Thyroid Hormone Analogs and Methods of Use

• US 20100112079A1
• Filed: 11/25/2009
• Published: 05/06/2010
• Est. Priority Date: 09/15/2003
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: Ordway Research Institute, Inc.
• Inventors: Davis, Paul J., Mousa, Shaker A., Davis, Faith B.
• Granted Patent: US 8,518,451 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 31/198 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 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 47/60 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 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• 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 9/08 : Vasodilators for multiple indications
• 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
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

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 for promoting angiogenesis in a patient, said method comprising administering to a subject in need thereof an effective amount of levothyroxine (T4) or triiodothyronine (T3) conjugated via a polymer, wherein said polymer is polyglycolide, polylactic acid, or co-polymers thereof, wherein said polymer is formulated into a nanoparticle, wherein the nanoparticle is less than 200 nanometers, and wherein the levothyroxine (T4) or triiodothyronine (T3) acts at the cell membrane level and has pro-angiogenic properties that are independent of the nuclear thyroid hormone receptor effects.

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, wound healing and burns.

3. The method of claim 1, wherein the mode of administration of the angiogenic agent is parenteral, oral, topical, or combinations thereof.

4. The method of claim 3, wherein said parenteral administration is subcutaneous, intraperitoneal, intramuscular, intravenous, or combinations thereof.

5. The method of claim 1, wherein the angiogenic agent is administered via catheter.

6. The method of claim 5, wherein the angiogenic agent is applied to the inside of a blood vessel via said catheter.

7. The method of claim 1, wherein the angiogenic agent 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.

8. The method of claim 7, 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.

9. The method of claim 7, wherein said vasodilator is adenosine, adenosine derivatives, or combinations thereof.

10. The method of claim 7, wherein said anticoagulant is heparin, heparin derivatives, anti-factor Xa, anti-thrombin, aspirin, clopidgrel, or combinations thereof.

11. The method of claim 7, wherein the angiogenic agent is administered as a bolus injection prior to or post-administering said growth factor, vasodilator, anti-coagulant, or combinations thereof.

12. A method for inhibiting angiogenesis in a patient, said method comprising administering to a subject in need thereof an effective amount of tetraiodothyroacetic acid (TETRAC) conjugated via a covalent bond to a polymer, wherein said polymer is polyglycolide, polylactic acid, or co-polymers thereof, wherein said polymer is formulated into a nanoparticle, wherein the nanoparticle is less than 200 nanometers, and wherein the tetraiodothyroacetic acid (TETRAC) acts at the cell membrane level to inhibit pro-angiogenesis agents.

13. The method of claim 12, wherein said condition amenable to treatment by inhibiting angiogenesis is selected from the group consisting of a primary or metastatic tumor, and diabetic retinopathy.

14. The method of claim 12, wherein the mode of administration of the anti-angiogenesis agent is parenteral, oral, rectal, topical, or combinations thereof.

15. The method of claim 12, wherein the anti-angiogenesis agent is co-administered with one or more other anti-angiogenesis therapies or chemotherapeutic agents.