Treatment of a coronary condition by delivery of therapeutics to the pericardial space

• US 20030060415A1
• Filed: 10/02/2002
• Published: 03/27/2003
• Est. Priority Date: 11/01/1995
• Status: Abandoned Application

• Current Assignee: Chiron Corporation (Bayer AG)
• Original Assignee: Chiron Corporation (Bayer AG)
• Inventors: Hung, David T.
• Application Number:
  US10/263,408
• Publication Number:
  US 20030060415A1
• Time in Patent Office: Days
• US Class Current: 514/12
• 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 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Abstract

The invention is a treatment for coronary conditions by delivering a therapeutic agent to the pericardial space. The therapeutic agent can be delivered by internal entry through the atrium or venticle, or by external entry through the chest cavity. The therapeutic agent can be a polypeptide, polynucleotide or other drug.

Claims

1. A method of treatment or prevention of a coronary condition comprising:

(a) providing a first pharmaceutical composition comprising a therapeutically effective amount of a first therapeutic agent, and

(b) administering the first pharmaceutical composition to the pericardial space of a patient.

2. The method of claim 1 comprising a first therapeutic agent selected from the group consisting of a polypeptide, a polynucleotide, a small organic molecule, a peptide, and a peptoid.

3. The method of claim 1 wherein the first therapeutic agent comprises a fibroblast growth factor polypeptide (FGF).

4. The method of claim 3 comprising an FGF polypeptide selected from the group consisting of bFGF, aFGF, and FGF-5.

5. The method of claim 1 wherein the first therapeutic agent comprises insulin-like growth factor-I polypeptide (IGF-I).

6. The method of claim 1 wherein the pharmaceutical composition further comprises a therapeutically effective amount of a second therapeutic agent.

7. The method of claim 6 comprising a second therapeutic agent selected from the group consisting of a polypeptide, a polynucleotide, a small organic molecule, a peptide, and a peptoid.

8. The method of claim 6 wherein the second therapeutic agent comprises a fibroblast growth factor polypeptide (FGF).

9. The method of claim 8 comprising an FGF polypeptide selected from the group consisting of bFGF, aFGF, and FGF-5.

10. The method of claim 6 wherein the second therapeutic agent comprises insulin-like growth factor-I polypeptide (IGF-I).

11. The method of claim 1 further comprising:

(a) providing a second pharmaceutical composition comprising a therapeutically effective amount of a second therapeutic agent, and

(b) administering the second-pharmaceutical composition to the pericardial space of a patient.

12. The method of claim 1, wherein administration to the pericardial space consisting is accomplished by internal entry or external entry.

13. The method of claim 12 comprising an internal entry selected from the group consisting of entry through the left atrium, entry through the right ventricle, and entry through the left ventricle.

14. The method of claim 12 comprising an external entry selected from the group consisting of an open chest procedure, minimally invasive surgery (MIS), and percutaneous entry.

15. The method of claim 14 comprising a percutaneous entry facilitated by a device selected from the group consisting of needle, catheter, cannula, and trocar.

16. The method of claim 1, comprising an administration to the pericardial space accomplished by a procedure selected from the group consisting of injection, catheterization, creation of laser-created perfusion channels, cannulization, use of a particle gun, and use of a pump.

17. The method of claim 1 wherein the first pharmaceutical composition comprises a component selected from the group consisting of a liposome, cyclodextrin liposome, heterovesicular liposome, a synthetic membrane vesicle, a gel, a polymer, an excipient, matrices, a charged particle and a buffer.

18. The method of claim 11 wherein the second pharmaceutical composition comprises a component selected from the group consisting of a liposome, cyclodextrin liposome, heterovesicular liposome, a synthetic membrane vesicle, a gel, a polymer, an excipient, matrices, a charged particle and a buffer.

