Thyroid Hormone Analogs and Methods of Use

• US 20080124280A1
• Filed: 09/15/2005
• Published: 05/29/2008
• Est. Priority Date: 09/15/2003
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: Albany College of Pharmacy & Health Sciences
• Inventors: Davis, Paul J., Mousa, Shaker A., Davis, Faith B.
• Granted Patent: US 8,071,134 B2
• Time in Patent Office: Days
• US Class Current: 424/9.3
• 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 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/4365 the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• 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 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/12 Macromolecular compounds
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61K 51/065 : conjugates with carriers being macromolecules
• CPC Class Codes: A61L 2300/43 : Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/606 : Coatings
• CPC Class Codes: A61L 27/34 : Macromolecular materials
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 : Macromolecular materials
• CPC Class Codes: A61L 29/16 : Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

Disclosed are methods of treating subjects having conditions related to angiogenesis including administering an effective amount of a polymeric form of thyroid hormone, or an antagonist thereof, to promote or inhibit angiogenesis in the subject. Compositions of the polymeric forms of thyroid hormone, or thyroid hormone analogs, are also disclosed.

Claims

1. A method of treating a condition amenable to treatment by promoting angiogenesis, said method comprising administering to a subject in need thereof an amount of a thyroid hormone, thyroid hormone analog, or polymeric forms thereof, effective for promoting angiogenesis in said subject.

2. The method of claim 1, wherein said condition amenable to treatment by promoting angiogenesis is selected from the group consisting of:

occlusive vascular disease, coronary disease, erectile dysfunction, myocardial infarction, ischemia, stroke, peripheral artery vascular disorders, and wounds.

3. The method of claim 1, wherein the thyroid hormone or analog is conjugated to a member selected from the group consisting of:

polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethyleneglycol (PEG), polylactic acid, and agarose.

4. The method of claim 1, wherein the thyroid hormone analog is levothyroxine (T4), triiodothyronine (T3), 3,5-dimethyl-4-(4′

-hydroxy-3′

-isopropylbenzyl)-phenoxy acetic acid (GC-1), or 3,5-diiodothyropropionic acid (DITPA).

5. The method of claim 1, wherein the mode of administration of the thyroid hormone, thyroid hormone analog, or polymeric forms thereof, is parenteral, oral, rectal, topical, or combinations thereof.

6. The method of claim 5, wherein said parenteral administration is subcutaneous, intraperitoneal, intramuscular, intravenous, or combinations thereof.

7. The method of claim 1, wherein the thyroid hormone, thyroid hormone analog, or polymeric forms thereof is encapsulated or incorporated in a microparticle, liposome, or polymer.

8. The method of claim 7, wherein the polymer is polyglycolide, polylactide, or co-polymers thereof.

9. The method of claim 7, wherein the liposome or microparticle has a size of less than about 200 nm.

10. The method of claim 7, wherein the liposome or microparticle is administered intravenously.

11. The method of claim 10, wherein the liposome or microparticle is lodged in capillary beds surrounding ischemic tissue.

12. The method of claim 1, wherein the thyroid hormone, thyroid hormone analog, or polymeric forms thereof is administered via catheter.

13. The method of claim 12, wherein the thyroid hormone, thyroid hormone analog, or polymeric forms thereof is present in a polymeric system applied to the inside of a blood vessel via said catheter.

14. The method of claim 1, wherein the thyroid hormone, thyroid hormone analog, or polymeric forms thereof is co-administered with one or more compounds selected from the group consisting of:

a growth factor, a vasodilator, an anti-coagulant, and combinations thereof.

15. The method of claim 14, wherein said growth factor is selected from the group consisting of:

transforming growth factor alpha (TGFα

), transforming growth factor beta (TGFβ

), basic fibroblast growth factor, vascular endothelial growth factor, epithelial growth factor, nerve growth factor, platelet-derived growth factor, and vascular permeability factor.

16. The method of claim 14, wherein said vasodilator is adenosine, adenosine derivatives, or combinations thereof.

17. The method of claim 14, wherein said anticoagulant is heparin, heparin derivatives, anti-factor Xa, anti-thrombin, aspirin, clopidgrel, or combinations thereof.

18. The method of claim 14, wherein the thyroid hormone, thyroid hormone analog, or polymeric forms thereof is administered as a bolus injection prior to or post-administering said growth factor, vasodilator, anti-coagulant, or combinations thereof.

19. A method for promoting angiogenesis along or around a medical device, said method comprising coating the device with a thyroid hormone, thyroid hormone analog, or polymeric forms thereof, prior to inserting the device into a patient.

20. The method of claim 19, wherein said coating step further comprises coating the device with a growth factor, a vasodilator, an anti-coagulant, or combinations thereof.

21. The method of claim 19, wherein said medical device is a stent, a catheter, a cannula, or an electrode.

22. A method for treating a condition amenable to treatment by inhibiting angiogenesis, said method comprising administering to a subject in need thereof an amount of an anti-angiogenesis agent effective for inhibiting angiogenesis in said subject.

23. The method of claim 22, wherein said condition amenable to treatment by inhibiting angiogenesis is selected from the group consisting of:

a primary or metastatic tumor, glioma, breast cancer, and diabetic retinopathy.

24. The method of claim 22, wherein said anti-angiogenesis agent is tetraiodothyroacetic acid (TETRAC), triiodothyroacetic acid (TRIAC), monoclonal antibody LM609, XT 199 or combinations thereof.

25. The method of claim 22, wherein the mode of administration of the anti-angiogenesis agent is parenteral, oral, rectal, topical, or combinations thereof.

26. The method of claim 22, wherein the anti-angiogenesis agent is co-administered with one or more other anti-angiogenesis therapies or chemotherapeutic agents.

