Compositions and methods for the treatment of anorectal disorders

Abstract

Compositions and methods for the treatment of anorectal disorders are provided in which certain combinations of NO donors, PDE inhibitors, superoxide (O 2 − ) scavengers, β-adrenergic agonists, cAMP-dependent protein kinase activators, α 1 -adrenergic antagonists, L-type Ca 2+ channel blockers, estrogens, ATP-sensitive K + channel activators and smooth muscle relaxants are used.

What is claimed is:  
     
         1 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising a NO donor in admixture with a second agent selected from the group consisting of phosphodiesterase type II inhibitors, phosphodiesterase type IV inhibitors, phosphodiesterase type V inhibitors, nonspecific phosphodiesterase inhibitors, superoxide scavengers, β-adrenergic agonists, cAMP-dependent protein kinase activators, α 1 -adrenergic antagonists, estrogens, ATP-sensitive K +  channel activators and smooth muscle relaxants, with a pharmaceutically acceptable carrier.  
     
     
         2 . A composition in accordance with    claim 1   , wherein said NO donor is selected from the group consisting of nitroglycerin, L-arginine, SNAP − , GSNO and SIN-1, and said second agent is a superoxide scavenger selected from the group consisting of superoxide dismutase and chemical superoxide dismutase mimetics.  
     
     
         3 . A composition in accordance with    claim 1   , wherein said carrier is formulated for local application.  
     
     
         4 . A composition in accordance with    claim 1   , wherein said second agent is selected from the group consisting of phosphodiesterase type II inhibitors phosphodiesterase type IV inhibitors, phosphodiesterase type V inhibitors, and nonspecific phosphodiesterase inhibitors.  
     
     
         5 . A composition in accordance with    claim 1   , wherein said second agent is selected from the group consisting of β-adrenergic agonists.  
     
     
         6 . A composition in accordance with    claim 5   , wherein said β-adrenergic agonist is selected from the group consisting of β 2 -adrenergic agonists and β 3 -adrenergic agonists.  
     
     
         7 . A composition in accordance with    claim 1   , wherein said second agent is selected from the group consisting of ATP-sensitive K +  channel activators.  
     
     
         8 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising a phosphodiesterase inhibitor and a pharmaceutically acceptable carrier.  
     
     
         9 . A composition in accordance with    claim 8   , wherein said phosphodiesterase inhibitor is selected from the group consisting of phosphodiesterase type II inhibitors, phosphodiesterase type IV inhibitors, phosphodiesterase type V inhibitors, and nonspecific phosphodiesterase inhibitors.  
     
     
         10 . A composition in accordance with    claim 9   , further comprising an agent selected from the group consisting of β-adrenergic agonists, cAMP-dependent protein kinase activators, α 1 -adrenergic antagonists, L-type Ca 2+  channel blockers, estrogens, ATP-sensitive K +  channel activators and smooth muscle relaxants.  
     
     
         11 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising a β-adrenergic agonist and a pharmaceutically acceptable carrier.  
     
     
         12 . A composition in accordance with    claim 11   , wherein said β-adrenergic agonist is specific for a receptor isoform selected from the group consisting of β 2 , β 3  and combinations thereof.  
     
     
         13 . A composition in accordance with    claim 11   , wherein said β-adrenergic agonist is isoproterenol.  
     
     
         14 . A composition in accordance with    claim 11   , further comprising an agent selected from the group consisting of cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors, α 1 -adrenergic antagonists, estrogens, L-type Ca 2+  channel blockers, ATP-sensitive K +  channel activators and smooth muscle relaxants.  
     
     
         15 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising an ATP-sensitive K +  channel activator and a pharmaceutically acceptable carrier.  
     
     
         16 . A composition in accordance with    claim 15   , further comprising an agent selected from the group consisting of cAMP-dependent protein kinase activators, estrogens, α 1 -adrenergic antagonists, L-type Ca 2+  channel blockers and smooth muscle relaxants.  
     
     
         17 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising an α 1 -adrenergic antagonist and a pharmaceutically acceptable carrier.  
     
     
         18 . A composition in accordance with    claim 17   , said composition further comprising an agent selected from the group consisting of cAMP-hydrolyzing phosphodiesterase inhibitors, estrogens and smooth muscle relaxants.  
     
     
         19 . A composition in accordance with    claim 17   , wherein said cAMP-hydrolyzing phosphodiesterase inhibitor is a phosphodiesterase type IV inhibitor.  
     
     
         20 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith said composition comprising a cAMP-dependent protein kinase activator and an L-type Ca 2+  channel blocker.  
     
     
         21 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising a cGMP-dependent protein kinase activator and a pharmaceutically acceptable carrier.  
     
     
         22 . A composition for the treatment of an anorectal disorder, and for controlling the pain associated therewith, said composition comprising a nonspecific cyclic nucleotide-dependent protein kinase activator, optionally in admixture with a smooth muscle relaxant.  
     
     
         23 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amounts of a NO donor and a second agent selected from the group consisting of phosphodiesterase type II inhibitors, phosphodiesterase type IV inhibitors, phosphodiesterase type V inhibitors, nonspecific phosphodiesterase inhibitors, superoxide scavengers, β-adrenergic agonists, cAMP-dependent protein kinase activators, α 1 -adrenergic antagonists, estrogens, L-type Ca 2+  channel blockers, ATP-sensitive K +  channel activators and smooth muscle relaxants.  
     
     
         24 . A method in accordance with    claim 23   , wherein said NO donor and said second agent are administered in combination.  
     
     
         25 . A method in accordance with    claim 23   , wherein said second agent is administered prior to said NO donor.  
     
     
         26 . A method in accordance with    claim 23   , wherein said anorectal disorder is an anal fissure.  
     
     
         27 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a phosphodiesterase inhibitor.  
     
     
         28 . A method in accordance with    claim 27   , further comprising administering to said subject a second agent selected from the group consisting of β-adrenergic agonists, cAMP-dependent protein kinase activators, α 1 -adrenergic antagonists, estrogens, L-type Ca 2+  channel blockers, ATP-sensitive K +  channel activators and smooth muscle relaxants.  
     
     
         29 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a β-adrenergic agonist.  
     
     
         30 . A method in accordance with    claim 29   , further comprising administering to said subject a second agent selected from the group consisting of cAMP-dependent protein kinase activators, α 1 -adrenergic antagonists, estrogens, L-type Ca 2+  channel blockers, ATP-sensitive K +  channel activators and smooth muscle relaxants.  
     
     
         31 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising an ATP-sensitive potassium channel opener and an agent that promotes cAMP-mediated anal sphincter relaxation.  
     
     
         32 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a potassium channel opener, wherein said therapeutically effective amount decreases hypertonicity of an anal sphincter muscle of the subject.  
     
     
         33 . A method of treating an anorectal disorder, and for controlling the pain associated therewith, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and an agent which increases a level of cyclic guanidine monophosphate or cyclic adenosine monophosphate in a tissue of an anal sphincter muscle of the subject, thereby decreasing hypertonicity of the anal sphincter muscle of the subject.