19. The method of claim 1 wherein the first therapeutic agent is selected from the group consisting of an anti-apoptotic agent, a thrombolytic agent, a pro-angiogenic agent, an anti-arrythmic agent, a contractility improving agent, a complement blocker, an inhibitor of reperfusion injury, a calcium channel blocker, a beta-blocker, an afterload reducer, a preload reducer, a vasoactive agent, an anti-thrombotic agent, an anti-platelet agent, anti-proliferative agent, an anti-inflammatory agent, an immunomodulating agent, an immunosuppressive agent, an inhibitor of reactive oxygen metabolites, an anti-angiogenic agent, a myocyte growth factor, a vasoactive agent, a cardioprotective agent, an iron-chelating agent, an anti-hypertensive agent, an anti-integrin agent, a pro-apoptotic agent, an anti-viral agent, an anti-parasitic agent, a free radical scavenger, an anti-tumor agent, a protein that may be deficient or downregulated during development of cardiomyopathy, and biologically active derivatives thereof.

20. The method of claim 6 wherein the second therapeutic agent is selected from the group consisting of an anti-apoptotic agent, a thrombolytic agent, a pro-angiogenic agent, an anti-arrythmic agent, a contractility improving agent, a complement blocker, an inhibitor of reperfusion injury, a calcium channel blocker, a beta-blocker, an afterload reducer, a preload reducer, a vasoactive agent, an anti-thrombotic agent, an anti-platelet agent, anti-proliferative agent, an anti-inflammatory agent, an immunomodulating agent, an immunosuppressive agent, an inhibitor of reactive oxygen metabolites, an anti-angiogenic agent, a myocyte growth factor, a vasoactive agent, a cardioprotective agent, an iron-chelating agent, an anti-hypertensive agent, an anti-integrin agent, a pro-apoptotic agent, an anti-viral agent, an anti-parasitic agent, a free radical scavenger, an anti-tumor agent, a protein that may be deficient or downregulated during development of cardiomyopathy, and biologically active derivatives thereof.

21. The method of claim 11 wherein the second therapeutic agent is selected from the group consisting of an anti-apoptotic agent, a thrombolytic agent, a pro-angiogenic agent, an anti-arrythmic agent, a contractility improving agent, a complement blocker, an inhibitor of reperfusion injury, a calcium channel blocker, a beta-blocker, an afterload reducer, a preload reducer, a vasoactive agent, an anti-thrombotic agent, an anti-platelet agent, anti-proliferative agent, an anti-inflammatory agent, an immunomodulating agent, an immunosuppressive agent, an inhibitor of reactive oxygen metabolites, an anti-angiogenic agent, a myocyte growth factor, a vasoactive agent, a cardioprotective agent, an iron-chelating agent, an anti-hypertensive agent, an anti-integrin agent, a pro-apoptotic agent, an anti-viral agent, an anti-parasitic agent, a free radical scavenger, an anti-tumor agent, a protein that may be deficient or downregulated during development of cardiomyopathy, and biologically active derivatives thereof.

22. The method of claim 19, wherein the protein that may be deficient or downregulated during development of cardiomyopathy is troponin C.

23. The method of claim 19, wherein the first therapeutic agent is an anti-tumor agent and the anti-tumor agent is selected from the group consisting of a chemotherapeutic agent, a radiation sensitizer, and a radioactive implant.

24. The method of claim 1, wherein the first therapeutic agent is an inhibitor.

25. The method of claim 24, wherein the inhibitor is selected from the group consisting of an inhibitor of lipid or cholesterol synthesis or deposition, an inhibitor of macrophage or inflammatory cell recruitment or activation, a microtubule inhibitor, an anti-inflammatory agent, an anti-thrombotic agent, an anti-platelet agent, and an inhibitor of neointimal proliferation.

26. The method of claim 24, wherein the inhibitor is an inhibitor of NFκ

B.

27. The method of claim 26, wherein the inhibitor of NFκ

B is selected from the group consisting of IKB, PDTC, NAC metal chelators and anti-oxidants.

38. The method of claim 19, wherein the first therapeutic agent is an anti-proliferative agent and the anti-proliferative agent is selected from the group consisting of a ribozyme, an antisense oligonucleotide, an antibody, an inhibitor against one of c-myb, ras, raf, PI3 kinase, and cyclin, a suicide protein, a suicide gene, a proapoptotic protein, and a proapoptotic gene.

39. The method of claim 24, wherein the inhibitor is selected from the group consisting of a protein, a peptide, an oligopeptide or a small molecule.

