Organ arrest, protection and preservation

Abstract

The present invention relates to a method for arresting, protecting and/or preserving an organ which includes administering effective amounts of (i) a potassium channel opener or agonist and/or an adenosine receptor agonist and (ii) local anaesthetic to a subject in need thereof. The present invention also relates to a method for arresting, protecting and/or preserving an organ which comprises adding a composition which includes effective amounts of (i) a potassium channel opener or agonist and/or an adenosine receptor agonist and (ii) a local anaesthetic to the organ. The present invention further provides a pharmaceutical or veterinary composition which includes effective amounts of (i) a potassium channel opener or agonist and/or an adenosine receptor agonist and (ii) a local anaesthetic.

1 . A composition comprising: 
 a pharmaceutically acceptable carrier;    a compound chosen from a potassium channel opener, a potassium channel agonist and an adenosine receptor agonist; and    a local anesthetic;    wherein the compound and the local anesthetic are present in the composition in an amount sufficient to protect an organ.    
     
     
         2 . The composition of  claim 1 , wherein the potassium channel opener or potassium channel agonist is selected from nicorandil, diazoxide, minoxidil, pinicadil, aprikalim, cromokulim, NS-1619 (1,3-dihydro-1-[2-hydroxy5(trifluoromethyl) phenyl]5-(trifluoromethyl)2-H-benimidazol-one), amlodipine, Bay K 8644(L-type)(1,4-dihydro-26-dimethyl-5-nitro-4[2(trifluoromethyl)phenyl]-3-pyridine carboxylic acid (methyl ester)), bepridil HCl (L-type), calciseptine (L-type), omega-conotoxin GVIA (N-type), omega-conotoxin MVIIC (Q-type), cyproheptadine HCl, dantrolene sodium (Ca 2+  release inhibitor), diltiazem HCl (L-type), filodipine, flunarizine HCl (Ca 2+ /Na + ), fluspirilene (L-type), HA-1077 2HCl (1-(5 isoquinolinyl sulphonyl) homo piperazine.HCl), isradipine, loperamide HCl, manoalide (Ca 2+  release inhibitor), nicardipine HCl (L-type), nifedipine (L-type), niguldipine HCl (L-type), nimodipine (L-type), nitrendipine (L-type), pimozide (L- and T-type), ruthenium red, ryanodine (SR channels), taicatoxin, verapamil HCl (L-type), methoxy-verapamil HCl (L-type), YS-035 HCl (L-type)N[2(3,4-dimethoxyphenyl)ethyl]-3,4-dimethoxy N-methyl benzene ethaneamine HCl) and AV blockers.  
     
     
         3 . The composition of  claim 2 , wherein the adenosine receptor agonist is selected from N 6 -cyclopentyladenosine (CPA), N-ethylcarboxamido adenosine (NECA), 2-[p-(2-carboxyethyl)phenethyl-amino-5′-N-ethylcarboxamido adenosine (CGS-21680),2-chloroadenosine, N 6 -[2-(3,5-dimethoxyphenyl)-2-(2-methoxyphenyl]ethyladenosine, 2-chloro-N 6 -cyclopentyladenosine (CCPA), N-(4-aminobenzyl)-9-[5-(methylcarbonyl)-beta-D-robofuranosyl]-adenine (AB-MECA), ([IS-[1a, 2b, 3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methyl-propyl]amino]-3H-imidazole[4,5-b]pyridyl-3-yl]cyclopentane carboxamide (AMP579, N 6 -(R)-phenylisopropyladenosine (R-PLA), aminophenylethyladenosine [9](APNEA) and cyclohexyladenosine (CHA).  
     
     
         4 . The composition of  claim 3 , wherein the local anesthetic is selected from mexiletine, diphenylhydantoin, prilocaine, procaine, mepivicaine and Class 1B antiarrhythmic agents.  
     
     
         5 . The composition of  claim 4 , wherein the Class 1B antiarrhythmic agents is lignocaine.  
     
     
         6 . The composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises a buffer which maintains the pH of the composition in the range from about 6 to about 9.  
     
