Methods for treatment of thiol-containing compound deficient conditions

Abstract

Methods for therapy of cystic fibrosis and other conditions are provided. The methods comprise one or more agents capable of increasing thiol-containing compound transport via a transporter system (i.e. ABC transporters such as MDR-1 or MRP-2) in cells. Other embodiments include the use of agents to modulate transport of thiol-containing compounds within the cell. Therapeutic methods involve the administration of such agents to a patient afflicted with cystic fibrosis and/or another condition responsive to stimulation of thiol-containing compound transport.

1 . A method comprising: 
 contacting one or more cells with an agent to increase transport of at least one thiol-containing compound; and    modulating secretion of thiol-containing compound(s) from the cell (s).    
     
     
         2 . The method of  claim 1 , wherein modulating the secretion of thiol-containing compounds comprises increasing the excretion of thiol-containing compounds from the cell(s).  
     
     
         3 . The method of  claim 1 , wherein the agent activates a thiol-containing compound transporter system localized on the apical surface of the cell(s).  
     
     
         4 . The method of  claim 3 , wherein the transporter system comprises an ABC(ATP-binding cassette) transporter.  
     
     
         5 . The method of  claim 4 , the ABC transporter comprises at least one transporter selected from the group consisting of an MRP-2 (multi-drug resistance-associated protein) transporter; an MRP-1 (multi-drug resistance-associated protein) transporter; an MDR-1 (multi-drug resistance) transporter and cystic fibrosis transmembrane conductance regulator (CFTR).  
     
     
         6 . The method of  claim 1 , wherein the cell comprises a lung cell.  
     
     
         7 . The method of  claim 6 , further comprising replenishing thiol-containing compounds in the lung epithelial lining fluid (ELF).  
     
     
         8 . The method of  claim 1 , wherein the agent comprises a gene vector encoding a thiol-containing compound transporter.  
     
     
         9 . The method of  claim 1 , wherein the agent comprises a protein.  
     
     
         10 . The method of  claim 1 , wherein the agent comprises a thiol-containing compound transporter gene promoter.  
     
     
         11 . A method comprising, 
 contacting one or more cells with a composition comprising at least one molecule selected from the group consisting of a flavone, a flavanone, a isoflavone, a flavanol, a benzoic acid derivative, an indole derivative, a 1,4-Naphthoquinone, a 3-Phenylcoumarin, a 2-phenyl-4-quinoline, a 1-thioflavone, and a thioflavin; and    increasing the secretion of thiol-containing compound(s) from the cell.    
     
     
         12 . The method of  claim 11 , wherein the composition comprises at least one molecule selected from the group consisting of sulfasalzine, 2-chloro-3-morphilino-1,4-Naphthoquinone, 4-methyl-3-phenylcoumarin, methyl-2-phenyl-4-quinolonecarbonylate, 2-phenylthiochromen-flavone, thioflavin T (basic yellow  1 ), daidzein and ebselen.  
     
     
         13 . The method of  claim 12 , wherein the composition comprises sulfasalzine or a modified sulfasalazine or a sulfasalazine analog.  
     
     
         14 . A method comprising, 
 contacting one or more cells with at least one of a composition comprising a steroid; and    increasing the secretion of thiol-containing compound(s) from the cell.    
     
     
         15 . The method of  claim 14 , wherein the steroid is dexamethasone or a modified dexamethasone or a dexamethasone analog.  
     
     
         16 . A method comprising, 
 contacting one or more cells with a composition comprising at least one naturally occurring alkaloid; and    increasing the secretion of thiol-containing compound(s) from the cell(s).    
     
     
         17 . The method of  claim 16 , wherein the naturally occurring alkaloid composition is berberine or a modified berberine or a berberine analog.  
     
     
         18 . The method of  claim 16 , wherein the naturally occurring alkaloid composition is hydrazine or a modified hydrazine or a hydrazine analog.  
     
     
         19 . A method comprising; 
 identifying a subject with a deficiency of a thiol-containing compounds; and    contacting one or more cells of said subject with an agent to increase transport of thiol-containing compounds; and    modulating secretion of thiol-containing compound(s) from the cell (s).    
     
     
         20 . The method of  claim 19 , wherein the deficiency comprises a lung disease.  
     
     
         21 . The method of  claim 20 , wherein the lung disease comprises at least one disease selected from the group consisting of cystic fibrosis, asthma, emphysema, chronic obstructive lung disease, infant respiratory distress syndrome, interstitial lung disease or adult respiratory distress syndrome, Adult respiratory distress syndrome (ARDS), sepsis, and  Bronchopulmonary dysplasia  (BPD).  
     