40. The method of claim 19, wherein the first therapeutic agent is a proapoptotic protein and the proapoptotic protein is selected from the group consisting of fas, fab, and interleukin 1b converting enzyme.

41. The method of claim 19, wherein the first therapeutic agent is an anti-angiogenic agent and the antiangiogenic agent is selected from the group consisting of platelet factor 4, thrombospondin, a tissue inhibitor of a metaloproteinase, angiostatin, TFG-β

, interferon-α

, a proliferin-related protein, a biologically active fragment thereof, and a chimera thereof.

42. The method of claim 19, wherein the first therapeutic agent is an antibiotic and the antibiotic is selected from the group consisting of an anti-viral agent, anti-trypanosomal agent, anti-bacterial agent, and an anti-fungal agent.

43. The method of claim 19, wherein the first therapeutic agent is an immunomodulating agent and the immunomodulating agent is selected from the group consisting of a cytotoxic agent, a steroid, cyclosporin, and a complement inhibitor.

44. The method of claim 43, wherein the immunomodulating agent is a complement inhibitor and the complement inhibitor is selected from the group consisting of DAF, CAB-2, a biologically active fragment thereof, and a chimera thereof.

45. The method of claim 19, wherein the first therapeutic agent is an antiinflammatory agent and the antiinflammatory agent is selected from the group consisting of a steroid, a non-steroidal antiinflammatory agent, cyclosporin, a chemotherapeutic agent, and a complement inhibitor.

46. The method of claim 19, wherein the first therapeutic agent is an anti-arrhythmic agent and the anti-arrythmic agent is selected from the group consisting of adenosine, quinidine, propranolol, digoxin, lidocaine, bretylium, amiodarone, and verapamil.

47. The method of claim 19, wherein the first therapeutic agen is an anti-hypertensive agent, and the antihypertensive agent is selected from the group consisting of hydralazine, propranolol, atrial naturetic peptide, and an endothelin antagonist.

48. The method of claim 1, wherein the first therapeutic agent is a polypeptide selected from the group consisting of tissue plasminogen activator (tPA), an inhibitor of interleukin 1β

converting enzyme, urokinase plasminogen activator (uPA), urokinase, streptokinase, an inhibitor of α

2 plasmin inhibitor, an inhibitor of plasminogen activator inhibitor-1 (PAI-1), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), angiogenin, transforming growth factor a (TGF-α

), transforming growth factor β

(TGF-β

), tumor necrosis factor-α

(TNF-α

), platelet derived growth factor (PDGF), placental growth factor (PGF), hepatocyte growth factor, proliferin, decay accelerating factor, CAB-2, tissue factor pathway inhibitor (TFPI), heparin, hirudin, protein C, protein S, anti-thrombin III, tick anti-coagulant peptide (TAP), anti-stasin, glycoprotein IIb/IIa antagonist, antibodies, Herpes thymidine kinase, fas, faf, platelet factor 4, thrombospondin, a tissue inhibitor of a metalloproteinase, prolactin, bFGF soluble receptor, a proliferin-related protein, myocyte growth factor, superoxide dismutase (SOD), troponin C, beta-adrenergic receptor, insulin-like growth factor I (IGF-I), nematode anti-coagulant protein (NAP), biologically active fragments thereof, and chimeras thereof.

49. The method of claim 6, wherein the second therapeutic agent is a polypeptide selected from the group consisting of tissue plasminogen activator (tPA), an inhibitor of interleukin 1β

converting enzyme, urokinase plasminogen activator (uPA), urokinase, streptokinase, an inhibitor of α

2 plasmin inhibitor, an inhibitor of plasminogen activator inhibitor-1 (PAI-1), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), angiogenin, transforming growth factor α

(TGF-α

), transforming growth factor β

(TGF-β

), tumor necrosis factor-α

(TNF-α

), platelet derived growth factor (PDGF), placental growth factor (PGF), hepatocyte growth factor, proliferin, decay accelerating factor, CAB-2, tissue factor pathway inhibitor (TFPI), heparin, hirudin, protein C, protein S, anti-thrombin III, tick anti-coagulant peptide (TAP), anti-stasin, glycoprotein IIb/IIa antagonist, antibodies, Herpes thymidine kinase, fas, faf, platelet factor 4, thrombospondin, a tissue inhibitor of a metalloproteinase, prolactin, bFGF soluble receptor, a proliferin-related protein, myocyte growth factor, superoxide dismutase (SOD), troponin C, beta-adrenergic receptor, insulin-like growth factor I (IGF-I), nematode anti-coagulant protein (NAP), biologically active fragments thereof, and chimeras thereof.

