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 comprising administering a cyclic guanosine 3′,5′-monophosphate (cGMP) type 5 phosphodiesterase (PDE-5) inhibitor according to a continuous, long-term regimen to an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis, wherein the PDE-5 inhibitor is selected from the group consisting of sildenafil, tadalafil, and vardenafil, wherein the PDE-5 inhibitor is administered at a dosage of up to 1.5 mg/kg/day, and wherein the PDE′″5 inhibitor is administered for greater than or equal to 45 days. 
     
     
         2 . The method of  claim 1 , wherein the PDE-5 inhibitor is sildenafil. 
     
     
         3 . The method of  claim 1 , wherein the PDE-5 inhibitor is tadalafil. 
     
     
         4 . The method of  claim 1 , wherein the PDE-5 inhibitor is vardenafil. 
     
     
         5 . The method of  claim 1 , wherein the individual has penile tunical fibrosis. 
     
     
         6 . The method of  claim 1 , wherein the individual has corporal tissue fibrosis. 
     
     
         7 . The method of  claim 5 , wherein the penile tunical fibrosis is Peyronie's disease 
     
     
         8 . The method of  claim 6 , wherein the penile corporal fibrosis is corporal veno-occlussive dysfunction. 
     
     
         9 . The method of  claim 1 , wherein the PDE-5 inhibitor is administered orally, by injection, or by local administration to a penis. 
     
     
         10 . The method of  claim 9 , wherein the PDE-5 inhibitor is administered orally. 
     
     
         11 . The method of  claim 1 , wherein administering according to a continuous, long-term regimen comprises administering for months. 
     
     
         12 . The method of  claim 1 , wherein administering according to a continuous, long-term regimen comprises administering for years. 
     
     
         13 . The method of  claim 1 , wherein administering according to a continuous, long-term regimen comprises administering at least once per day. 
     
     
         14 . The method of  claim 1 , wherein administering according to a continuous, long-term regimen comprises administering in a single dosage once per day. 
     
     
         15 . The method of  claim 1 , wherein the PDE-5 inhibitor is constantly present in the individual during the continuous, long-term regimen. 
     
     
         16 . The method of  claim 1 , wherein the PDE-5 inhibitor administration arrests, reduces, or regresses the penile tunical fibrosis in the individual. 
     
     
         17 . The method of  claim 1 , wherein the PDE-5 inhibitor administration arrests, reduces, or regresses the corporal tissue fibrosis in the individual. 
     
     
         18 . The method of  claim 1 , wherein the PDE-5 inhibitor is tadalafil orally administered to the individual once per day for months. 
     
     
         19 . A method comprising orally administering tadalafil to an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis, wherein tadalafil is administered at least once per day at a dosage of up to 1.5 mg/kg, and wherein tadalafil is administered for greater than or equal to 45 days. 
     
     
         20 . The method of  claim 19 , wherein the individual has penile tunical fibrosis. 
     
     
         21 . The method of  claim 19 , wherein the individual has corporal tissue fibrosis. 
     
     
         22 . The method of  claim 20 , wherein the penile tunical fibrosis is Peyronie's disease. 
     
     
         23 . The method of  claim 21 , wherein the penile corporal fibrosis is corporal veno-occlussive dysfunction. 
     
     
         24 . The method of  claim 19 , wherein tadalafil is administered for months. 
     
     
         25 . The method of  claim 19 , wherein tadalafil is administered for years. 
     
     
         26 . The method of  claim 19 , wherein the tadalafil is orally administered to the individual once per day for months. 
     
     
         27 . The method of  claim 19 , wherein the tadalafi is constantly present in the individual during the administration. 
     
     
         28 . The method of  claim 19 , wherein tadalafil administration arrests, reduces, or regresses the penile tunical fibrosis in the individual. 
     
     
         29 . The method of  claim 19 , wherein tadalafil administration arrests, reduces, or regresses the corporal tissue fibrosis in the individual. 
     
     
         30 . A kit comprising a PDE-5 inhibitor and instructions for administering the inhibitor at a dosage of up to 1.5 mg/kg/day to an individual with at least one of a penile tunical fibrosis and corporal tissue fibrosis according to a continuous, long-term regimen of greater than or equal to 45 days.