L-arginine and phosphodiesterase (PDE) inhibitor synergism

Abstract

This invention pertains to the discovery that L-arginine and type V phosphodiesterases act synergistically to inhibit vasospasm and/or to induce vasodilation. Methods are provided using combinations of L-arginine and type V phosphodiesterase inhibitors in the treatment of cardiac pathologies and/or the treatment of erectile dysfunction.

What is claimed is:  
     
         1 . A method for ameliorating erectile dysfunction in a male individual, comprising administering to the individual an effective amount of a pharmaceutical composition comprising a Type V phosphodiesterase inhibitor and L-arginine.  
     
     
         2 . The method of  claim 1 , wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of zaprinast; dipyridamole; pyrazolopyrimidinones; griseolic acid derivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines; pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones; imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 4-bromo-5-(pyridylmethylamino)-6-[3 -(4-chlorophenyl)propoxy]-3(2H)pyridazi none; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-4-piper idine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-meth yl-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-7 H-pyrazolo(4,3-d)pyrimidin-7-one; and 1-[4[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]4-piperidi necarboxylic acid, monosodium salt.  
     
     
         3 . The method of  claim 2 , wherein the type V phosphodiesterase inhibitor is zaprinast.  
     
     
         4 . The method of  claim 2 , wherein the Type V phosphodiesterase is a pyrazolopyrimidinone.  
     
     
         5 . The method of  claim 4 , wherein the Type V phosphodiesterase is sildenafil.  
     
     
         6 . The method of  claim 1 , further comprising administering to the individual a beta blocker.  
     
     
         7 . The method of  claim 1 , wherein the individual is given a daily dose of phosphodiesterase inhibitor in the range of approximately 0.1 to 500 mg/day.  
     
     
         8 . The method of  claim 1 , wherein the erectile dysfunction is vasculogenic impotence.  
     
     
         9 . The method of  claim 1 , wherein the phosphodiesterase inhibitor is contained within a unit dosage pharmaceutical formulation.  
     
     
         10 . A method of inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft, said method comprising contacting the coronary artery or bypass graft with L-arginine and a type V phosphodiesterase inhibitor, whereby said L-arginine and said type V phosphodiesterase inhibitor act synergistically to induce or increase vasodilation or to inhibit vasospasm of said coronary artery or bypass graft.  
     
     
         11 . The method of  claim 10 , wherein said L-arginine is administered at a concentration ranging from about 10 −5  M to about 10 −2  M and said type V phosphodiestersase inhibitor is administered at a concentration ranging from about 1×10 −7  M to about 5×10 −4  M to inhibit vasospasm.  
     
     
         12 . The method of  claim 11 , wherein said type V phosphodiesterase inhibitor is sildenafil administered at a concentration ranging from about 2×10 −7  M to about 2×10 −4 M.  
     
     
         13 . The method of  claim 11 , wherein said type V phosphodiesterase inhibitor is zaprinast administered at a concentration ranging from about 5×10 −7  M to about 5×10 −4  M.  
     
     
         14 . The method of  claim 10 , wherein said L-arginine is administered at a concentration ranging from about about 10 −5  M to about 10 −2  M and said type V phosphodiestersase inhibitor is administered at a concentration ranging from about about 10 −7  M to about 10 −4  M to induce vasodilation.  
     
     
         15 . The method of  claim 10 , wherein said L-arginine and said phosphodiestersase inhibitor are combined in a single formulation.  
     
     
         16 . The method of  claim 15  wherein said L-arginine and said phosphodiestersase inhibitor are combined with a pharmaceutically acceptable excipient.  
     
     
         17 . The method of  claim 10 , wherein said L-arginine is formulated as L-arginine hydrochloride.  
     
     
         18 . The method of  claim 10 , wherein said phosphodiestersase inhibitor is selected from the group consisting of zaprinast, sildenafilm, DMPPO, and 1-arylnaphthalene lignan series, in which 1-(3-bromo-4, 5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinylcarbon yl]-2-(methoxycarbonyl)naphthalene hydrochloride.  
     
     
         19 . The method of  claim 10 , wherein said contacting comprises an intravenous injection of the L-arginine and the phosphodiesterase inhibitor.  
     
     
         20 . The method of  claim 10 , wherein said contacting comprises an oral administration of the L-arginine and the phosphodiesterase inhibitor.  
     
     
         21 . A pharmaceutical composition for inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft, said composition comprising L-arginine and a type V phosphodiesterase inhibitor.  
     
     
         22 . The composition of  claim 21 , further comprising a pharmaceutically acceptable excipient.  
     
