ANTITHROMBOTIC AGENTS AND METHODS OF USE THEREOF

• US 20110104146A1
• Filed: 06/19/2008
• Published: 05/05/2011
• Est. Priority Date: 06/19/2007
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Faraday, Nauder
• Granted Patent: US 9,585,899 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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

The instant invention provides methods and compositions for the treatment, prevention and diagnosis of for example, platelet aggregation or clot formation in a subject. The invention inhibits the activity of decreases the amount of neutrophils in the subject by inhibiting the activity or production of IL-6, interferon-gamma, STAT1, or cathepsin D. The invention addresses decreasing the amount of neutrophils in an attempt to treat subjects that have or are at risk of developing a vascular occlusive disease, an ischemia or reperfusion injury, an acute or chronic inflammatory state, autoimmune disease, myelodysplastic syndrome, tissue injury from surgery or accidental trauma, acute bacterial or viral infection, has undergone a microvascular surgical reconstructive procedure, is receiving granulocyte colony stimulating factor therapy, receiving stem cell therapy, or has sickle cell anemia.

Claims

1. A method of inhibiting platelet aggregation or clot formation in a subject, comprising:

inhibiting the activity or decreasing the amount of neutrophils in the subject;

thereby inhibiting platelet aggregation or clot formation.

2. The method of claim 1, wherein inhibiting the activity or decreasing the amount of neutrophils in the subject is by inhibiting the activity or production of IL-6.

3. The method of claim 1, wherein inhibiting the activity or decreasing the amount of neutrophils in the subject is by inhibiting the activity or production of Interferon-gamma.

4. The method of claim 1, wherein the subject is administered an inhibitor of Interferon-gamma activity or production.

5. The method of claim 4, wherein the subject is administered an inhibitor of IL-6 activity or production.

7. The method of claim 5, wherein the IL-6 inhibitor is Am-80, madindoline A, madindoline B, 20S,21-Epoxy-resibufogenin-3-formate, or tocilizumab.

8. The method of claim 5, wherein the Interferon gamma inhibitor is Secretory leucocyte protease inhibitor, Fontolizumab, or MD-1.

9. The method of claim 5, wherein the inhibitor of IL-6 or Interferon-gamma is an inhibitor of STAT1 activity or expression.

10. The method of claim 1, wherein the subject has, or is at risk of developing, a vascular occlusive disease, an ischemia or reperfusion injury, an acute or chronic inflammatory state, autoimmune disease, myelodysplastic syndrome, tissue injury from surgery or accidental trauma, acute bacterial or viral infection, has undergone a microvascular surgical reconstructive procedure, is receiving granulocyte colony stimulating factor therapy, receiving stem cell therapy, or has sickle cell anemia.

6. (canceled)

11-20. -20. (canceled)

21. A method of inhibiting platelet aggregation or clot formation in a subject, comprising:

inhibiting the expression or activity of cathepsin G in the subject;

thereby inhibiting platelet aggregation or clot formation.

22. The method of claim 21, wherein the cathepsin G is produced by neutrophils.

23. The method of claim 21, wherein the inhibiting the expression or activity of cathepsin G comprises administering the subject an inhibitor selected from the group consisting of a nucleic acid, polypeptide, peptide, antibody, or small molecule.

24. The method of claim 23, wherein the inhibitor of cathepsin G is Z-gly-leu-phe-chloromethyl ketone, cathepsin G inhibitor 1 (C₃₆H₃₃N₂O₆P), Gly-Leu-Phe, benzyloxycarbonyl-Gly-Leu-Phe-chloromethyl ketone, Ala-Ala-Pro-Phe, N-(Methoxysuccinyl)-Ala-Ala-Pro-Phe-chloromethyl ketone, Ala-Ala-Pro-Val, N-(Methoxysuccinyl)-Ala-Ala-Pro-Val-chloromethyl ketone, Acetyl-Thr-Glu-Phe-Gly-Ser-Glu-Leu-Lys-Ser-Phe-Pro-Glu-Val-Val-Gly-Lys-Thr-Val-Asp-Gln-Ala-Arg-Glu-Tyr-Phe-Thr-Leu-His-Tyr-Pro-Gln-Tyr-Asp-Val-Tyr-Phe-Leu-Pro-Glu-Gly-Ser-Pro-Val-Thr-Leu-Asp-Leu-Arg-Tyr-Asn-Arg-Val-Arg-Val-Phe-Tyr-Asn-Pro-Gly-Thr-Asn-Val-Val-Asn-His-Val-Pro-His-Val-Gly-OH (acetyl-eglin C), Pro-Val-Thr-Leu, Ser-Pro-Val-Thr-Leu-Asp-Leu-Arg-Tyr, monocyte neutrophil elastase inhibitor, maspin, secretory leukocyte protease inhibitor, Gly-Thr-Glu-Ala-Ala-Ala-Ala-Thr-Ala-Gly-Ile-Ala-Thr-Phe-Cys, Met-Leu-Met-Phe-Glu-Glu-Asn-Phe-Thr-Ala-Asp-His-Pro-Phe, Gly-Thr-Glu-Ala-Ala-Ala-Ala-Thr-Gly-Gly-Ile-Ala-Thr-Phe-Cys, Met-Leu-Leu-Pro-Glu-Glu-Glu-Phe-Thr-Val-Asp-His-Pro-Phe, Gly-Thr-Glu-Ala-Ala-Ala-Ala-Thr-Gly-Gly-Ile-Ile-Gln-Val-Leu-Cys-Glu-Lys-Met-Pro-Thr-Pro-Gln-Glu-Val-Phe-Thr-Val-Asp-His-Pro-Phe, β

-ketophosphonate 1 (JNJ-10311795;

RWF-355871), Ac-Ala-Ala-ANva-OPh, Ac-Ala-Ala-ANIe-OPh, Ac-Ala-Ala-ANle-OCH2CF3, or Ac-Ala-Ala-ANle-OEt.