     
         22 . The method of  claim 21 , wherein the lung disease comprises cystic fibrosis.  
     
     
         23 . The method of  claim 19 , wherein the thiol-containing compound deficiency comprises a pancreatic disease.  
     
     
         24 . The method of  claim 19 , wherein the thiol-containing compound deficiency comprises a bowel disorder.  
     
     
         25 . The method of  claim 24 , wherein the bowel-disorder comprises at least one disease selected from the group consisting of Crohn's disease, Colitis and inflammatory bowel disease (IBD).  
     
     
         26 . The method of  claim 19 , wherein the deficiency is caused by an infection.  
     
     
         27 . The method of  claim 26 , wherein the infection comprises a bacterial or a viral infection.  
     
     
         28 . The method of  claim 26 , wherein the infection comprises an infection in the lung.  
     
     
         29 . The method of  claim 19 , wherein the deficiency comprises at least one disease selected from the group consisting of a vascular disease, a neurodegenerative disease, a biliary disease, and an inflammatory disease.  
     
     
         30 . The method of  claim 19 , wherein the deficiency contributes to male infertility.  
     
     
         31 . The method of  claim 19 , wherein the agent is administered by at least one route selected from the group consisting of intranasally, intratracheally, by inhalation, intravenously, intraperitoneally, subcutaneously, intradermally, intranodally, intramuscularly, orally, rectally, intravaginally, and topically.  
     
     
         32 . The method of  claim 31 , wherein the agent is administered orally or by inhalation.  
     
     
         33 . The method of  claim 19 , wherein the agent is administered in a pharmaceutically acceptable delivery vehicle.  
     
     
         34 . The method of  claim 19 , wherein the thiol-containing compound transporter is an ABC transporter.  
     
     
         35 . The method of  claim 19 , wherein the cell is a lung cell.  
     
     
         36 . The method of  claim 19 , wherein the agent comprises one or more molecules selected from the group consisting of a flavone, flavanone, isoflavone, flavanol, benzoic acid derivative, indole derivative, 1,4-Naphthoquinone, 3-Phenylcoumarin, 2-phenyl-4-quinoline, 1-thioflavone, and thioflavin.  
     
     
         37 . The method of  claim 19 , wherein the agent comprises a gene encoding an ABC transporter.  
     
     
         38 . The method of  claim 19 , wherein the agent comprises an ABC transporter protein.  
     
     
         39 . A system for identifying thiol-containing compound transporter modulators comprising; 
 one or more cells;    a potential thiol-containing compound transporter modulating agent; and    a thiol-containing compound measuring device.    
     
     
         40 . The system of  claim 39 , further comprising an adherence filter.  
     
     
         41 . The system of  claim 40 , wherein said device measures excretion of thiol-containing compounds from the apical surface of the one or more cells.  
     
     
         42 . The system of  claim 39 , wherein the cell comprises a lung carcinoma cell line.  
     
     
         43 . The system of  claim 39 , wherein the cell is contained in a whole animal.  
     
     
         44 . The system of  claim 40 , further comprising the lung of a whole animal.  
     
     
         45 . The system of  claim 37 , wherein the thiol-containing compound measuring device comprises an HPLC (High Performance Liquid Chromatography).  
     
     
         46 . A kit comprising: 
 a delivery lumen;    at least one agent, delivered from the delivery lumen,    the at least one agent comprising a compound capable of increasing transport of thiol-containing compounds    
     
     
         47 . The kit of  claim 46 , wherein the delivery lumen further comprises a delivery lumen of an inhalant device.  
     
     
         48 . The kit of  claim 46 , wherein the agent comprises sulfasalazine.  
     
     
         49 . A composition comprising: 
 a delivery vehicle; and    a compound capable of modulating the transport of thiol-containing compounds.    
     
     
         50 . The composition of  claim 49 , wherein the delivery vehicle comprises a bioerodible particle.  
     
     
         51 . The composition of  claim 49 , wherein the compound comprises a naturally occurring alkaloid.  
     
     
         52 . A method comprising: 
 contacting one or more cells with an agent to increase transport of at least one thiol-containing compound; and    modulating transport of thiol-containing compound(s) in the cell (s).    
     
     
         53 . The method of  claim 52 , wherein modulating incorporation further comprises modulating transport of thiol-containing compound(s) in a compartment within the cell (s).  
     
     
         54 . The method of  claim 53 , wherein the compartment within the cell(s) is the mitochondria.