51. The method of claim 11, wherein the second therapeutic agent is a polypeptide selected from the group consisting of tissue plasminogen activator (tPA), an inhibitor of interleukin 1β

converting enzyme, urokinase plasminogen activator (uPA), urokinase, streptokinase, an inhibitor of α

2 plasmin inhibitor, an inhibitor of plasminogen activator inhibitor-1 (PAI-1), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), angiogenin, transforming growth factor α

(TGF-α

), transforming growth factor β

(TGF-β

), tumor necrosis factor-α

(TNF-α

), platelet derived growth factor (PDGF), placental growth factor (PGF), hepatocyte growth factor, proliferin, decay accelerating factor, CAB-2, tissue factor pathway inhibitor (TFPI), heparin, hirudin, protein C, protein S, anti-thrombin III, tick anti-coagulant peptide (TAP), anti-stasin, glycoprotein IIb/IIa antagonist, antibodies, Herpes thymidine kinase, fas, faf, platelet factor 4, thrombospondin, a tissue inhibitor of a metalloproteinase, prolactin, bFGF soluble receptor, a proliferin-related protein, myocyte growth factor, superoxide dismutase (SOD), troponin C, beta-adrenergic receptor, insulin-like growth factor I (IGF-I), nematode anti-coagulant protein (NAP), biologically active fragments thereof, and chimeras thereof.

52. The method of claim 1, wherein the coronary condition is a condition selected from the group consisting of coronary artery occlusion, ischemic syndromes, cardiomyopathy, arrhythmia, dysrrhythmia, infection, and an inflammatory condition.

53. The method of claim 52, wherein the coronary condition is coronary artery occlusion and the coronary artery occlusion results from or is associated with lipid/cholesterol deposition, macrophage/inflammatory cell recruitment, plaque rupture, thrombosis, platelet deposition, or neointimal proliferation.

54. The method of claim 52, wherein the coronary condition is an ischemic syndrome and the ischemic syndrome results from or is associated with myocardial infarction, stable angina, unstable angina, coronary artery restenosis or reperfusion injury.

55. The method of claim 52, wherein the coronary condition is cardiomyopathy and the cardiomyopathy results from or associated with an ischemic syndrome, a cardiotoxin, an infection, hypertension, a metabolic disease, radiation, a neuromuscular disease, an infiltrative disease, trauma, or an idiopathic cause.

56. The method of claim 55, wherein the cardiomyopathy results from an infiltrative disease and the infiltrative disease is selected from the group consisting of sarcoidosis, hemochromatosis, amyloidosis, Fabry'"'"'s disease, and Hurler'"'"'s syndrome.

57. The method of claim 55, wherein the cardiomyopathy results from a metabolic disease and the metabolic disease is selected from the group consisting of uremia, beriberi, and glycogen storage disease.

58. The method of claim 52, wherein the coronary condition is an arrhythmia or a dysrythmia resulting from or associated with an ischemic syndrome, a cardiotoxin, adriamycin, an infection, hypertension, a metabolic disease, radiation, a neuromuscular disease, an infiltrative disease, trauma, or an idiopathic cause.

60. The method of claim 52, wherein the coronary condition is an infection caused by a pathogenic agent selected from the group consisting of a bacterium, a virus, a fungus, and a parasite.

62. The method of claim 52, wherein the coronary condition is an inflammatory condition and the inflammatory condition is associated with myocarditis, pericarditis, endocarditis, immune cardiac rejection, and an inflammatory conditions resulting from one of idiopathic, autoimmune, or a connective tissue disease.

63. The method of claim 1 further comprising the step of:

(c) enhancing access of the first therapeutic agent to myocardial tissue prior to administering the pharmaceutical composition.

