Treating Renal and Liver Dysfunction with TLR4 Antagonists

• US 20180256669A1
• Filed: 01/08/2018
• Published: 09/13/2018
• Est. Priority Date: 08/17/2010
• Status: Active Grant

• Current Assignee: Yaqrit Limited
• Original Assignee: Yaqrit Limited
• Inventors: JALAN, Rajiv, SHAH, Naina
• Granted Patent: US 10,639,346 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: G01N 2333/705 Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/28 Neurological disorders
• CPC Class Codes: G01N 2800/347 Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention derives from the finding that increased levels of Toll like receptor 4 (TLR4) is associated with liver failure and renal dysfunction and/or brain dysfunction and that by decreasing TLR4 levels in vivo, the kidney and brain consequences of liver disease that are precipitated by superimposed infection or inflammation may be reduced. Accordingly, the invention provides TLR4 antagonists for use in a method of treating an individual suffering from liver disease presenting with renal or brain dysfunction.

Claims

1-13. -13. (canceled)

14. A method for reducing plasma ammonia in a patient comprising administering to the patient an effective amount of an antagonist of TLR4.

15. The method of claim 14, wherein the patient has been diagnosed with organ dysfunction.

16. The method of claim 14, wherein the patient has been diagnosed with dysfunction or swelling of the brain.

17. The method of claim 14, wherein the patient has been diagnosed with hyperammonemia.

18. The method of claim 14, wherein the TLR4 antagonist comprises one or more of a peptide, polypeptide, protein, antibody, polynucleotide, and small molecule.

19. The method of claim 14, wherein the TLR4 antagonist comprises one or more of STM28, TAK-242, eritoran, NI-0101, OxPAPC, IAXO-101, IAXO-102 Methyl 6-Deoxy-6-amino-2,3-di-O-tetradecyl-a-D-glucopyranoside, and IAXO-103.

20. The method of claim 19, wherein the TLR4 antagonist comprises TAK-242.

21. A method of treating hyperammonemia in a patient comprising administering to said patient a therapeutically-effective amount of an antagonist of TLR4.

22. The method of claim 21, wherein the patient has been diagnosed with organ dysfunction.

23. The method of claim 22, wherein the patient has been diagnosed with dysfunction or swelling of the brain.

24. The method of claim 21, wherein the patient has been diagnosed with hyperammonemia.

25. The method of claim 21, wherein the TLR4 antagonist comprises one or more of a peptide, polypeptide, protein, antibody, polynucleotide, and small molecule.

26. The method of claim 21, wherein the TLR4 antagonist comprises one or more of STM28, TAK-242, eritoran, NI-0101, OxPAPC, IAXO-101, IAXO-102 Methyl 6-Deoxy-6-amino-2,3-di-O-tetradecyl-a-D-glucopyranoside, and IAXO-103.

27. The method of claim 26, wherein the TLR4 antagonist comprises TAK-242.