Mucolytic and anti-elastase compounds and methods of use thereof

Abstract

Disclosed are compositions and methods for decreasing the viscosity and/or cohesiveness of and/or increasing the liquefaction of excessively or abnormally viscous or cohesive mucus or sputum. Also disclosed are compositions and methods for inhibiting elastase in a patient. The compositions contains a compound containing a dithiol active-site in reduced state and optionally further contains a reducing system.

1 . A method to inhibit elastase in a patient that has a disease or condition associated with excessive elastase activity, comprising administering to the patient a composition comprising a compound containing a dithiol active-site in reduced state effective to reduce elastase levels and/or activity, as compared to prior to the step of contacting; 
 wherein the composition is administered in the absence of a protease inhibitor.    
     
     
         2 . The method of  claim 1 , wherein the composition is administered in the absence of a 1-antitrypsin.  
     
     
         3 . The method of  claim 1 , wherein the composition is administered in the absence of a requirement for elevated temperature conditions.  
     
     
         4 . The method of  claim 1 , wherein the step of contacting the patient with the composition is performed by introducing the composition to the patient by a route selected from the group consisting of nasal, intratracheal, bronchial, direct installation into the lung and inhaled.  
     
     
         5 . The method of  claim 1 , wherein the compound can be catalytically recycled to a reduced state after oxidation of the compound.  
     
     
         6 . The method of  claim 1 , wherein the compound is a non-protein dithiol that can be catalytically recycled to a reduced state after oxidation of the compound.  
     
     
         7 . The method of  claim 1 , wherein the compound is dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         8 . The method of  claim 1 , wherein the compound is orally administered α-lipoic acid, or a biologically active derivative thereof.  
     
     
         9 . The method of  claim 1 , wherein the compound is a protein or peptide having a thioredoxin active-site.  
     
     
         10 . The method of  claim 9 , wherein the thioredoxin active-site comprises the amino acid sequence C-X-X-C, wherein C residues are in reduced state, and wherein X residues are any amino acid residue.  
     
     
         11 . The method of  claim 9 , wherein the thioredoxin active-site comprises the amino acid sequence X-C-X-X-C-X, wherein C residues are in reduced state, and wherein X residues are any amino acid residue.  
     
     
         12 . The method of  claim 9 , wherein the thioredoxin active-site comprises the amino acid sequence X-C-G-P-C-X (SEQ ID NO:2), wherein C residues are in reduced state, and wherein X residues are any amino acid residue.  
     
     
         13 . The method of  claim 9 , wherein the thioredoxin active-site comprises the amino acid sequence W-C-G-P-C-K (SEQ ID NO:3), wherein C residues are in reduced state.  
     
     
         14 . The method of  claim 9 , wherein the protein is a thioredoxin selected from the group consisting of prokaryotic thioredoxin, yeast thioredoxin, plant thioredoxin, and mammalian thioredoxin.  
     
     
         15 . The method of  claim 9 , wherein the protein is human thioredoxin.  
     
     
         16 . The method of  claim 9 , wherein the protein is recombinant human thioredoxin.  
     
     
         17 . The method of  claim 16 , wherein the recombinant human thioredoxin is produced in a substantially reduced, monomeric state.  
     
     
         18 . The method of  claim 9 , wherein the composition further comprises nicotinamide-adenine dinucleotide phosphate (reduced form) (NADPH) for reducing the thioredoxin active site of the protein.  
     
     
         19 . The method of  claim 18 , wherein the composition further comprises thioredoxin reductase.  
     
     
         20 . The method of  claim 9 , wherein the composition further comprises dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         21 . The method of  claim 1 , wherein the patient has cystic fibrosis.  
     
     
         22 . The method of  claim 1 , wherein the patient has chronic obstructive pulmonary disease (COPD).  
     
     
         23 . The method of  claim 1 , wherein the composition is administered to the patient in a pharmaceutically acceptable carrier.  
     
     
         24 . The method of  claim 1 , wherein the compound is administered to the patient in an amount that is between about 1.5 mmoles/kg weight of the patient and about 150 mmoles/kg weight of the patient.  
     
     
         25 . The method of  claim 1 , wherein the compound has a half-life in the patient of between about 5 minutes and about 24 hours.  
     
     
         26 . The method of  claim 1 , further comprising administering DNase to the patient.  
     
     
         27 . The method of  claim 26 , wherein the DNase is administered prior to the compound.  
     
     
         28 . A method to increase the liquefaction of mucus or sputum in a patient that has excessively viscous or cohesive mucus or sputum, comprising contacting the mucus or sputum of the patient with a composition comprising a compound containing a dithiol active-site in reduced state effective to increase the liquefaction of the mucus or sputum as compared to prior to the step of contacting.  
     
     
         29 . The method of  claim 28 , wherein the patient has a lung disease in which abnormal or excessive viscosity or cohesiveness of mucus or sputum is a symptom or cause of the disease.  
     
     
         30 . The method of  claim 28 , wherein the step of contacting the mucus or sputum of the patient with the composition is performed by introducing the composition to the patient by a route selected from the group consisting of oral, nasal, intratracheal, bronchial, direct installation into the lung and inhaled.  
     
     
         31 . The method of  claim 28 , wherein the mucus or sputum to be contacted is located in the respiratory tract, the gastrointestinal tract or the reproductive tract of the patient.  
     
