Organ arrest, protection and preservation
The present invention relates to a method for arresting, protecting and/or preserving an organ which includes administering effective amounts of (i) 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 compound is a potassium channel opener or potassium channel agonist selected from nicorandil, diazoxide, minoxidil, pinacidil, 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 MVHIIC (Q-type), cyproheptadine HGl, filodipine, fluspirilene (L-type), HA-1077 2HGl(1-(5 isoquinolinyl sulphonyl) homo piperazine.HGl), isradipine, loperamide HCl, 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 1 , wherein the compound is an adenosine receptor agonist 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 1 , 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. The composition of claim 1 further including magnesium.
9. The composition of claim 1 further including magnesium up to 2.5 mM.
10. The composition of claim 1 wherein the organ is a heart.
11. Method of protecting an organ including the step of contacting the organ with a composition according to claim 1 .
12. The method of claim 11 wherein the composition is at a temperature between about 15° C. to about 37° C.
13. The method of claim 11 wherein the organ is a heart.
14. The method of claim 11 wherein the organ is a heart of a patient with heart ischaemia.
15. The method of claim 11 wherein the compound is adenosine and the local anaesthetic is lignocaine.
16. The method of claim 11 wherein the organ is a heart and the composition is administered to a subject who has suffered or is developing a heart attack.
17. A method of protecting an organ comprising contacting the organ with a composition according to claim 8 .
18. A method of protecting an organ comprising contacting the organ with a composition according to claim 8 to treat heart ischaemia.
19. A method of reducing heart damage before, during or following cardiovascular intervention comprising administering the composition of claim 8 to a subject who has suffered or is developing a heart attack.
20. 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.
21. The composition of claim 20 wherein the compound is a potassium channel opener or potassium channel agonist selected from nicorandil, diazoxide, minoxidil, pinacidil, 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 HGl, filodipine, fluspirilene (L-type), HA-1077 2HCl(1-(5isoquinolinyl sulphonyl) homo piperazine.HCl), isradipine, loperamide HGl, 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.
22. The composition of claim 20 , wherein the compound is an adenosine receptor agonist 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).
23. The composition of claim 20 , wherein the local anesthetic is selected from mexiletine, diphenylhydantoin, prilocaine, procaine, mepivacaine and Class B antiarrhythmic agents.
24. The composition of claim 23 , wherein the Class 1B antiarrhythmic agents is lignocaine.
25. The composition of claim 20 , wherein the composition is a cardioplegic or cardioprotectant composition.
26. The composition of claim 20 , wherein the pharmaceutically acceptable carrier comprises a buffer which maintains the pH of the composition in the range from about 6 to about 9.
27. The composition of claim 20 , wherein the pharmaceutically acceptable carrier includes potassium at a concentration of less than about 10 mM.
28. The composition of claim 20 further including magnesium.
29. The composition of claim 20 further including magnesium up to 2.5 mM.
30. The composition of claim 20 wherein the organ is a heart.
31. Method of preserving an organ including the step of contacting the organ with a composition according to claim 20 .
32. The method of claim 31 wherein the composition is at a temperature between about 15° C. to about 37° C.
33. The method of claim 31 wherein the compound is adenosine and the local anaesthetic is lignocaine.
34. A composition comprising:
a pharmaceutically acceptable carrier;
adenosine, and
a local anesthetic, in amounts sufficient to protect or preserve an organ.
35. The composition of claim 34 , wherein the local anesthetic is lignocaine.
36. The composition of claim 34 wherein the organ is a heart.
37. A method for preserving or protecting an organ comprising contacting the organ with the composition of claim 34 .
38. The method of claim 37 wherein the composition is at a temperature between about 15° C. to about 37° C.
39. The method of claim 37 wherein the organ is a heart.