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 the group consisting of 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 arrest an organ.   
     
     
         2 . The composition of  claim 1 , wherein the potassium channel opener or potassium channel agonist is selected from the group consisting of nicorandil, diazoxide, minoxidil, pinicadil, aprikalim, cromokulim, NS-1619 (1,3-dihydro-1-[2-hydroxy-5(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-035HCl (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 AV blocker is adenosine. 
     
     
         4 . The composition of  claim 1 , wherein the adenosine receptor agonist is selected from the group consisting of 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 APNEA) and cyclohexyladenosine (CHA). 
     
     
         5 . The composition of  claim 1 , wherein the local anesthetic is selected from the group consisting of mexiletine, diphenylhydantoin, prilocalne, procaine, mepivicaine and Class 1B antiarrhythmic agents. 
     
     
         6 . The composition of  claim 5 , wherein the Class 1B antiarrhythmic agents is lignocaine. 
     
     
         7 . 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. 
     
     
         8 . The composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises magnesium having a concentration of about 2.5 mM. 
     
     
         9 . The composition of  claim 3 , wherein the concentration of adenosine is about 0.001 to about 2 mM, about 0.01 to about 10 mM, or about 0.05 to about 5 mM. 
     
     
         10 . The composition of  claim 6 , wherein the concentration of lignocaine is about 0.001 to about 2 mM, about 0.01 to about 10 mM, or about 0.05 to about 5 mM. 
     
     
         11 . Method of arresting an organ including the step of contacting the organ with an effective amount of a composition according to  claim 1 . 
     
     
         12 . Method of  claim 11 , wherein the organ is a heart intact in the body of a subject or is an isolated heart. 
     
     
         13 . A method of  claim 12 , wherein the heart is arrested during open-heart surgery. 
     
     
         14 . A method according to  claim 13 , further comprising preserving and/or protecting the heart with the composition. 
     
     
         15 . A method according to  claim 11 , wherein the potassium channel opener or potassium channel agonist is selected from the group consisting of 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-035HCl (L-type)N[2(3,4-dimethoxyphenyl)ethyl]-3,4-dimethoxy N-methyl benzene ethaneamine HCl) and AV blockers. 
     
     
         16 . A method according to  claim 15 , wherein the AV blocker is adenosine. 
     
     
         17 . A method according to  claim 11 , wherein the adenosine receptor agonist is selected from the group consisting of 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 APNEA) and cyclohexyladenosine (CHA). 
     
     
         18 . A method of  claim 17 , wherein the local anesthetic is selected from the group consisting of mexiletine, diphenylhydantoin, prilocalne, procaine, mepivicaine and Class 1B antiarrhythmic agents. 
     
     
         19 . A method of  claim 18 , wherein the Class 1B antiarrhythmic agents is lignocaine. 
     
     
         20 . A method of  claim 16 , wherein the concentration of adenosine is about 0.001 to about 2 mM, about 0.01 to about 10 mM, or about 0.05 to about 5 mM. 
     
     
         21 . A method of  claim 19 , wherein the concentration of lignocaine is about 0.001 to about 2 mM, about 0.01 to about 10 mM, or about 0.05 to about 5 mM.