Combination therapy for treatment of erectile dysfunction

Abstract

In the field of treatment of erectile dysfunction there is disclosed a novel therapy in which the actions of an agent or agents, produce a combination of effects to induce effective erection (and avoid priapism) while reducing or entirely avoiding pain. The method taught combines a first action of an agent which is to antagonize a drug-induced pain stimulus within nociceptive nerves of penile tissue with a second action of either the same agent or of a second agent, which enhances, synergistically, smooth muscle relaxation. The synergism allows for at least an equivalent effect of smooth muscle relaxation to be obtained at significantly lower doses of a smooth muscle relaxing agent such as PGE1 which in standard therapy is also in 40-45% of cases pain-inducing at doses which achieve effective erection. Thus in an anatomical site where nociceptive tissue is in close proximity to one or more effector systems, the method enhances the effector system while reducing nociception in the nociceptive tissue which nociception would be caused by an agent such as PGE1 which is used to trigger the effector system.

We claim:  
     
         1 . method of augmenting the actions of cAMP in an effector system while reducing cAMP action in a nociceptive system comprising application of one or more of the various forms of NO, or CO, to a site wherein the said cAMP exists.  
     
     
         2 . A method as claimed in  claim 1  wherein alteration of the said actions of cAMP is caused by application of an agent which increases cGMP.  
     
     
         3 . A method as claimed in  claim 1  wherein alteration of the said actions of cAMP is caused by application of an agent which inhibits phosphodiesterase in smooth muscle and activates cAMP phosphodiesterase in nervous tissue.  
     
     
         4 . In an anatomical site where nociceptive tissue is in close proximity to one or more effector systems, a method for enhancing said effector system while reducing nociception in said nociceptive tissue comprising modifying the actions of cAMP at said site by application of one or more of the various forms of NO or CO.  
     
     
         5 . A method as claimed in  claim 4  wherein said actions of cAMP are modified by application of one or more agents which increase cGMP.  
     
     
         6 . A method as claimed in  claim 4  wherein said anatomical site is the penis.  
     
     
         7 . A method as claimed in  claim 4  wherein said anatomical site is the clitoris.  
     
     
         8 . A method for enhancing penile or clitoral erection with minimal or no pain comprising the use of at least one agent in an effective amount that can augment the effect of cAMP as well as augment the effect of cGMP.  
     
     
         9 . A method as claimed in  claim 8  wherein said one or more agents can augment the effect of cAMP in smooth muscle as well as augment the effect of cGMP in nervous tissue.  
     
     
         10 . A method as claimed in  claim 8  wherein said one or more agents augment the effect of cAMP by stimulating adenylyl cyclase as well as inhibiting PDE3 activity in smooth muscle while augmenting the effect of cGMP in nervous tissue.  
     
     
         11 . A method as claimed in  claim 10  wherein said one or more agents augment the effect of cGMP and inhibits said PDE3 by generating nitric oxide.  
     
     
         12 . A method as claimed in  claim 11  wherein said agent is selected from the group consisting of glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium-nitroprusside, 3morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine, S-nftrosoglutathionLi, N-hydroxy-L-arginine, S,S-dinitrosodithiol, and NO gas.  
     
     
         13 . A method as claimed in  claim 5  whereby said agent is delivered by any route that will affect penile or clitoral smooth muscle and nerves.  
     
     
         14 . A method as claimed in  claim 8  wherein two agents are used and the agent that can augment the effect of cGMP does so by generating NO or CO.  
     
     
         15 . A method as claimed in  claim 8  wherein two agents are used, one of said agents augments the effect of cAMP by stimulating adenylyl cyclase in smooth muscle and the second of said agents inhibits PDE3 in smooth muscle.  
     
     
         16 . A method as claimed in  claim 8  wherein said agent which generates NO is selected from the group consisting of glyceryl tdnitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosydnonimine molsidomine, S-nitroso-Nacetylpenicillamine, S-nitrosoglutathione, N-hydroxy-L-arginine, S,S-dinitrosodithiol and NO gas.  
     
     
         17 . A method as claimed in  claim 8  wherein the agent that augments or potentiates the effect of cAMP is selected from the group consisting of PGE1, VIP, forstolin, acetylcholine, and calcitonin related peptide.  
     
     
         18 . A method as claimed in  claim 8  whereby said agents are delivered by any route that will affect penile or clitoral smooth muscle and nerves.  
     
     
         19 . In an anatomical site where nociceptive tissue is in close proximity to one or more effector systems, a method for enhancing said effector system while reducing nociception in said nociceptive tissue comprising application of an agent or agents that potentiate or augment the action of cAMP in said effector systems and in said nociceptive tissue causes an increase of cGMP relative to cAMP.