33. The method of claim 21, wherein the subject has experienced tissue injury from surgery or accidental trauma.

34. The method of claim 21, wherein the subject has an acute bacterial or viral infection selected from the group consisting of pneumonia, bronchitis, urinary tract infection, and sepsis.

35. The method of claim 21, wherein the subject has undergone a microvascular surgical reconstructive procedure.

36. The method of claim 21, wherein the subject is receiving granulocyte colony stimulating factor therapy.

37. The method of claim 21, wherein the subject is receiving stem cell therapy.

38. The method of claim 21, wherein the subject has sickle cell anemia.

39. The method of claim 21, wherein the vascular occlusive disease is a heart attack, myocardial infarction, unstable angina, stroke, peripheral arterial occlusive disease or thromboembolism, venous thromboembolism, thromboembolism of a coronary artery bypass graft, coronary artery stent, native carotid artery after surgical endarterectomy, carotid artery stent, renal artery bypass graft, renal artery stent, subclavian artery bypass graft, subclavian artery stent, aortic artery graft, aortic artery stent, iliac artery bypass graft, iliac artery stent, femoral artery bypass graft, femoral artery stent, peripheral artery bypass graft, or peripheral artery stent.

25-32. -32. (canceled)

40-41. -41. (canceled)

42. A method of inhibiting the activity of neutrophils in a subject, comprising:

inhibiting the activity or expression of IL-6, Interferon-gamma, and/or STAT1-alpha;

thereby inhibiting the activity of neutrophils in a subject.

45. The method of claim 42, wherein the subject is administered an IL-6 inhibitor.

47. The method of claim 45, wherein the IL-6 inhibitor is Am-80, madindoline A, madindoline B, 20S,21-Epoxy-resibufogenin-3-formate, or tocilizumab.

48. The method of claim 42, wherein the subject is administered an Interferon-gamma inhibitor.

50. The method of claim 42, wherein the Interferon-gamma inhibitor is Secretory leucocyte protease inhibitor, Fontolizumab, or MD-1.

51. The method of claim 42, wherein the subject is administered a STAT1-alpha inhibitor.

52. The method of claim 51, wherein the inhibitor is a nucleic acid, polypeptide, peptide, antibody, or small molecule.

53. The method of claim 52, wherein the STAT1-alpha inhibitor is parthenolide or STAT1-beta.

43-44. -44. (canceled)

46. (canceled)

49. (canceled)

54-63. -63. (canceled)

64. A method of treating a subject having, or at risk of developing, a vascular occlusive disease comprising:

administering to the subject (1) an effective amount of a compound that inhibits the expression or activity of IL-6, (2) an effective amount of a compound that inhibits the expression or activity of Interferon-gamma, (3) an effective amount of a compound that inhibits the expression or activity of STAT1-alpha, or (4) an effective amount of a compound that inhibits the expression or activity of capthesin G;

thereby treating the subject.

65-78. -78. (canceled)

79. A method of treating a subject having, or at risk of developing, a disease or disorder characterized by platelet aggregation comprising:

administering to the subject (1) an effective amount of a compounds that inhibits the expression or activity of capthesin G, (2) an effective amount of a compound that inhibits the expression or activity of IL-6, (3) an effective amount of a compound that inhibits the expression or activity of Interferon-gamma, and/or (4) an effective amount of a compound that inhibits the expression or activity of STAT1-alpha,

thereby treating the subject.

80-90. -90. (canceled)

91. A method for diagnosing the presence of a vascular occlusive disease comprising:

measuring the amount or activity of cathepsin G in serum, plasma, or leukocytes, wherein an increased amount or activity as compared to a control is indicative of an increased risk of developing a vascular occlusive disease or measuring the amount or activity of interferon-gamma in serum, plasma, or leukocytes, wherein an increased amount or activity as compared to a control is indicative of an increased risk of developing a vascular occlusive disease.

92-98. -98. (canceled)

99. A kit for the prevention or treatment of a vascular occlusive disease comprising a capthesin G inhibitor and instructions for use, or

a kit for the prevention or treatment of a vascular occlusive disease comprising an IL-6 inhibitor and instructions for use, or

a kit for the prevention or treatment of a vascular occlusive disease comprising an IL-6 inhibitor and instructions for use, or

a kit for the prevention or treatment of a vascular occlusive disease comprising an IL-6 inhibitor and instructions for use, or

a kit for the prevention or treatment of a vascular occlusive disease comprising an Interferon-gamma inhibitor and instructions for use,

a kit for the prevention or treatment of a vascular occlusive disease comprising an Interferon-gamma inhibitor and instructions for use, or

a kit for the prevention or treatment of a vascular occlusive disease comprising an Interferon-gamma inhibitor and instructions for use, or

a kit for the prevention or treatment of a vascular occlusive disease comprising a STAT1-alpha inhibitor and instructions for use.

100-105. -105. (canceled)