18 . The method of  claim 17 , wherein administration is of a therapeutically effective amount of an inhibitor of S-nitrosothiol breakdown.  
     
     
         19 . The method of  claim 18 , wherein the inhibitor of S-nitrosothiol breakdown is an inhibitor of gamma-glutamyltranspeptidase.  
     
     
         20 . The method of  claim 19 , wherein the inhibitor of gamma-glutamyltranspeptidase is selected from the group consisting of L-gamma-glutamyl-(o-carboxy)phenylhydrazide, D-gamma-glutamyl-(o-carboxy)phenylhydrazide, acivicin, and the combination of L-serine and borate.  
     
     
         21 . The method of  claim 18 , wherein the inhibitor of S-nitrosothiol bereakdown is an inhibitor of xanthine oxidase.  
     
     
         22 . The method of  claim 18 , wherein the inhibitor of S-nitrosothiol breakdown is a chelator of copper and/or heme or non-heme iron.  
     
     
         23 . The method of  claim 18 , wherein the inhibitor of S-nitrosothiol breakdown is an inhibitor of an enzyme or a non-enzymatic protein containing a thiol group or a selenothiol group, which inhibitor is not a gold containing compound.  
     
     
         24 . The method of  claim 17 , wherein administration is of therapeutically effective amounts of an NO donor and of an inhibitor of S-nitrosothiol breakdown.  
     
     
         25 . The method of  claim 24 , wherein the NO donor is an S-nitrosothiol which is subject to breakdown by catalysts which cause S-nitrosothiol breakdown in asthma.  
     
     
         26 . The method of  claim 25 , wherein the inhibitor of S-nitrosothiol breakdown is selected from the group consisting of inhibitors of gamma-glutamyl transpeptidase, inhibitors of xanthine oxidase, chelators of copper and/or heme iron, and inhibitors of enzymes and non-enzymatic proteins containing thiol groups and/or selenothiol groups.  
     
     
         27 . The method of  claim 26 , wherein the inhibitor of enzymes and non-enzymatic proteins containing thiol groups and/or selenothiol groups is selected from the group consisting of aurothioglucose, gold sodium thiomalate and (1-thio-beta-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold.  
     
     
         28 . The method of  claim 17 , wherein administration is of a therapeutically effective amount of an NO donor which is itself an S-nitrosothiol or which generates an S-nitrosothiol in vivo which is resistant to breakdown by catalysts which cause S-nitrosothiol breakdown.  
     
     
         29 . The method of  claim 28 , wherein the NO donor is an NO x  derivative of an asthma drug selected from the group consisting of β 2 -adrenergic agonists, cromolyn, theophylline and atrovent, where x ranges from 1 to 2.  
     
     
         30 . The method of  claim 29 , wherein the NO donor is an S-nitrosothiol derivative of an asthma drug selected from the group consisting of β 2 -adrenergic agonists, cromolyn, theophylline and atrovent.