64. The method of claim 63, wherein enhancing access comprises a step selected from the group consisting of increasing penetration of myocardial tissue by the first therapeutic agent, and creating perfusion channels.

65. The method of claim 64, wherein increasing penetration comprises an administration of a proangiogenic factor to a pericardial space of a patient to increase vascularization of myocardial tissue.

66. The method of claim 64, wherein increasing penetration comprises administering the first therapeutic agent in a formulation that increases tissue penetration of the first therapeutic agent.

68. The method of claim 17, wherein the component is a gel and the gel comprises Focalgel®

.

69. The method of claim 17, wherein the component is a liposome and the liposome comprises Depofoam®

.

70. The method of claim 18, wherein the component is a gel and the gel comprises Focalgel®

.

71. The method of claim 18, wherein the component is a liposome and the liposome comprises Depofoam®

.

98. The method of claim 1 wherein the first therapeutic agent comprises L-aromatic amino acid decarboxylase.

99. The method of claim 98 further comprising the step of:

(c) administering a second therapeutic agent selected from the group consisting of L-Dopa, tyrosine, a polynucleotide encoding tyrosine hydroxylase, and a tyrosine hydroxylase polypeptide.

100. The method of claim 1 wherein the first therapeutic agent comprises vascular epithelial growth factor (VEGF), a biologically active fragment thereof or a chimera thereof.

72. A method of treating cardiac muscle tissue comprising:

(a) identifying an infarct or ischemic zone,

(b) accessing a pericardial space in the region of the infarct or ischemic zone, and

(c) delivering a pharmaceutical composition comprising a therapeutic agent to the region of the infarct or ischemic zone.

73. The method of claim 72 wherein the pharmaceutical composition further comprises a component selected from the group consisting of an adherent gel, a polymer, a targeting ligand, a targeting antibody, and an agent active at low pH.

74. The method of claim 72 wherein the pharmaceutical composition comprises a combination of at least two therapeutic agents.

75. The method of claim 72 wherein the therapeutic agent is selected from the group consisting of an anti-apoptotic agent, a thrombolytic agent, a pro-angiogenic agent, an anti-arrythmic agent, a contractility improving agent, a complement blocker, an inhibitor of reperfusion injury, a calcium channel blocker, a beta-blocker, an afterload reducer, a preload reducer, a vasoactive agent, an anti-thrombotic agent, an anti-platelet agent, anti-proliferative agent, an anti-inflammatory agent, an immunomodulating agent, an immunosuppressive agent, an inhibitor of reactive oxygen metabolites, an anti-angiogenic agent, a myocyte growth factor, a vasoactive agent, a cardioprotective agent, an iron-chelating agent, an anti-hypertensive agent, an anti-integrin agent, a pro-apoptotic agent, an anti-viral agent, an anti-parasitic agent, a free radical scavenger, an anti-tumor agent, a protein that may be deficient or downregulated during development of cardiomyopathy, and biologically active derivatives thereof.

76. The method of claim 72, wherein the therapeutic agent comprises a polypeptide selected from the group consisting of tissue plasminogen activator (tPA), an inhibitor of interleukin 1β

converting enzyme, urokinase plasminogen activator (uPA), urokinase, streptokinase, an inhibitor of α

2 plasmin inhibitor, an inhibitor of plasminogen activator inhibitor-1 (PAI-1), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), angiogenin, transforming growth factor α

(TGF-α

), transforming growth factor β

(TGF-β

), tumor necrosis factor-α

(TNF-α

), platelet derived growth factor (PDGF), placental growth factor (PGF), hepatocyte growth factor, proliferin, decay accelerating factor, CAB-2, tissue factor pathway inhibitor (TFPI), heparin, hirudin, protein C, protein S, anti-thrombin III, tick anti-coagulant peptide (TAP), anti-stasin, glycoprotein IIb/IIa antagonist, antibodies, Herpes thymidine kinase, fas, faf, platelet factor 4, thrombospondin, a tissue inhibitor of a metalloproteinase, prolactin, bFGF soluble receptor, a proliferin-related protein, myocyte growth factor, superoxide dismutase (SOD), troponin C, beta-adrenergic receptor, insulin-like growth factor I (IGF-I), nematode anti-coagulant protein (NAP), biologically active fragments thereof, and chimeras thereof.

