INHIBITORS OF NCCA-ATP CHANNELS FOR THERAPY

• US 20100311639A1
• Filed: 06/20/2008
• Published: 12/09/2010
• Est. Priority Date: 06/22/2007
• Status: Active Grant

• Current Assignee: U.S. Of America As Represented By The Dept Of Veterans Affairs
• Original Assignee: U.S. Of America As Represented By The Dept Of Veterans Affairs
• Inventors: Simard, J. Marc
• Granted Patent: US 8,557,867 B2
• Time in Patent Office: Days
• US Class Current: 514/1.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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

Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NCca-ATP channel and include, for example, inhibitors of SUR1 and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant.

Claims

1. A method of treating and/or preventing progressive hemorrhagic necrosis in an individual, comprising the step of providing to the individual an effective amount of an inhibitor of a NC_Ca-ATP channel.

2. The method of claim 1, wherein the progressive hemorrhagic necrosis is a direct or indirect result of spinal cord injury.

3. The method of claim 1, wherein the inhibitor of the channel is a SUR1 inhibitor, a TRPM4 inhibitor, or a combination or mixture thereof.

4. The method of claim 3, wherein the SUR1 inhibitor is a sulfonylurea compound or a benzamido derivative.

5. The method of claim 4, wherein the sulfonylurea compound is selected from the group consisting of glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, gliclazide, glimepiride, and a combination thereof.

6. The method of claim 4, wherein the benzamido derivative is selected from the group consisting of repaglinide, nateglinide, and meglitinide.

7. The method of claim 1, wherein the inhibitor comprises a protein, a peptide, a nucleic acid, or a small molecule.

8. The method of claim 7, wherein the nucleic acid comprises an RNAi molecule or antisense RNA.

9. The method of claim 1, wherein said inhibitor is provided intravenously, subcutaneously, intramuscularly, intracutaneously, or intragastrically.

10. The method of claim 1, further comprising administering MgADP to the individual.

49. The method of claim 1, wherein said inhibitor is provided intravenously.

50. The method of claim 1, further comprising determining the effective amount of the inhibitor to be provided to the individual.

11. (canceled)

12. A kit for treating and/or preventing PHN, comprising an inhibitor of NC_Ca-ATP channel.

13. The kit of claim 12, wherein the channel inhibitor is a SUR1 inhibitor, a TRPM4 inhibitor, or a mixture or combination thereof.

14. The kit of claim 12, further comprising an additional compound for PHN or spinal cord injury.

15. A method of treating intraventricular hemorrhage in the brain of an infant or preventing intraventricular hemorrhage in the brain of an infant at risk for developing intraventricular hemorrhage, comprising administering an effective amount of an inhibitor of NC_Ca-ATP channel to the infant following birth and/or the mother prior to birth.

16. The method of claim 15, wherein the infant is a premature infant.

17. The method of claim 15, wherein the infant weighs less than 1500 grams at birth.

18. The method of claim 15, wherein the infant weighs less than 1000 grams at birth.

19. The method of claim 15, wherein the inhibitor is provided to the mother prior to 37 weeks of gestation.

20. The method of claim 15, wherein the mother is at risk for premature labor.

21. The method of claim 15, wherein the pregnancy is less than 37 weeks in gestation and the mother has one or more symptoms of labor.

22. The method of claim 15, wherein the infant was born at less than 37 weeks of gestation.

36. The method of claim 15, wherein the inhibitor of the channel is a SUR1 inhibitor, a TRPM4 inhibitor, or a combination or mixture thereof.

37. The method of claim 36, wherein the SUR1 inhibitor is a sulfonylurea compound or a benzamido derivative.

38. The method of claim 37, wherein the sulfonylurea compound is selected from the group consisting of glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, gliclazide, glimepiride, and a combination thereof.

39. The method of claim 37, wherein the benzamido derivative is selected from the group consisting of repaglinide, nateglinide, and meglitinide.

41. The method of claim 15, wherein the inhibitor comprises a protein, a peptide, a nucleic acid, or a small molecule.

42. The method of claim 41, wherein the nucleic acid comprises an RNAi molecule or antisense RNA.

43. The method of claim 15, wherein said inhibitor is provided intravenously, subcutaneously, intramuscularly, intracutaneously, or intragastrically.

44. The method of claim 15, further comprising administering MgADP to the individual.

51. The method of claim 15, wherein said inhibitor is provided intravenously.

52. The method of claim 15, further comprising determining the effective amount of the inhibitor to be provided to the infant, mother, or both.

23. (canceled)

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26. (canceled)

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32. (canceled)

33. (canceled)

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35. (canceled)

40. (canceled)

45. A kit for treating and/or preventing intraventricular hemorrhage, comprising an inhibitor of NC_Ca-ATP channel.

46. The kit of claim 45, wherein the channel inhibitor is a SUR1 inhibitor, a TRPM4 inhibitor, or a mixture or combination thereof.

47. The kit of claim 45, further comprising an additional compound for intraventricular hemorrhage.

48. The kit of claim 45, wherein the inhibitor is formulated for administration in utero.