Methods of Use of Inhibitors of Phosphodiesterases and Modulators of Nitric Oxide, Reactive Oxygen Species, and Metalloproteinases in the Treatment of Peyronie's Disease, Arteriosclerosis and Other Fibrotic Diseases

Abstract

The present methods and compositions are of use for treatment of conditions involving fibrosis, such as Peyronie's disease plaque, penile corporal fibrosis, penile veno-occlusive dysfunction, Dupuytren's disease nodules, vaginal fibrosis, clitoral fibrosis, female sexual arousal disorder, abnormal wound healing, keloid formation, general fibrosis of the kidney, bladder, prostate, skin, liver, lung, heart, intestines or any other localized or generalized fibrotic condition, vascular fibrosis, arterial intima hyperplasia, atherosclerosis, arteriosclerosis, restenosis, cardiac hypertrophy, hypertension or any condition characterized by excessive fibroblast or smooth muscle cell proliferation or deposition of collagen and extracellular matrix in the blood vessels and/or heart. In certain embodiments, the compositions may comprise a PDE-4 inhibitor, a PDE-5 inhibitor, a compound that elevates cGMP and/or PKG, a stimulator of guanylyl cyclase and/or PKG, a combination of a compound that elevates cGMP, PKG or NO with an antioxidant that decreases ROS, or a compound that increases MMP activity.

1 . A method of treating a condition involving penile tissue fibrosis comprising administering an amount of a cyclic guanosine 3′,5′-monophosphate (cGMP) type 5 phosphodiesterase (PDE 5) inhibitor according to a continuous, long term regimen to an individual having a penile tissue fibrosis involving at least one of tunical fibrosis, Peyronie's disease, corporal fibrosis or corporal veno-occlusive dysfunction. 
     
     
         2 . The method of  claim 1 , wherein the PDE 5 inhibitor comprises one of sildenafil, tadalafil and vardenafil. 
     
     
         3 . A treatment method comprising:
 administering to an individual an amount of a cyclic guanosine 3′,5′-monophosphate (cGMP) type 5 phosphodiesterase (PDE 5) inhibitor according to a continuous long-term regimen effective to arrest, regress or prevent a penile tissue fibrosis.   
     
     
         4 . The method of  claim 3 , wherein the continuous long-term regimen comprises not less than 45 days. 
     
     
         5 . The method of  claim 4 , wherein the PDE-5 inhibitor is administered at a dosage of up to 1.5 mg/kg/day. 
     
     
         6 . The method of  claim 3 , wherein the penile tissue fibrosis is at least one of tunical fibrosis and Peyronie's disease. 
     
     
         7 . The method of  claim 3 , wherein the penile tissue fibrosis comprises corporal tissue fibrosis. 
     
     
         8 . The method of  claim 3 , wherein the penile tissue fibrosis manifests in corporal veno-occlusive dysfunction. 
     
     
         9 . The method of  claim 3 , wherein the penile tissue fibrosis is at least one of tunical fibrosis or Peyronie's disease, and the method further comprising administering a metalloproteinase or a metalloproteinase activator. 
     
     
         10 . A method of treating a penile tissue fibrosis in a human comprising administering to a human having an erectile dysfunction an amount of tadalafil effective to arrest or regress penile tissue fibrosis wherein said amount is up to 1.5 mg/kg/day and wherein said administration is for at least 45 days. 
     
     
         11 . A method of treating a penile tissue fibrosis in a human comprising administering to a human having a penile tissue fibrosis an amount of tadalafil effective to arrest or regress penile tissue fibrosis wherein said amount is up to 1.5 mg/kg/day and wherein said administration is for at least 45 days. 
     
     
         12 . A method of treating a penile tissue fibrosis in a human comprising administering to a human having Peyronie's disease an amount of tadalafil effective to arrest or regress penile tissue fibrosis wherein said amount is up to 1.5 mg/kg/day and wherein said administration is for at least 45 days. 
     
     
         13 . A method of treating Peyronie's disease or corporal veno-occlusive dysfunction which comprises administering an amount of tadalafil effective to arrest or regress penile tissue fibrosis to a human having Peyronie's disease or corporal veno-occlusive dysfunction wherein said amount is up to 1.5 mg/kg/day for at least 45 days. 
     
     
         14 . The method of  claim 10  wherein the penile tissue fibrosis is tunical fibrosis. 
     
     
         15 . The method of  claim 10  wherein the penile tissue fibrosis is corporal tissue fibrosis.