Methods of use of inhibitors of phosphodiesterases and modulators of nitric oxide, reactive oxygen species, and metalloproteinases in the treatment of peyronie's disease, arteriosclerosis and other fibrotic diseases

• US 20050085486A1
• Filed: 02/13/2004
• Published: 04/21/2005
• Est. Priority Date: 10/21/2003
• Status: Active Grant

• Current Assignee: Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center (University of California)
• Original Assignee: Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center (University of California)
• Inventors: Rajfer, Jacob, Gonzalez-Cadavid, Nestor F.
• Granted Patent: US 8,133,903 B2
• Time in Patent Office: Days
• US Class Current: 514/252.160
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• 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
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: C12N 2830/85 mammalian

Abstract

The present methods and compositions are of use for treatment of conditions involving fibrosis, such as Peyronie'"'"'s disease plaque, penile corporal fibrosis, penile veno-occlusive dysfunction, Dupuytren'"'"'s disease nodules, vaginal fibrosis, clitoral fibrosis, female sexual arousal disorder, abnormal wound healing, keloid formation, general fibrosis of the kidney, bladder, prostate, skin, liver, lung, heart, intestines or any other localized or generalized fibrotic condition, vascular fibrosis, arterial intima hyperplasia, atherosclerosis, arteriosclerosis, restenosis, cardiac hypertrophy, hypertension or any condition characterized by excessive fibroblast or smooth muscle cell proliferation or deposition of collagen and extracellular matrix in the blood vessels and/or heart. In certain embodiments, the compositions may comprise a PDE-4 inhibitor, a PDE-5 inhibitor, a compound that elevates cGMP and/or PKG, a stimulator of guanylyl cyclase and/or PKG, a combination of a compound that elevates cGMP, PKG or NO with an antioxidant that decreases ROS, or a compound that increases MMP activity.

Claims

1. A method of preventing or treating a condition involving fibrosis comprising:

a) administering a PDE inhibitor to an individual with a condition involving fibrosis; and

b) preventing or treating the fibrosis.

2. The method of claim 1, wherein the PDE inhibitor inhibits PDE-4 and/or PDE-5.

3. The method of claim 2, wherein the administration of a PDE inhibitor comprises long term oral prevention or treatment with sildenafil, tadalafil, vardenafil, pentoxifyllin, rolipram or another inhibitor of PDE5A and/or PDE-4.

4. The method of claim 3, wherein the PDE inhibitor is administered at the same dosage per unit of body weight as the dosages administered to rodents.

5. The method of claim 3, wherein the PDE inhibitor is administered at a different dosage than the dosages administered to rodents.

6. The method of claim 1, wherein the condition is Peyronie'"'"'s disease plaque, penile corporal fibrosis, penile veno-occlussive dysfunction, Dupuytren'"'"'s disease nodules, vaginal fibrosis and/or clitoral fibrosis in female sexual arousal disorder, abnormal wound healing, keloid formation, general fibrosis of the kidney, bladder, prostate, skin, liver, lung, heart, intestines or any other localized or generalized fibrotic condition.

7. The method of claim 6, wherein the condition is Peyronie'"'"'s disease plaque or Dupytren'"'"'s disease nodules.

8. The method of claim 1, wherein the condition is vascular fibrosis, arterial intima hyperplasia, atherosclerosis, arteriosclerosis, restenosis, hypertension, cardiac hypertrophy or any other condition characterized by excessive fibroblast or smooth muscle cell proliferation or deposition of collagen and extracellular matrix in the blood vessels and/or heart.

9. The method of claim 8, wherein the condition is arteriosclerosis or hypertension.

10. The method of claim 2, wherein the PDE-4 or PDE-5 inhibitor is administered orally, by injection, by local administration to the penis or other target tissue.

11. The method of claim 2, wherein the PDE inhibitor comprises an antisense or siRNA vector for PDE-4 and/or PDE-5.

12. The method of claim 2, wherein the PDE-5 inhibitor is specific for PDE-5 variant 3.

25. The method of claim 1, wherein said administering comprises long term continuous treatment for weeks, months or years.

13. A method of preventing or treating a condition involving fibrosis comprising:

a) administering a compound that elevates cGMP or PKG to an individual with a condition involving fibrosis; and

b) preventing or treating the fibrosis.

14. The method of claim 13, wherein the compound is a stimulator of guanylyl cyclase and/or PKG.

15. The method of claim 13, wherein the compound is a gene therapy vector comprising a PKG cDNA.

16. The method of claim 13, wherein the condition is Peyronie'"'"'s disease plaque, penile corporal fibrosis, penile veno-occlussive dysfunction, Dupuytren'"'"'s disease nodules, vaginal fibrosis, clitoral fibrosis, female sexual arousal disorder, abnormal wound healing, keloid formation, general fibrosis of the kidney, bladder, prostate, skin, liver, lung, heart, intestines or any other localized or generalized fibrotic condition, vascular fibrosis, arterial intima hyperplasia, atherosclerosis, arteriosclerosis, restenosis, cardiac hypertrophy, hypertension or any condition characterized by excessive fibroblast or smooth muscle cell proliferation or deposition of collagen and extracellular matrix in the blood vessels and/or heart.

26. The method of claim 13, wherein said administering comprises long term continuous treatment for weeks, months or years.

17. A method of preventing or treating a condition involving fibrosis comprising:

a) administering a compound that elevates NO(NO donor or generator) and/or decreases ROS to an individual with a condition involving fibrosis; and

b) preventing or treating the fibrosis.

18. The method of claim 17, wherein the compound is an NO donor, an NO generator, a gene therapy vector comprising an NOS cDNA, or a PDE inhibitor.

19. The method of claim 18, further comprising administering an antioxidant in combination with the NO donor, NO generator, gene therapy vector comprising an NOS cDNA, or PDE inhibitor.

20. The method of claim 19, wherein the combination is effective to provide an antifibrotic effect without damaging non-fibrotic tissues by excessive peroxynitrite formation.

21. The method of claim 17, wherein the condition is Peyronie'"'"'s disease plaque, penile corporal fibrosis, penile veno-occlussive dysfunction, Dupuytren'"'"'s disease nodules, vaginal fibrosis, clitoral fibrosis, female sexual arousal disorder, abnormal wound healing, keloid formation, general fibrosis of the kidney, bladder, prostate, skin, liver, lung, heart, intestines or any other localized or generalized fibrotic condition, vascular fibrosis, arterial intima hyperplasia, atherosclerosis, arteriosclerosis, restenosis, cardiac hypertrophy, hypertension or any condition characterized by excessive fibroblast or smooth muscle cell proliferation or deposition of collagen and extracellular matrix in the blood vessels and/or heart.

27. The method of claim 17, wherein said administering comprises long term continuous treatment for weeks, months or years.

22. A method of preventing or treating a condition involving fibrosis comprising:

a) administering a compound that increases MMP activity to an individual with a condition involving fibrosis; and

b) preventing or treating the fibrosis.

23. The method of claim 22, wherein the compound is an MMP activator, an antagonist of an MMP inhibitor, or a gene therapy vector comprising an MMP cDNA.

24. The method of claim 23, wherein the compound is a Beta thymosin or another peptide in the thymosin family.

28. The method of claim 22, wherein said administering comprises long term continuous treatment for weeks, months or years.

29. A method comprising:

administering an amount of a cyclic guanosine 3′

,5′

-monophosphate (CGMP) type 5 phosphodiesterase (PDE

     5) inhibitor to effect a condition comprising fibrosis.