Methods and compositions to enhance the efficacy of phosphodiesterase inhibitors

Abstract

Methods for treatment of sexual dysfunction in men and women using combination of phosphodiesterase (PDE) type 5 inhibitors and 1-deprenyl or propargylamine compounds are described. Methods of reducing the dosage and preventing the side effects of PDE type5 inhibitors are also described. The methods comprise administering a therapeutically effect amount of 1-deprenyl or propargylamine compounds (also called monoamine oxidase [MAO] inhibitors) in combination with PDE inhibitors. Stimulation of nitric oxide production and vasodilation by 1-deprenyl and propargylamine compounds augments the actions of PDE inhibitors or other drugs and methods used in the treatment of sexual dysfunction. The composition described here enhances the actions of PDE inhibitors primarily by increasing the generation of cyclic GMP by stimulating the nitric oxide pathway and secondarily by providing several additional benefits such as enhanced dopamine activity. Methods of enhancing the efficacy of various PDE inhibitors in the treatment of a number of disorders other than sexual dysfunction are also disclosed.

1 . A method for enhancing the efficacy of phosphodiesterase inhibitors in treating conditions other than erectile dysfunction, comprising:
 administering to the individual an effective amount of a pharmaceutical composition comprising phosphodiesterase type 5 inhibitor; and   1-deprenyl or propargylamine compound.   
     
     
         2 . The method according to  claim 1 , wherein the other conditions belong to a group consisting of sexual dysfunction in men following prostate surgery, hypogonadism in men, sexual dysfunction in women, primary pulmonary hypertension, urinary tract symptoms due to benign prostatic hyperplasia, urinary incontinence, sickle cell anemia, and endothelial dysfunction in patients with primary pulmonary hypertension. 
     
     
         3 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is selected from the group consisting of consisting of sildenafil, tadalafil, vardenafil, avanafil, zaprinast, dipyridamole, 3-isobutyl-1-methyxanthine, propentofylline, papaverine, 4-bromo-5-(pryidylmethylamino)-6-[3-(4-chlorophenyl)propxy]-3(2H)pyridazinone, 1-[4-[(1,3-benzodiozol-5-9pyridylmethylamino)-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifloromethyl)-phenylmethyl-5-methyl cyclopent-4,5]imidazo[2.1-b]purin-4(3H)one, furazlocillin, cis-2-hexyl-5-methyl 3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one, 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3(2H)pyridazinone, 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, 1-[4[(1,3-benzyodioxol-5-methyl)amino]-6-chloro-2-quinazolinyl]4-piperidine carboxylic acid. 
     
     
         4 . The method of  claim 3 , wherein the phosphodiesterase inhibitor is administered between 0.1 mg and 500 mg. 
     
     
         5 . The method of  claim 1 , wherein the 1-deprenyl is administered at a concentration selected from the group consisting of 10 ng and 1 mg/kg. 
     
     
         6 . The method of  claim 1 , wherein the propargylamine compound is selected from the group consisting rasagiline, lazabemide, N-propargylamine compounds, N-methyl propargylamine, and N-methyl-N-(2-pentyl)-propargylamine. 
     
     
         7 . A method for enhancing the efficacy of phosphodiesterase inhibitors in treating conditions other than erectile dysfunction comprising:
 administering to the individual an effective amount of a pharmaceutical composition comprising phosphodiesterase type 5 inhibitor;   1-deprenyl or propargylamine compound, and   wherein the condition is selected from the group consisting of sexual dysfunction in men following prostate surgery, hypogonadism in men, sexual dysfunction in women, primary pulmonary hypertension, urinary tract symptoms due to benign prostatic hyperplasia, urinary incontinence, sickle cell anemia, and endothelial dysfunction in patients with primary pulmonary hypertension.   
     
     
         8 . The method of  claim 7 , wherein the phosphodiesterase inhibitor is selected from the group consisting of consisting of sildenafil, tadalafil, vardenafil, avanafil, zaprinast, dipyridamole, 3-isobutyl-1-methyxanthine, propentofylline, papaverine, 4-bromo-5-(pryidylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridazinone, 1-[4-[(1,3-benzodiozol-5-9pyridylmethylamino)-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifloromethyl)-phenylmethyl-5-methyl cyclopent-4,5]imidazo[2.1-b]purin-4(3H)one, furazlocillin, cis-2-hexyl-5-methyl 3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one, 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3(2H)pyridazinone, 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, 1-[4[(1,3-benzyodioxol-5-methyl)amino]-6-chloro-2-quinazolinyl]4-piperidine carboxylic acid. 
     
     
         9 . The method of  claim 8 , wherein the phosphodiesterase inhibitor is administered between 0.1 mg and 500 mg. 
     
     
         10 . The method of  claim 7 , wherein the 1-deprenyl is administered at a concentration selected from the group consisting of 10 ng and 1 mg/kg. 
     
     
         11 . The method of  claim 7 , wherein the propargylamine compound is selected from the group consisting rasagiline, lazabemide, N-propargylamine compounds, N-methyl propargylamine, and N-methyl-N-(2-pentyl)-propargylamine.