     
         7 . The composition according to  claim 1 , wherein the pharmaceutically acceptable carrier includes potassium at a concentration of less than about 10 mM.  
     
     
         8 . A composition comprising: 
 a pharmaceutically acceptable carrier;    a compound chosen from a potassium channel opener, a potassium channel agonist and an adenosine receptor agonist; and    a local anesthetic;    wherein the compound and the local anesthetic are present in the composition in an amount sufficient to preserve an organ.    
     
     
         9 . The composition of  claim 8 , wherein the potassium channel opener or potassium channel agonist is selected from nicorandil, diazoxide, minoxidil, pinicadil, aprikalim, cromokulim, NS-1619 (1,3-dihydro-1-[2-hydroxy5(trifluoromethyl) phenyl]5-(trifluoromethyl)2-H-benimidazol-one), amlodipine, Bay K 8644(L-type)(1,4-dihydro-26-dimethyl-5-nitro-4[2(trifluoromethyl)phenyl]-3-pyridine carboxylic acid (methyl ester)), bepridil HCl (L-type), calciseptine (L-type), omega-conotoxin GVIA (N-type), omega-conotoxin MVIIC (Q-type), cyproheptadine HCl, dantrolene sodium (Ca 2+  release inhibitor), diltiazem HCl (L-type), filodipine, flunarizine HCl (Ca 2+ /Na + ), fluspirilene (L-type), HA-1077 2HCl(1-(5 isoquinolinyl sulphonyl) homo piperazine.HCl), isradipine, loperamide HCl, manoalide (Ca 2+  release inhibitor), nicardipine HCl (L-type), nifedipine (L-type), niguldipine HCl (L-type), nimodipine (L-type), nitrendipine (L-type), pimozide (L- and T-type), ruthenium red, ryanodine (SR channels), taicatoxin, verapamil HCl (L-type), methoxy-verapamil HCl (L-type), YS-035 HCl (L-type)N[2(3,4-dimethoxyphenyl)ethyl]-3,4-dimethoxy N-methyl benzene ethaneamine HCl) and AV blockers.  
     
     
         10 . The composition of  claim 8 , wherein the adenosine receptor agonist is selected from N 6 -cyclopentyladenosine (CPA), N-ethylcarboxamido adenosine (NECA), 2-[p-(2-carboxyethyl)phenethyl-amino-5′-N-ethylcarboxamido adenosine (CGS-21680),2-chloroadenosine, N 6 -[2-(3,5-dimethoxyphenyl)-2-(2-methoxyphenyl]ethyladenosine, 2-chloro-N 6 -cyclopentyladenosine (CCPA), N-(4-aminobenzyl)-9-[5-(methylcarbonyl)-beta-D-robofuranosyl]-adenine (AB-MECA), ([IS-[1a, 2b, 3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methyl-propyl]amino]-3H-imidazole[4,5-b]pyridyl-3-yl]cyclopentane carboxamide (AMP579, N 6 -(R)-phenylisopropyladenosine (R-PLA), aminophenylethyladenosine [9](APNEA) and cyclohexyladenosine (CHA).  
     
     
         11 . The composition of  claim 8 , wherein the local anesthetic is selected from mexiletine, diphenylhydantoin, prilocaine, procaine, mepivacaine and Class 1B antiarrhythmic agents.  
     
     
         12 . The composition of  claim 8 , wherein the Class 1B antiarrhythmic agents is lignocaine.  
     
     
         13 . The composition of  claim 8 , wherein the composition is a cardioplegic or cardioprotectant composition.  
     
     
         14 . The composition of  claim 8 , wherein the pharmaceutically acceptable carrier comprises a buffer which maintains the pH of the composition in the range from about 6 to about 9.  
     
     
         15 . The composition of  claim 8 , wherein the pharmaceutically acceptable carrier includes potassium at a concentration of less than about 10 mM.  
     
     
         16 . Method of protecting an organ including the step of contacting the organ with a composition according to  claim 1 .  
     
     
         17 . Method of preserving an organ including the step of contacting the organ with a composition according to  claim 8.