Reciprocal regulation of inflammation and lipid metabolism by liver X receptors

• US 20040259948A1
• Filed: 01/12/2004
• Published: 12/23/2004
• Est. Priority Date: 01/10/2003
• Status: Abandoned Application

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Joseph, Sean B., Castrillo, Antonio, Tontonoz, Peter
• Application Number:
  US10/755,720
• Publication Number:
  US 20040259948A1
• Time in Patent Office: Days
• US Class Current: 514/560
• 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 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention is related to the role of liver X receptors (LXRs) in inflammation and immunity. More particularly, methods are disclosed for identifying and using LXR agonists for the treatment of inflammatory processes.

Claims

1. A method of reducing of inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of an LXR agonist.

15. The method of claim 1, wherein said inflammatory disease is atherosclerosis, rheumatoid arthritis, or glomerulonephritis.

17. The method of any one of claims 1, 2, 3, 4, 5, 6, 7, 9, 1113, 14, or 16, wherein said LXR agonist is GW3965 or T0901317.

2. A method of reducing inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of an LXR agonist, wherein said therapeutically effective amount of said LXR agonist exhibits a relatively greater effect on expression of an inflammatory gene than on expression of a lipid metabolism gene, such that inflammation is reduced without a significant effect on lipid metabolism.

3. A method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an LXR agonist.

4. A method for treating, controlling, preventing or reducing the risk of contracting an inflammatory disease or condition in a mammal comprising

selecting a mammal in need thereof, and

administering to said mammal a therapeutically effective amount of an LXR agonist.

5. The method of claim 4, wherein the inflammatory disease or condition is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, degenerative joint disease, one or more connective tissue diseases, ankylosing spondylitis, bursitis, Sjogren'"'"'s syndrome, psoriasis, psoriatic arthritis, neuralgia, synoviitis, glomerulonephritis, vasculitis, sarcoidosis, atherosclerosis, asthma, inflammatory bowel disease, inflammations that occur as sequellae to influenza, the common cold and other viral infections, gout, contact dermatitis, low back and neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, burns, injuries, and pain and inflammation that follow surgical and dental procedures in a patient.

6. A method for treating, controlling, preventing or reducing the risk of contracting an inflammatory disease or condition in a mammal, comprising

selecting a mammal in need thereof, and

administering to the mammal a therapeutically effective amount of an LXR agonist and one or more additional therapeutic compounds, wherein said additional therapeutic compounds are selected from the group consisting of a pain reliever, an NSAID, a corticosteroid, a caffeine, an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant, an antitussive, a diuretic, and a sedating or non-sedating antihistamine.

7. The method of claim 6, wherein said pain reliever is selected from the group consisting of acetominophen and phenacetin;

said NSAID is a non-selective or selective COX-2 inhibitor, said corticosteroid is selected from the group consisting of hydrocortisone, prednisolone, 6-alpha-methylprednisolone, triamcinolone, dexamethasone and betaroethasone, said decongestant selected from phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, and levo-desoxyephedrine;

said antitussive is selected from the group consisting of codeine, hydrocodone, caramiphen, carbetapentane, and dextramethorphan.

8. A method for treating, controlling, preventing or reducing the risk of contracting an inflammatory disease or condition in a mammal, comprising

selecting a mammalian patient in need thereof;

and

administering to the mammal a therapeutically effective amount of an LXR agonist and an NSAID.

9. The method of claim 8, wherein said NSAID is a non-selective COX-2 inhibitor.

10. The method of claim 8, wherein said NSAID is a selective COX-2 inhibitor.

11. The method of claim 10, wherein said selective COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, celecoxib, parecoxib and valdecoxib.

12. A method for treating, controlling, preventing or reducing the risk of contracting an inflammatory disease or condition in a mammal, comprising

selecting a mammal in need thereof;

and

administering to the mammal a therapeutically effective amount of an LXR agonist and a corticosteroid.

13. The method of claim 12, wherein said corticosteroid is selected from the group consisting of hydrocortisone, prednisolone, 6-alpha-methylprednisolone, triamcinolone, dexamethasone and betaroethasone.

14. A method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an LXR agonist, wherein said inflammatory disease is macrophage-dependentt.

16. A method for inhibiting inflammatory gene expression in a mammal, comprising administering to the mammal an amount of an LXR agonist sufficient to antagonize NF-κ

B signaling such that said inflammatory gene expression is inhibited.

18. A screening method for identifying an anti-inflammatory compound, comprising:

(a) treating a cell with a test compound;

(b) measuring expression in said cell of a gene involved in lipid metabolism in response to said test compound;

(c) measuring expression in said cell of a gene involved in inflammation in response to said test compound;

(d) repeating steps (a)-(c) with another test compound; and

(e) identifying the compound which preferentially alters the expression of the gene involved in inflammation.

19. A method of reducing of inflammation in a mammal, comprising

administering to the mammal a therapeutically effective amount of the compound identified by the screening method of claim 18.

20. A pharmaceutical composition, comprising a first agent comprising the anti-inflammatory compound identified by the screening method of claim 18 and a second agent selected from the group consisting of a NSAID and a glucocorticoid, wherein therapeutically effective amounts of the first and second agents are formulated in a pharmaceutically acceptable carrier.