Macrocyclic lactone compounds and methods for their use

1. A method of inhibiting smooth muscle cell proliferation or cytokine production in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the formula:

or

a salt or isomer thereof;

wherein the compound is administered with a pharmaceutically acceptable excipient, thereby inhibiting smooth muscle cell proliferation or cytokine production.

2. The method of claim 1 , wherein the compound is administered systemically, locally or via a combination thereof.

3. The method of claim 1 , wherein the compound is administered orally, as a suppository, topically, parenterally, intravascularly, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally, pulmonarily, mucosally, transdermally, ophthalmically, subcutaneously or intrathecally.

4. The method of claim 1 , wherein the administration of the compound is via delivery from a temporary device or an implant.

5. The method of claim 4 , wherein the temporary device is selected from the group consisting of a catheter and a porous balloon.

6. The method of claim 4 , wherein the implant is a vascular prosthesis.

7. The method of claim 1 , wherein the effective dose of the compound is from about 0.1 mg to about 20 mg.

8. The method of claim 7 , wherein the effective dose of the compound is from about 0.5 mg to about 10 mg.

9. The method of claim 7 , wherein the effective dose of the compound is from about 1 mg to about 5 mg.

10. The method of claim 1 , wherein the compound is administered in combination with an additional therapeutic agent.

11. The method of claim 10 , wherein the additional therapeutic agent is a member selected from the group consisting of heparin, clopidogrel, coumadin, aspirin, ticlid, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid, fenoprofen, nambumetone (RELAFEN®), acetaminophen, nimesulide, NS-398, flosulid, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxib sodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067, L-748780, L-761066, o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS), etodolac, meloxicam, S-2474, tacrolimus, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, triamcinolone, paramethasone, fluprednisolone, betamethasone, dexamethasone, fludrocortisone, desoxycorticosterone, rapamycin, and cyclosporine.

12. The method of claim 1 , wherein the pharmaceutically acceptable excipient is a member selected from the group consisting of a polymer, a solvent, an antioxidant, a binder, a filler, a disintegrant, a lubricant, a coating, a sweetener, a flavor, a stabilizer, a colorant, a metal, a ceramic, a semi-metal, a preserving agent, a glidant, a wetting agent, an emulsifying agent, a suspending agent, a dispensing agent, an acidifying agent, and a perfuming agent.

13. The method of claim 12 , wherein the pharmaceutically acceptable excipient is a polymer.

14. The method of claim 13 , wherein the polymer is selected from the group consisting of polyurethane, polyethylene imine, ethylene vinyl alcohol copolymer, silicone, C-flex, nylons, polyamide, polyimide, polytetrafluoroethylene (PTFE), parylene, parylast, poly(methacrylate), poly(vinyl chloride), poly(dimethyl siloxane), poly(ethylene vinyl acetate), polycarbonate, polyacrylamide gels, poly(methyl methacrylate), poly(n-butyl methacrylate), poly (butyl methacrylate) copolymer or blended with poly(ethylene vinyl acetate), poly(methyl methacrylate), poly(2-hydroxy ethyl methacrylate), poly(ethylene glycol methacrylates), poly(ethylene carbonate), Poly L lactide-glycolide copolymer, poly L lactide-trimethylene carbonate copolymer and Poly L-lactide.

15. The method of claim 14 , wherein the polymer is selected from the group consisting of poly(ethylene carbonate), Poly L lactide-glycolide copolymer, and poly(n-butylmethacrylate).

16. The method of claim 13 , wherein the compound is present in an amount of at least 25% (w/w) in a mixture of the compound and the polymer.

17. The method of claim 16 , wherein the compound is present in an amount of at least 50% (w/w).

18. The method of claim 16 , wherein the compound is present in an amount of at least 75% (w/w).

19. The method of claim 4 , wherein the temporary device or implant is configured to release the compound to a body lumen or organ within an intracorporeal body.

20. The method of claim 6 , wherein the vascular prosthesis has a luminal surface and a tissue facing surface, and wherein the compound is associated with at least one of the luminal and tissue facing surfaces.

21. The method of claim 4 , wherein the amount of the compound associated with the temporary device or implant is from about 1 nanogram/cm 2 to about 1000 microgram/cm 2 .

22. The method of claim 21 , wherein the amount of the compound associated with the temporary device or implant is from about 1 microgram/cm 2 to about 500 microgram/cm 2 .

23. The method of claim 21 , wherein the amount of the compound associated with the temporary device or implant is from about 10 microgram/cm 2 to about 400 microgram/cm 2 .

24. The method of claim 4 , wherein the concentration of the compound in tissue adjacent to the temporary device or implant is from about 0.001 μg/gm tissue to about 1000 μg/gm tissue.

25. The method of claim 24 , wherein the concentration of the compound in tissue adjacent to the temporary device or implant is from about 1 ng/gm tissue to about 500 μg/gm tissue.

26. The method of claim 24 , wherein the concentration of the compound in tissue adjacent to the temporary device or implant is from about 100 ng/gm tissue to about 100 μg/gm tissue.

27. The method of claim 1 , wherein

the compound is administered via a vascular prosthesis; and

the pharmaceutically acceptable excipient comprises a polymer selected from the group consisting of poly(ethylene carbonate), Poly L lactide-glycolide copolymer, and poly(n-butylmethacrylate).

28. The method of claim 1 , wherein the compound is racemic at the C-16 position.

29. The method of claim 1 , wherein the compound has an (R)-stereochemistry at the C-16 position.

30. The method of claim 1 , wherein the compound has an (S)-stereochemistry at the C-16 position.

31. The method of claim 6 , wherein the vascular prosthesis comprises an expandable structure.

32. The method of claim 6 , wherein the vascular prosthesis comprises a scaffold formed at least in part from an open lattice.

33. The method of claim 6 , wherein the vascular prosthesis comprises a stent.

34. The method of claim 6 , wherein the vascular prosthesis comprises a graft.