Method of treating ischemia/reperfusion injury with nitroxyl donors

• US 20040038947A1
• Filed: 06/16/2003
• Published: 02/26/2004
• Est. Priority Date: 06/14/2002
• Status: Abandoned Application

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America), Regents of the University of California (University of California)
• Original Assignee: GOV of The US of America As Represented By The SEC of The Dept of Health & Human Services, Johns Hopkins University
• Inventors: Paolocci, Nazareno, Wink, David A., Feelisch, Martin, Kass, David A., Fukuto, Jon M., Pagliaro, Pasquale, Miranda, Katrina M.
• Application Number:
  US10/463,084
• Publication Number:
  US 20040038947A1
• Time in Patent Office: Days
• US Class Current: 514/149
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli'"'"'s salt or IPA/NO.

Claims

1. A method of reducing ischemia/reperfusion injury comprising;

selecting a subject at risk for an ischemic event; and

administering to a subject a therapeutically effective dose of at least one nitroxyl anion donating compound wherein the compound is administered prior to the onset of ischemia.

2. The method of claim 1, wherein the nitroxyl anion donating compound is a nitroxyl-donating diazeniumdiolate.

3. The method of claim 2, wherein the nitroxyl-donating diazeniumdiolate has the formula

4. The method of claim 3, wherein J is oxide.

5. The method of claim 3, wherein J is lower alkyl.

6. The method of claim 3, wherein J is amine.

7. The method of claim 6, wherein J is primary amine.

8. The method of claim 7, wherein the nitroxyl-donating diazeniumdiolate has the formula

9. The method of claim 8, wherein R is alkyl.

10. The method of claim 9, wherein R is lower alkyl.

11. The method of claim 10, wherein R is isopropyl.

12. The method of claim 1, wherein the ischemia/reperfusion injury is an injury of the myocardium or brain.

13. The method of claim 12, wherein the ischemia/reperfusion injury is an injury of the myocardium.

14. The method of claim 13, wherein the size of infarction is reduced by about 35% or more.

15. The method of claim 14, wherein the size of infarction is reduced by about 35% to about 55%.

16. The method of claim 1, wherein selecting a subject at risk of an ischemic event comprises selecting a subject with no evidence of current ischemia.

17. A method of reducing ischemia/reperfusion injury comprising, administering a dose of at least one nitroxyl donating compound to an organ that is to be transplanted, wherein the dose is effective to reduce ischemia/reperfusion injury upon reperfusion of the organ in a recipient.

18. The method of claim 17, wherein the nitroxyl anion donating compound is a nitroxyl-donating diazeniumdiolate.

19. The method of claim 18, wherein the nitroxyl-donating diazeniumdiolate has the formula

20. The method of claim 19, wherein J is oxide.

21. The method of claim 19, wherein J is lower alkyl.

22. The method of claim 19, wherein J is amine.

23. The method of claim 22, wherein J is primary amine.

24. The method of claim 23, wherein the nitroxyl-donating diazeniumdiolate has the formula

25. The method of claim 24, wherein R is alkyl.

26. The method of claim 25, wherein R is lower alkyl.

27. The method of claim 26, wherein R is isopropyl.