77. The method of claim 72 wherein the therapeutic agent is an FGF polypeptide.

78. The method of claim 77 wherein the FGF polypeptide is selected from the group consisting of bFGF, AFGF, and FGF-5.

79. The method of claim 72 wherein the therapeutic agent is an IGF-I polypeptide.

80. A method of accessing the pericardial space for administration of a therapeutic agent to the pericardial space comprising:

(a) providing an agent capable of lysing a pericardial/epicardial adhesion,

(b) administering the agent to the pericardial space.

81. The method of claim 80 further comprising the step of:

(c) expanding the pericardial space.

82. The method of claim 81 wherein expanding the pericardial space comprises temporary administration of liquid or gas.

83. The method of claim 80 wherein the agent capable of lysing a pericardial/epicardial adhesion is an agent selected from the group consisting of any fibrinolytic agent, tissue plasminogen activator (tPA), streptokinase, urokinase, collagenase, and a matrix metalloprotease.

84. The method of claim 80 wherein the therapeutic agent is selected from the group consisting of an anti-apoptotic agent, a thrombolytic agent, a pro-angiogenic agent, an anti-arrythmic agent, a contractility improving agent, a complement blocker, an inhibitor of reperfusion injury, a calcium channel blocker, a beta-blocker, an afterload reducer, a preload reducer, a vasoactive agent, an anti-thrombotic agent, an anti-platelet agent, anti-proliferative agent, an anti-inflammatory agent, an immunomodulating agent, an immunosuppressive agent, an inhibitor of reactive oxygen metabolites, an anti-angiogenic agent, a myocyte growth factor, a vasoactive agent, a cardioprotective agent, an iron-chelating agent, an anti-hypertensive agent, an anti-integrin agent, a pro-apoptotic agent, an anti-viral agent, an anti-parasitic agent, a free radical scavenger, an anti-tumor agent, a protein that may be deficient or downregulated during development of cardiomyopathy, and biologically active derivatives thereof.

85. The method of claim 80, wherein the therapeutic agent comprises a polypeptide selected from the group consisting of tissue plasminogen activator (tPA), an inhibitor of interleukin 1β

converting enzyme, urokinase plasminogen activator (uPA), urokinase, streptokinase, an inhibitor of α

2 plasmin inhibitor, an inhibitor of plasminogen activator inhibitor-1 (PAI-1), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), angiogenin, transforming growth factor α

(TGF-α

), transforming growth factor β

(TGF-β

), tumor necrosis factor-α

(TNF-α

), platelet derived growth factor (PDGF), placental growth factor (PGF), hepatocyte growth factor, proliferin, decay accelerating factor, CAB-2, tissue factor pathway inhibitor (TFPI), heparin, hirudin, protein C, protein S, anti-thrombin III, tick anti-coagulant peptide (TAP), anti-stasin, glycoprotein IIb/IIa antagonist, antibodies, Herpes thymidine kinase, fas, faf, platelet factor 4, thrombospondin, a tissue inhibitor of a metalloproteinase, prolactin, bFGF soluble receptor, a proliferin-related protein, myocyte growth factor, superoxide dismutase (SOD), troponin C, beta-adrenergic receptor, insulin-like growth factor I (IGF-I), nematode anti-coagulant protein (NAP), biologically active fragments thereof, and chimeras thereof.

86. Use of a therapeutic agent administered intrapericardially to treat a coronary condition wherein the therapeutic agent is selected from the group consisting of an anti-apoptotic agent, a thrombolytic agent, a pro-angiogenic agent, an anti-arrythmic agent, a contractility improving agent, a complement blocker, an inhibitor of reperfusion injury, a calcium channel blocker, a beta-blocker, an afterload reducer, a preload reducer, a vasoactive agent, an anti-thrombotic agent, an anti-platelet agent, anti-proliferative agent, an anti-inflammatory agent, an immunomodulating agent, an immunosuppressive agent, an inhibitor of reactive oxygen metabolites, an anti-angiogenic agent, a myocyte growth factor, a vasoactive agent, a cardioprotective agent, an iron-chelating agent, an anti-hypertensive agent, an anti-integrin agent, a pro-apoptotic agent, an anti-viral agent, an anti-parasitic agent, a free radical scavenger, a protein that may be deficient or downregulated during development of cardiomyopathy, and biologically active derivatives thereof.

