Cardiac glycosides to treat cystic fibrosis and other il-8 dependent disorders

Abstract

A method of inhibiting the secretion of IL-8 and other pro-inflammatory cytokines from cells secreting elevated levels of these compounds is provided. The method includes contacting the cell with a composition comprising a cardiac glycoside such as oleandrin. The cardiac glycoside can be used to treat cystic fibrosis and other IL-8 dependent disorders by lowering levels of spontaneously secreted IL-8 and other pro-inflammatory cytokines. Oleandrin was found to suppress the secretion of IL-8 from cultured CF lung epithelial cells in the nanomolar concentration range. Structure-activity relationships (SARs) for cardiac glycosides are also elucidated.

1 . A method of inhibiting or reducing the secretion of IL-8 from a cell secreting elevated levels of IL-8, the method comprising contacting the cell with a composition comprising a cardiac glycoside.  
   
   
       2 . The method of  claim 1 , wherein the cell is a CF lung epithelial cell.  
   
   
       3 . The method of  claim 1 , wherein the cardiac glycoside is selected from the group consisting of oleandrin, digitoxin, digoxin, ouabain, digoxigenen, digitoxigenen, and acetyl-stropanthidin.  
   
   
       4 . The method of  claim 1 , wherein the cardiac glycoside is oleandrin.  
   
   
       5 . The method of  claim 1 , wherein the cardiac glycoside is digitoxin.  
   
   
       6 . The method of  claim 1 , wherein the cardiac glycoside is digoxin.  
   
   
       7 . A method of treating disease conditions characterized by elevated levels of IL-8, the method comprising administering to a mammal suffering from the disease a composition comprising an effective amount of a cardiac glycoside.  
   
   
       8 . The method of  claim 7 , wherein the mammal is a human.  
   
   
       9 . The method of  claim 8 , wherein the elevated levels of IL-8 result from a condition selected from the group consisting of: cardiopulmonary bypass surgery; cardiopulmonary arrest; inflammatory bowel disease; lung disorders and lung conditions; traumatic brain injury; stroke; cerebral reperfusion injury; diabetes; transplant graft rejection; Alzheimer's disease; Parkinson's disease; HIV; viral infections; cancer; fevers; psoriasis; arthritis; Sjogren's syndrome; Behcet's disease; glomerulonephritis; and cystic fibrosis.  
   
   
       10 . (canceled)  
   
   
       11 . A method of treating conditions characterized by elevated levels of IL-8 in a human suffering from cystic fibrosis, the method comprising administering to the human an effective amount of a composition comprising a cardiac glycoside.  
   
   
       12 . The method of  claim 11 , wherein the composition further comprises a pharmaceutically acceptable carrier.  
   
   
       13 . The method of  claim 9 , wherein the lung disorders and lung conditions comprise asthma, noneosinophilic asthma, non-specific airway hyper-responsiveness, chronic pulmonary obstructive disease, nosocomial pneumonia, endotoxemia-induced acute respiratory distress syndrome or related conditions.  
   
   
       14 . The method of  claim 9 , wherein the condition is diabetes or a related condition.  
   
   
       15 . The method of  claim 9 , wherein the HIV condition comprises AIDS, HIV-1 associated dementia, or related conditions.  
   
   
       16 . The method of  claim 9 , wherein the condition is cancer or a related condition.  
   
   
       17 . The method of  claim 7 , wherein the composition is immobilized in a biocompatible, biodegradable substance.  
   
   
       18 . The method of  claim 7 , wherein the composition further comprises a pharmaceutically acceptable carrier.  
   
   
       19 . The method of  claim 7 , wherein the composition is formulated for oral, transdermal, or aerosol administration, or for administration by injection.  
   
   
       20 . The method of  claim 19 , wherein the composition is formulated as an elixer, a powder, a tablet, a capsule, an acid stable capsule, a gargle, a soluble solution for intravenous or subdermal injection, as nose drops, nasal spray, a salve, a solution for transdermal administration, a patch, a suppository, ear drops or eye drops.  
   
   
       21 . The method of  claim 7 , wherein the composition is formulated for instant release.  
   
   
       22 . The method of  claim 7 , wherein the composition is formulated for controlled release.