     
         32 . The method of  claim 28 , wherein a liquid phase of a total volume of a sample of mucus or sputum from the patient shows a statistically significant increase after administration of the composition.  
     
     
         33 . The method of  claim 28 , wherein the compound is a non-protein dithiol that can be catalytically recycled to a reduced state after oxidation of the compound.  
     
     
         34 . The method of  claim 28 , wherein the compound is dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         35 . The method of  claim 28 , wherein the compound is orally administered α-lipoic acid, or a biologically active derivative thereof.  
     
     
         36 . The method of  claim 28 , wherein the protein is recombinant human thioredoxin.  
     
     
         37 . The method of  claim 36 , wherein the recombinant human thioredoxin is produced in a substantially reduced, monomeric state.  
     
     
         38 . The method of  claim 36 , wherein the composition further comprises dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         39 . The method of  claim 28 , further comprising administering an additional mucolytic compound to the patient.  
     
     
         40 . The method of  claim 39 , wherein the additional mucolytic compound is a DNase.  
     
     
         41 . The method of  claim 39 , wherein the additional mucolytic compound is administered prior to the compound containing a dithiol active-site in reduced state.  
     
     
         42 . A composition for use in the inhibition of elastase in a patient, consisting essentially of a compound comprising a dithiol active-site in reduced state and at least one additional agent for treatment of a disease or condition associated with excessive elastase activity, wherein the compound can be catalytically recycled to a reduced state after oxidation of the compound, and wherein the composition does not comprise a protease inhibitor.  
     
     
         43 . The composition of  claim 42 , wherein the compound is dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         44 . The composition of  claim 42 , wherein the compound is a protein or peptide comprising a thioredoxin active-site in reduced form.  
     
     
         45 . The composition of  claim 44 , wherein the thioredoxin active-site comprises the amino acid sequence X-C-X-X-C-X, wherein C residues are in reduced state, and wherein the X residues are any amino acid residue.  
     
     
         46 . The composition of  claim 44 , wherein the thioredoxin active-site comprises the amino acid sequence X-C-G-P-C-X (SEQ ID NO:2), wherein C residues are in reduced state, and wherein the X residues are any amino acid residue.  
     
     
         47 . The composition of  claim 44 , wherein the thioredoxin active-site comprises the amino acid sequence W-C-G-P-C-K (SEQ ID NO:3), wherein C residues are in reduced state.  
     
     
         48 . The composition of  claim 44 , wherein the protein is thioredoxin selected from a group consisting of prokaryotic thioredoxin, yeast thioredoxin, plant thioredoxin, and mammalian thioredoxin.  
     
     
         49 . The composition of  claim 44 , wherein the protein comprises human thioredoxin.  
     
     
         50 . The composition of  claim 44 , wherein the protein is recombinant human thioredoxin.  
     
     
         51 . The composition of  claim 50 , wherein the recombinant human thioredoxin is produced in a substantially reduced, monomeric state.  
     
     
         52 . The composition of  claim 44 , wherein the composition further comprises nicotinamide-adenine dinucleotide phosphate (reduced form) (NADPH).  
     
     
         53 . The composition of  claim 52 , wherein the composition further comprises thioredoxin reductase.  
     
     
         54 . The composition of  claim 44 , wherein the composition further comprises dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         55 . The composition of  claim 42 , wherein the composition further comprises a compound to catalytically reduce the compound comprising a dithiol active-site after the compound comprising the dithiol active-site has been oxidized.  
     
     
         56 . The composition of  claim 42 , wherein the additional agent is formulated separately for administration prior to the administration of the compound comprising a dithiol active-site.  
     
     
         57 . A composition for the inhibition of elastase in a patient, comprising α-lipoic acid, wherein the composition is formulated for oral delivery.  
     
     
         58 . The composition of  claim 57 , wherein the composition further comprises at least one additional agent for treatment of a disease or condition associated with excessive elastase activity.  
     
     
         59 . A composition for use in the liquefaction of mucus or sputum, comprising a compound comprising a dithiol active-site in reduced state and at least one additional agent for treatment of excessively viscous or cohesive mucus or sputum, wherein the compound can be catalytically recycled to a reduced state after oxidation of the compound.  
     
     
         60 . The composition of  claim 59 , wherein the compound is a non-protein dithiol that can be catalytically recycled to a reduced state after oxidation of the compound.  
     
     
         61 . The composition of  claim 59 , wherein the compound is dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         62 . The composition of  claim 59 , wherein the protein is recombinant human thioredoxin.  
     
     
         63 . The composition of  claim 62 , wherein the recombinant human thioredoxin is produced in a substantially reduced, monomeric state.  
     
     
         64 . The composition of  claim 62 , wherein the composition further comprises dihydrolipoic acid or a biologically active derivative thereof.  
     
     
         65 . A composition for use in the liquefaction of mucus or sputum, comprising α-lipoic acid and at least one additional agent for treatment of excessively viscous or cohesive mucus or sputum, wherein the composition is formulated for oral delivery.  
     
     
         66 . A method to increase the liquefaction of mucus or sputum in a patient that has excessively viscous or cohesive mucus or sputum, comprising contacting the mucus or sputum in the respiratory tract of the patient with a composition comprising dihydrolipoic acid or a biologically active derivative thereof, wherein the contact of composition increases the volume of the liquid phase in a sample of mucus or sputum from the patient as compared to prior to contact with the composition.