Articles of manufacture

Abstract

The present invention relates to highly selective phosphodiesterase (PDE) enzyme inhibitors and to their use in pharmaceutical articles of manufacture. In particular, the present invention relates to potent inhibitors of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase type 5 (PDE5) that when incorporated into a pharmaceutical product at about 1 to about 20 mg unit dosage are useful for the treatment of sexual dysfunction. The articles of manufacture described herein are characterized by selective PDE5 inhibition, and accordingly, provide a benefit in therapeutic areas where inhibition of PDE5 is desired, with minimization or elimination of adverse side effects resulting from inhibition of other phosphodiesterase enzymes.

What is claimed is:  
     
         1 . An article of manufacture for human pharmaceutical use comprising: 
 (a) an oral dosage form comprising about 1 to about 20 mg of a selective PDE5 inhibitor having 
 (i) at least a 100 fold differential in IC 50  values for the inhibition of PDE5 versus PDE6,  
 (ii) at least a 1000 fold differential in IC 50  values for the inhibition of PDE5 versus PDE1c,  
 (iii) an IC 50  for the inhibition of PDE5 less than 10 nM, and  
 (iv) sufficient bioavailability to be effective in about 1 to about 20 mg unit oral dosages;  
   (b) a package insert providing that the PDE5 inhibitor is useful to treat sexual dysfunction in a patient in need thereof, and that is free of contradictions associated with administration of organic nitrates; and    (c) a container.    
     
     
         2 . An article of manufacture for human pharmaceutical use comprising: 
 (a) an oral dosage form comprising about 1 to about 20 mg of selective PDE5 inhibitor having 
 (i) at least a 100 fold differential in IC 50  values for the inhibition of PDE5 versus PDE6,  
 (ii) at least a 1000 fold differential in IC 50  values for the inhibition of PDE5 versus PDE1c,  
 (iii) an IC 50  less than 10 nM, and  
 (iv) a sufficient bioavailability to be effective in about 1 to about 20 mg unit oral dosages;  
   (b) a package insert providing that the PDE5 inhibitor is useful to treat sexual dysfunction in a patient in need thereof and that is using an organic nitrate; and    (c) a container.    
     
     
         3 . An article of manufacture for human pharmaceutical use comprising: 
 (a) an oral dosage form comprising about 1 to about 20 mg of a selective PDE5 inhibitor having 
 (i) at least a 100 fold differential in IC 50  values for the inhibition of PDE5 versus PDE6,  
 (ii) at least 1000 fold differential in IC 50  values for the inhibition of PDE5 versus PDE1c,  
 (iii) an IC 50  less than 10 nM, and  
 (iv) a sufficient bioavailability to be effective in about 1 to about 20 mg unit oral dosages;  
   (b) a package insert providing that the PDE5 inhibitor is useful to treat sexual dysfunction in a patient in need thereof and that is suffering from a condition selected from the group consisting of a retinal disease, proneness to flushing, proneness to vision abnormalities, class 1 congestive heart failure, a myocardial infarction 90 days or more before onset of the sexual dysfunction treatment, and combinations thereof; and    (c) a container.    
     
     
         4 . The article of  claim 3  wherein the retinal disease is diabetic retinopathy or retinitis pigmentosa.  
     
     
         5 . The article of  claim 3  wherein said package insert reports that incidences of flushing are less than 2% of treated patients.  
     
     
         6 . The article of claims  1  through  5  wherein the oral dosage form comprises about 5 mg, about 10 mg, or about 20 mg, of a selective PDE5 inhibitor.  
     
     
         7 . The article of claims  1  through  5  wherein the package insert provides a maximum dosage of the selective PDE5 inhibitor of about 20 mg per 24-hour period.  
     
     
         8 . The article of claims  1  through  5 , wherein the selective PDE5 inhibitor has the structure  
       
         
           
           
               
               
           
         
       
     
     
         9 . A method of treating sexual dysfunction comprising using an article of manufacture of claims  1  through  5 .  
     
     
         10 . A method of treating sexual dysfunction in a patient being treated with an organic nitrate comprising administration of an oral dosage form of a PDE5 inhibitor in an amount of about 1 to about 20 mg.  
     
     
         11 . A method of treating sexual dysfunction in a patient prone to vision abnormalities, prone to flushing, suffering from a retinal disease, suffering from class 1 congestive heart failure, or that suffered a myocardial infarction 90 days or more prior to onset of the sexual dysfunction treatment comprising administration of an oral dosage form of a PDE5 inhibitor in an amount of about 1 to about 20 mg.