27. The method of claim 22, wherein the anti-angiogenesis agent acts at the cell surface.

28. An angiogenic agent comprising a thyroid hormone or analog thereof.

29. An angiogenic agent comprising a thyroid hormone or analog thereof conjugated to a polymer.

30. The angiogenic agent of claim 29, wherein said analog is selected from those compounds recited in FIG. 20, Tables A-D.

31. The angiogenic agent of claim 29, wherein said thyroid hormone analog is levothyroxine (T4), triiodothyronine (T3), 3,5-dimethyl-4-(4′

-hydroxy-3′

-isopropylbenzyl)-phenoxy acetic acid (GC-1), or 3,5-diiodothyropropionic acid (DITPA).

32. The angiogenic agent of claim 29, wherein said polymer is polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethyleneglycol (PEG), polylactic acid, or agarose.

33. The angiogenic agent of claim 29, wherein said conjugation is via a covalent or non-covalent bond.

34. The angiogenic agent of claim 33, wherein said covalent bond is an ester linkage or an anhydride linkage.

35. A pharmaceutical formulation comprising the angiogenic agent of claim 29 in a pharmaceutically acceptable carrier.

36. The pharmaceutical formulation of claim 35, further comprising one or more pharmaceutically acceptable excipients.

37. The pharmaceutical formulation of claim 35, wherein said agent is encapsulated or incorporated in a microparticle, liposome, or polymer.

38. The pharmaceutical formulation of claim 37, wherein the liposome or microparticle has a size less than 200 nm.

39. The pharmaceutical formulation of claim 35, wherein said formulation has a parenteral, oral, rectal, or topical mode of administration, or combinations thereof.

40. The pharmaceutical formulation of claim 35, wherein said formulation is co-administered to a subject in need thereof with one or more compounds selected from the group consisting of:

a growth factor, a vasodilator, an anti-coagulant, and combinations thereof.

41. A pharmaceutical composition for treating neurodegenerative diseases or disorders comprising a therapeutically effective amount of one or more thyroid hormone analogs.

42. The pharmaceutical composition of claim 41, wherein said thyroid hormone analog is T3, DITPA, or GC-1.

43. The pharmaceutical composition of claim 41, wherein said thyroid hormone analog is polymer conjugated.

44. The pharmaceutical composition of claim 43, wherein said polymer is selected from the group consisting of:

polyvinyl alcohol, polylactic acid, acrylic anhydride, polyethylene glycol, cellulose, and dendrimers.

45. The pharmaceutical composition of claim 41, wherein said thyroid hormone analog is conjugated to nanoparticles.

46. The pharmaceutical composition of claim 41, wherein said composition further comprises pro-angiogenesis factors, nerve growth factors, neurogenesis factors, anti-inflammatory agents, antioxidants, or combinations thereof.

47. The pharmaceutical composition of claim 46, wherein said pro-angiogenesis factor is FGF or VEGF.

48. The pharmaceutical composition of claim 46, wherein said antioxidant is vitamin C, vitamin E, resveratrol-like compounds, or combinations thereof.

49. The pharmaceutical composition of claim 46, wherein said anti-inflammatory agent is a compound selected from the group consisting of non-steroidal compounds, insulin sensitizers, and protesome inhibitors.

50. The pharmaceutical composition of claim 41, wherein the composition further comprises a pharmaceutically acceptable excipient.

51. The pharmaceutical composition of claim 41, wherein said therapeutically effective amount is a dosage of between 1 to 100 mg.

52. The pharmaceutical composition of claim 41, wherein said neurodegenerative disease or disorder is selected from the group consisting of:

motor neuron defects, amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, demyelinating diseases, myelopathies.

53. A method of treating a neurodegenerative disease or disorder, said method comprising administering to a subject in need thereof, a pharmaceutically effective amount of a pharmaceutical composition comprising one or more thyroid hormone analogs.

54. The method of claim 53, wherein the pharmaceutical composition is co-administered with nerve growth factors, neurogenesis factors, antioxidants, anti-inflammatory agents, or combinations thereof.

55. A method of repairing a damaged neural pathway of the peripheral nervous system or of the central nervous system, said method comprising administering to a subject in need thereof, a pharmaceutically effective amount of a pharmaceutical composition comprising one or more thyroid hormone analogs.

56. An imaging agent for diagnosing a neurodegenerative disease comprising a labeled thyroid hormone analog that binds to transthyretin.

57. The imaging agent of claim 56, wherein said agent passes the blood brain barrier.

58. The imaging agent of claim 56, wherein said thyroid hormone analog is selected from the group consisting of:

T3, T4 DITPA, GC-1.

59. The imaging agent of claim 56, wherein said thyroid hormone analog is polymer conjugated.

60. The imaging agent of claim 56, wherein said thyroid hormone analog is conjugated to a dendrimer.

61. The imaging agent of claim 56, wherein said neurodegenerative disease is Alzheimer'"'"'s disease.

62. The imaging agent of claim 61, wherein said agent inhibits the formation of amyloid fibrils.

63. The imaging agent of claim 56, wherein said agent is imaged by positron emission tomography, single photon emission computed tomography, or magnetic resonance imaging.

64. The imaging agent of claim 56, wherein said thyroid hormone analog is conjugated to retinoic acid, halogenated stilbestrols, or analogs thereof.

65. A method for diagnosing Alzheimer'"'"'s disease, the method comprising, administering to a subject suspected of having, or at risk for, Alzheimer'"'"'s disease an imaging agent comprising a labeled thyroid hormone analog that binds to transthyretin, and forming at least one image showing the distribution of the imaging agent within the brain of the subject using a brain imaging technique selected from the group consisting of:

positron emission tomography, single photon emission computed tomography, or magnetic resonance imaging