Packaged pharmaceuticals and methods for causing compounds and pharmaceutical compositions to be used as inhibitors of neoplastic lesions

Abstract

This invention provides pharmaceutical compositions containing compounds for the treatment of neoplasia in mammals. The phosphodiesterase inhibitory activity of a compound is determined along with COX inhibitory activity. Growth inhibitory and apoptosis inducing effects on cultured tumor cells are also determined. Compounds that exhibit phosphodiesterase inhibiton, growth inhibition and apoptosis induction, but prefereably not substantial prostaglandin inhibitory activity, are desirable for the treatment of neoplasia.

We claim  
     
         1 . A method of advancing the use of an anti-neoplastic PDE inhibitor, comprising: 
 (a) obtaining a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound characterized by neoplastic cell growth inhibitory activity and PDE inhibition activity wherein the PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase;  
   (b) informing physicians and patients that said compound has said characteristics; and    (c) providing said pharmaceutical composition to physicians and patients in need of treatment.    
     
     
         2 . The method of  claim 1  wherein said compound is further characterized by its ability to induce apoptosis in neoplastic cells.  
     
     
         3 . The method of  claim 2  wherein said compound is further characterized by lower COX inhibitory activity relative to the inhibitory activity of the compound against said PDE.  
     
     
         4 . A method of achieving the use of an anti-neoplastic PDE inhibitor by patients, comprising: 
 (a) obtaining a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound having PDE inhibitory activity wherein said PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase;  
   (b) informing physicians and patients that said compound has said characteristics;    (c) providing said pharmaceutical composition to physicians and patients in need of treatment; and    (d) causing a patient to receive said pharmaceutical composition.    
     
     
         5 . The method of  claim 7  wherein said compound is further characterized by its ability to induce apoptosis in neoplastic cells.  
     
     
         6 . The method of  claim 8  wherein said compound is further characterized by lower COX inhibitory activity relative to the inhibitory activity of the compound against said PDE.  
     
     
         7 . A method of improving the regulatory approvability of an anti-neoplastic pharmaceutical composition, comprising: 
 (a) obtaining a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound having PDE inhibitory activity wherein said PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase;  
   (b) conducting at least one trial of said pharmaceutical composition to establish safety and efficacy; and    (c) submitting information from such trial to regulatory authorities to obtain approval to market said pharmaceutical composition.    
     
     
         8 . The method of  claim 10  wherein said compound is further characterized by its ability to induce apoptosis in neoplastic cells.  
     
     
         9 . The method of  claim 11  wherein said compound is further characterized by lower COX inhibitory activity relative to the inhibitory activity of the compound against said PDE.  
     
     
         10 . A method of advancing the use of an anti-neoplastic PDE inhibitor, comprising: 
 (a) obtaining a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound selected by determining the neoplastic cell growth inhibitory activity of the compound; determining the PDE inhibition activity of the compound wherein the PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase; and  
 selecting the compound that exhibits neoplastic cell growth inhibitory activity and activity inhibitory of said PDE;  
   (b) informing physicians and patients that said compound has said characteristics; and    (c) providing said pharmaceutical composition to physicians and patients in need of treatment.    
     
     
         11 . A packaged pharmaceutical composition for the treatment of neoplasia, comprising: 
 (a) a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound selected by determining the neoplastic cell growth inhibitory activity of the compound; determining the PDE inhibition activity of the compound wherein the PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase; and  
 selecting the compound that exhibits neoplastic cell growth inhibitory activity and activity inhibitory of said PDE;  
   (b) written material describing said compound as having those characteristics; and    (c) packaging for carrying said pharmaceutical composition and said written material.    
     
     
         12 . A method of achieving the use of an anti-neoplastic PDE inhibitor by patients, comprising: 
 (a) obtaining a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound selected by determining the neoplastic cell growth inhibitory activity of the compound; determining the PDE inhibition activity of the compound wherein the PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase; and  
 selecting the compound that exhibits neoplastic cell growth inhibitory activity and activity inhibitory of said PDE;  
   (b) informing physicians and patients that said compound has said characteristics;    (c) providing said pharmaceutical composition to physicians and patients in need of treatment; and    (d) causing a patient to receive said pharmaceutical composition.    
     
     
         13 . A method of improving the regulatory approvability of an anti-neoplastic pharmaceutical composition, comprising: 
 (a) obtaining a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound selected by determining the neoplastic cell growth inhibitory activity of the compound; determining the PDE inhibition activity of the compound wherein the PDE is characterized by: 
 (i) cGMP specificity over cAMP;  
 (ii) positive cooperative kinetic behavior in the presence of cGMP substrate;  
 (iii) submicromolar affinity for cGMP; and  
 (iv) insensitivity to incubation with purified cGMP-dependent protein kinase; and  
 selecting the compound that exhibits neoplastic cell growth inhibitory activity and activity inhibitory of said PDE;  
   (b) conducting at least one trial of said pharmaceutical composition to establish safety and efficacy; and    (c) submitting information from such trial to regulatory authorities to obtain approval to market said pharmaceutical composition.