87. Use of a therapeutic agent administered intrapericardially to treat a coronary condition wherein the therapeutic agent is selected from the group consisting of tissue plasminogen activator (tPA), an inhibitor of interleukin 1β

converting enzyme, urokinase plasminogen activator (uPA), urokinase, streptokinase, an inhibitor of α

2 plasmin inhibitor, an inhibitor of plasminogen activator inhibitor-1 (PAI-1), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), angiogenin, transforming growth factor α

(TGF-α

), transforming growth factor β

(TGF-β

), tumor necrosis factor-α

(TNF-α

), platelet derived growth factor (PDGF), placental growth factor (PGF), hepatocyte growth factor, proliferin, decay accelerating factor, CAB-2, tissue factor pathway inhibitor (TFPI), heparin, hirudin, protein C, protein S, anti-thrombin III, tick anti-coagulant peptide (TAP), anti-stasin, glycoprotein IIb/IIa antagonist, antibodies, Herpes thymidine kinase, fas, faf, platelet factor 4, thrombospondin, a tissue inhibitor of a metalloproteinase, prolactin, bFGF soluble receptor, a proliferin-related protein, myocyte growth factor, superoxide dismutase (SOD), troponin C, beta-adrenergic receptor, insulin-like growth factor I (IGF-I), nematode anti-coagulant protein (NAP), biologically active fragments thereof, and chimeras thereof, to treat a coronary condition.

88. Use of intrapericardially delivered troponic C to treat cardiomyopathy.

89. Use of an intrapericardially delivered anti-tumor agent selected from the group consisting of a chemotherapeutic agent, a radiation sensitizer, and a radioactive implant to treat heart cancer.

90. Use of an intrapericardially delivered inhibitor selected from the group consisting of an inhibitor of lipid or cholesterol synthesis or deposition, an inhibitor of macrophage or inflammatory cell recruitment or activation, a microtubule inhibitor, an anti-inflammatory agent, an anti-thrombotic agent, an anti-platelet agent, and an inhibitor of neointimal proliferation to treat a cardiovascular indication.

91. Use of an intrapericardially delivered anti-proliferative agent to treat a coronary condition characterized by cell-proliferation selected from the group consisting of a ribozyme, an antisense oligonucleotide, an antibody, an inhibitor against c-myb, ras, raf, PI3 kinase, or cyclin, a suicide protein, a suicide gene, a proapoptotic protein, and a proapoptotic gene.

92. Use of an intrapericardially delivered anti-angiogenic agent to treat a coronary condition selected from the group consisting of platelet factor 4, thrombospondin, a tissue inhibitor of a metaloproteinase, angiostatin, TFG-β

, interferon-α

, a proliferin-related protein, biologically active fragments thereof, and chimeras thereof.

93. Use of an intrapericardially delivered antibiotic selected from the group consisting of an anti-viral agent, anti-trypanosomal agent, anti-bacterial agent, and an anti-fungal agent to treat a coronary infection.

94. Use of an intrapericardially delivered immunomodulating agent selected from the group consisting of a cytotoxic agent, a steroid, cyclosporin, and a complement inhibitor to treat a coronary condition.

95. Use of an intrapericardially delivered antiinflammatory agent selected from the group consisting of a steroid, a non-steroidal antiinflammatory agent, cyclosporin, a chemotherapeutic agent, and a complement inhibitor to treat a coronary condition characterized by inflammation.

96. Use of an intrapericardially delivered anti-arrhythmic agent selected from the group consisting of adenosine, quinidine, propranolol, digoxin, lidocaine, bretylium, amiodarone, and verapamil to treat a coronary condition.

97. Use of an intrapericardially delivered anti-hypertensive agent selected from the group consisting of hydralazine, propranolol, atrial naturetic peptide, and an endothelin antagonist to treat a coronary condition.