     
         23 . The composition of  claim 22 , wherein said type V phosphodiesterase inhibitor is selected from the group consisting of sildenafil, and zaprinast.  
     
     
         24 . The composition of  claim 21 , wherein said composition is in a unit dosage form for inhibiting vasospasm of a coronary artery or bypass graft, said unit dosage providing L-arginine in a concentration ranging from about 10 −5  M to about 10 −2  M.  
     
     
         25 . The composition of  claim 21 , wherein said composition is in a unit dosage form for reducing or inhibiting vasospasm of a coronary artery or bypass graft, said unit dosage providing said phosphodiesterase inhibitor in a concentration ranging from about 2×10 −7  M to about 2×10 −4 M.  
     
     
         26 . The composition of  claim 21 , wherein said composition is in a unit dosage form for inducing vasodilation of a coronary artery or bypass graft, said unit dosage providing L-arginine in a concentration ranging from about 10 −5  M to about 10 −2  M.  
     
     
         27 . The composition of  claim 21 , wherein said composition is in a unit dosage form for inducing vasodilation of a coronary artery or bypass graft, said unit dosage providing said phosphodiesterase inhibitor in a concentration ranging from about 2×10 −7  M to about 2×10 −4 M.  
     
     
         28 . In a mammal, a coronary artery or bypass graft contacted with an exogenously supplied L-arginine and an exogenously supplied phosphodiesterase inhibitor whereby said L-arginine and said phosphodiesterase inhibitor act synergistically to induce vasodilation or reducing vasospasm of said coronary artery or bypass graft.  
     
     
         29 . In the mammal of  claim 28 , said L arginine is at a concentration ranging from about 2×10 −4  to about 6×10 −4  M to inhibit vasospasm.  
     
     
         30 . In the mammal of  claim 28 , said phosphodiesterase inhibitor is at a concentration ranging from about 2×10 −7  to 2×10 −4  M to inhibit vasospasm.  
     
     
         31 . In the mammal of  claim 28 , said L arginine is at a concentration ranging from about 2×10 −3  to about 8×10 −3 M to induce vasodilation..  
     
     
         32 . In the mammal of  claim 28 , said phosphodiesterase inhibitor is at a concentration ranging from about 10 −7  M to about 10 −4  M to induce vasodilation.  
     
     
         33 . In the mammal of  claim 28 , said type V phosphodiesterase inhibitor is selected from the group consisting of sildenafil, and zaprinast.  
     
     
         34 . In the mammal of  claim 28 , wherein said mammal is a non-human mammal.  
     
     
         35 . A kit for inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft, said kit comprising one or more containers containing: 
 L-arginine; and    a type V phosphodiesterase inhibitor.    
     
     
         36 . The kit of  claim 35 , further comprising a pharmaceutically acceptable excipient.  
     
     
         37 . The kit of  claim 35 ,, wherein said type V phosphodiesterase inhibitor is selected from the group consisting of sildenafil, and zaprinast.  
     
     
         38 . The kit of  claim 35 ,, wherein said L-arginine is in a unit dosage form for inhibiting vasospasm of a coronary artery or bypass graft, said unit dosage providing L-arginine in a concentration ranging from about 2×10 −4  M to about 8×10 −3  M.  
     
     
         39 . The kit of  claim 35 , wherein said phosphodiesterase inhibitor is in a unit dosage form for reducing or inhibiting vasospasm of a coronary artery or bypass graft, said unit dosage providing said phosphodiesterase inhibitor in a concentration ranging from about 10 −7  M to about 10 −4  M.  
     
     
         40 . The kit of  claim 35 , wherein said L-arginine is in a unit dosage form for inducing vasodilation of a coronary artery or bypass graft, said unit dosage providing L-arginine in a concentration ranging from about 2×10 −4  M to about 8×10 −3 M.  
     
     
         41 . The kit of  claim 35 , wherein said phosphodiesterase inhibitor is in a unit dosage form for inducing vasodilation of a coronary artery or bypass graft, said unit dosage providing said phosphodiesterase inhibitor in a concentration ranging from about 10 −7  M to about 10 −4  M.  
     
     
         42 . The kit of  claim 35 , further comprising instructional materials teaching the synergistic combination of L-arginine and a type V phosphodiesterase inhibitor to inhibit vasosapasm of a coronary artery or bypass graft.  
     
     
         43 . The kit of  claim 35 , further comprising instructional materials teaching the synergistic combination of L-arginine and a type V phosphodiesterase inhibitor to induce vasodilation of a coronary artery or bypass graft.  
     
     
         44 . A kit for ameliorating erectile dysfunction, said kit comprising one or more containers containing: 
 L-arginine;    a type V phosphodiesterase inhibitor; and    a beta blocker.