Estradiol metabolites for the treatment of pulmonary hypertension

• US 20060194775A1
• Filed: 05/09/2006
• Published: 08/31/2006
• Est. Priority Date: 02/20/2003
• Status: Abandoned Application

• Current Assignee: University Of Pittsburgh (University of Pittsburgh of The Commonwealth System of Higher Education)
• Original Assignee: University Of Pittsburgh (University of Pittsburgh of The Commonwealth System of Higher Education)
• Inventors: Jackson, Edwin K., Tofovic, Stevan P.
• Application Number:
  US11/431,180
• Publication Number:
  US 20060194775A1
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L

Abstract

Methods are provided for the treatment of pulmonary hypertension and other conditions associated therewith. In particular, the methods include treatment of pulmonary hypertension with an estradiol metabolite or alkoxy analogue of an estradiol metabolite. The estradiol metabolite or alkoxy analogue thereof may be associated with biodegradable microparticles or nanoparticles alone or in combination with other therapeutic agents. Preferred estradiol metabolites include 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol and preferred alkoxy analogues of estradiol metabolites include 2-ethoxyestradiol, and/or to synthetic derivatives and analogues thereof or prodrugs thereof. The compositions may also be in the form of a controlled release formulation.

Claims

1. A method of treating pulmonary hypertension in an individual, comprising:

administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite or an alkoxy analogue of an estradiol metabolite.

2. The method of claim 1, wherein said estradiol metabolite is selected from the group consisting of 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestradiol and 4-methoxyestradiol and the alkoxy analogue of an estradiol metabolite is 2-ethoxyestradiol.

3. The method of claim 1, further comprising a prodrug of said estradiol metabolite or alkoxy analogue of said estradiol metabolite.

4. The method of claim 1, wherein said composition comprises a controlled release formulation.

5. The method of claim 1, wherein said treatment of pulmonary hypertension reduces one or more of:

central venous pressure;

heart weight;

lung weight;

right ventricular hypertrophy;

pulmonary vascular resistance;

pulmonary vascular fibrosis;

inflammation;

cellular proliferation;

vascular remodeling; and

vascular endothelial growth factor expression in the lungs, heart and pulmonary arteries.

6. The method of claim 5, wherein said estradiol metabolite is selected from the group consisting of 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestradiol and 4-methoxyestradiol and the alkoxy analogue of an estradiol metabolite is 2-ethoxyestradiol.

7. The method of claim 5, further comprising a prodrug of said estradiol metabolite or the alkoxy analogue of an estradiol metabolite.

8. The method of claim 5, wherein said composition comprises a controlled release formulation.

9. A method of treating heart failure in an individual, comprising:

administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite or alkoxy analogue of an estradiol metabolite.

10. The method of claim 9, wherein said estradiol metabolite is selected from the group consisting of 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestradiol and 4-methoxyestradiol and the alkoxy analogue of an estradiol metabolite is 2-ethoxyestradiol.

11. The method of claim 9, further comprising a prodrug of said estradiol metabolite or alkoxy analogue of an estradiol metabolite.

12. The method of claim 9, wherein said composition comprises a controlled release formulation.

13. A method of reducing a disease factor in an individual with pulmonary hypertension, comprising administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite or alkoxy analogue of an estradiol metabolite, wherein said disease factor to be reduced is selected from the group consisting of:

central venous pressure;

heart weight;

lung weight;

right ventricular hypertrophy;

pulmonary vascular resistance;

pulmonary vascular fibrosis;

inflammation;

cellular proliferation;

vascular remodeling; and

vascular endothelial growth factor expression in the lungs, heart and pulmonary arteries.

14. The method of claim 13, wherein said estradiol metabolite is selected from the group consisting of 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestradiol and 4-methoxyestradiol and the alkoxy analogue of an estradiol metabolite is 2-ethoxyestradiol.

15. The method of claim 13, further comprising a prodrug of said estradiol metabolite or alkoxy analogue of an estradiol metabolite.

16. The method of claim 13, wherein said composition comprises a controlled release formulation.