COMPOSITIONS AND METHODS FOR THE REDUCTION OR PREVENTION OF NON-ALCOHOLIC STEATOHEPATITIS (NASH)

• US 20170239253A1
• Filed: 03/01/2017
• Published: 08/24/2017
• Est. Priority Date: 09/01/2015
• Status: Active Application

• Current Assignee: Nusirt Sciences, Inc.
• Original Assignee: Nusirt Sciences, Inc.
• Inventors: Zemel, Michael, Bruckbauer, Antje
• Application Number:
  US15/447,049
• Publication Number:
  US 20170239253A1
• Time in Patent Office: Days
• 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 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: G01N 2333/495 Transforming growth factor [TGF]
• CPC Class Codes: G01N 2333/9108 with definite EC number (2.3.2.-)
• CPC Class Codes: G01N 2333/91188 transferring nitrogenous groups (2.6)
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

Methods useful for sustaining a reduction of non-alcoholic steatohepatitis are provided herein. Such methods may comprise administering to a subject in need thereof a sirtuin pathway activator and/or PDE5 inhibitor alone or in combination with an amount of a branched amino acid in free amino acid form, or a metabolite thereof. Also provided herein are compositions and kits for practicing any of the methods described herein.

Claims

1. A method of sustaining a reduction of non-alcoholic steatohepatitis (NASH) in a subject, said method comprising:

(a) measuring a level of one or more biomarkers or physiological indicators of non-alcoholic steatohepatitis (NASH) in the subject;

(b) administering to said subject a pharmaceutical composition comprising;

(i) an amount of leucine in the form of a free amino acid and/or a metabolite thereof;

(ii) an amount of metformin and/or an amount of sildenafil; and

(c) monitoring said level of said one or more biomarkers or physiological indicators in said subject;

wherein said one or more biomarkers is selected from the group consisting of transforming growth factor (TGF)-β

, cytokeratin 18, aspartate transaminase (AST), and gamma glutamyl transferase (GGT).

2. The method of claim 1, wherein said physiological indicator is liver stiffness evaluated by performing transient elastography (TE).

3. The method of claim 1, wherein said transforming growth factor (TGF)-β

, cytokeratin 18, aspartate transaminase (AST), and gamma glutamyl transferase (GGT) are evaluated by measuring their respective serum levels in said subject.

4. The method of claim 1, wherein said leucine is administered in a tablet or a capsule that does not contain sildenafil.

5. The method of claim 1, wherein the pharmaceutical composition comprises an amount of metformin and an amount of sildenafil.

6. The method of claim 5, wherein said metformin and said sildenafil are administered in the same tablet or capsule.

7. The method of claim 1, wherein said subject has been diagnosed with said non-alcoholic steatohepatitis (NASH).

8. The method of claim 1, wherein said subject exhibits a propensity to said non-alcoholic steatohepatitis (NASH).

9. The method of claim 1, wherein said subject exhibits a non-alcoholic fatty liver disease (NAFLD).

10. The method of claim 9, wherein said NAFLD is selected from the group consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and NASH-related cirrhosis.

11. The method of claim 1, wherein said subject has non-alcoholic steatohepatitis (NASH).

12. The method of claim 1, wherein said pharmaceutical composition is administered orally.

13. The method of claim 1, wherein said leucine metabolite thereof is β

-hydroxy β

-methylbutyrate (HMB) or keto-isocaproic acid (KIC).

14. The method of claim 1, wherein said pharmaceutical composition comprises two or more tablets or capsules.

21. The method of claim 1, wherein said pharmaceutical composition comprises about 0.25-3 g of leucine in the form of a free amino acid and/or a metabolite thereof, about 0.1-1 g of metformin, and about 0.1-3 mg of sildenafil.

22. The method of claim 1, wherein said pharmaceutical composition comprises about 0.25-3 g of leucine in the form of a free amino acid and/or a metabolite thereof.

24. The method of claim 1, wherein said pharmaceutical composition comprises about 0.1-1 g of metformin.

25. The method of claim 1, wherein said pharmaceutical composition comprises about 0.1-3 mg of sildenafil.

27. The method of claim 1, wherein said pharmaceutical composition is substantially free of one or more free amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

28. The method of claim 1, wherein a wt % of said leucine in the form of a free amino acid and/or a metabolite thereof in said pharmaceutical composition, excluding fillers, is about 50-95 wt %.

29. The method of claim 1, wherein a wt % of said metformin in said pharmaceutical composition, excluding fillers, is about 5-50 wt %.

30. The method of claim 1, wherein a wt % of said sildenafil in said pharmaceutical composition, excluding fillers, is about 0.01-1 wt %.

31. The method of claim 1, wherein a decrease of level of said one or more biomarkers or physiological indicators in said subject indicates a sustained reduction of non-alcoholic steatohepatitis (NASH) in said subject.

15-20. -20. (canceled)

23. (canceled)

26. (canceled)

32-54. -54. (canceled)