Amino acid compositions and methods for the treatment of liver diseases
This disclosure provides pharmaceutical compositions comprising amino acid entities and uses thereof. Methods for improving liver function and for treating liver diseases comprising administering an effective amount of the compositions to a subject in need thereof are also disclosed.
1. A method for treating liver dysfunction or liver disease in a human, wherein the method comprises administering to a human subject in need thereof an effective amount of a composition comprising:
(a) a leucine amino acid entity chosen from:
(i) L-leucine or a salt thereof,
(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-leucine, or
(iii) β-hydroxy-β-methylbutyrate (HMB) or a salt thereof;
(b) an arginine amino acid entity chosen from:
(i) L-arginine or a salt thereof,
(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-arginine,
(iii) ornithine or a salt thereof,
(iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising ornithine,
(v) creatine or a salt thereof, or
(vi) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising creatine;
(c) L-glutamine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-glutamine; and
(d) N-acetylcysteine (NAC) or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising NAC,
wherein when the composition is in powder form at least 50 wt. % of the total wt. of the composition is one or more amino acid entities in free form, and wherein the total wt. % of (a)-(d) is greater than the total wt. % of other amino acid entities in the composition.
2. The method of claim 1 , wherein the subject has a disease or disorder selected from non-alcoholic fatty liver (NAFL), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), or alcoholic steatohepatitis (ASH).
3. The method of claim 1 , wherein the subject has cirrhosis, hepatocarcinoma, metabolic syndrome, type 2 diabetes, obesity, or a combination thereof.
4. The method of claim 1 , wherein administration of the composition results in two or more of:
decreasing or preventing liver fibrosis;
decreasing or preventing liver injury;
decreasing or preventing hepatocyte inflammation;
improving glucose tolerance;
decreasing or preventing steatosis;
decreasing or preventing hepatocyte ballooning;
improving gut function;
decreasing or preventing fibrogenic gene expression;
decreasing or preventing liver or macrophage expression or secretion of inflammatory cytokines or chemokines; or
decreasing or preventing hepatocyte lipid accumulation.
5. The method of claim 1 , wherein the composition further comprises one or both of:
(e) L-isoleucine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-isoleucine; and
(f) L-valine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine.
6. The method of claim 1 , wherein one or both of the arginine amino acid entity and the L-glutamine or a salt thereof or the dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-glutamine are present at a higher amount (wt. %) than the leucine amino acid entity.
7. The method of claim 1 , wherein the composition further comprises a serine amino acid entity chosen from L-serine or glycine.
8. A method for treating a fatty liver disease, wherein the method comprises administering to a human subject in need thereof an effective amount of a composition comprising:
(a) a leucine amino acid entity chosen from:
(i) L-leucine or a salt thereof,
(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-leucine, or
(iii) β-hydroxy-β-methylbutyrate (HMB) or a salt thereof;
(b) an arginine amino acid entity chosen from:
(i) L-arginine or a salt thereof,
(ii) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-arginine,
(iii) ornithine or a salt thereof,
(iv) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising ornithine,
(v) creatine or a salt thereof, or
(vi) a dipeptide or salt thereof, or tripeptide or salt thereof, comprising creatine;
(c) L-glutamine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-glutamine; and
(d) N-acetylcysteine (NAC) or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising NAC,
wherein when the composition is in powder form at least 50 wt. % of the total wt. of the composition is one or more amino acid entities in free form, and wherein the total wt. % of (a)-(d) is greater than the total wt. % of other amino acid entities in the composition.
9. The method of claim 8 , wherein the fatty liver disease is non-alcoholic fatty liver (NAFL) or non-alcoholic fatty liver disease (NAFLD).
10. The method of claim 8 , wherein the fatty liver disease is non-alcoholic steatohepatitis (NASH).
11. The method of claim 8 , wherein the fatty liver disease is alcoholic fatty liver disease (ALFD) or alcoholic steatohepatitis (ASH).
12. The method of claim 8 , wherein the composition further comprises a serine amino acid entity chosen from L-serine or glycine.
13. The method of claim 8 , wherein one or both of the arginine amino acid entity or the L-glutamine or a salt thereof or the dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-glutamine are present at a higher amount (wt. %) than the leucine amino acid entity.
14. The method of claim 8 , wherein the composition further comprises L-isoleucine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-isoleucine.
15. The method of claim 14 , wherein the composition further comprises L-valine or a salt thereof or a dipeptide or salt thereof, or tripeptide or salt thereof, comprising L-valine.
16. The method of claim 8 , wherein the composition comprises:
(1) a wt. % of the (c) in the composition is greater than the wt. % of the arginine amino acid entity of (b);
(2) the wt. % of the (c) in the composition is greater than or equal to the wt. % of the leucine amino acid entity of (a);
(3) the wt. % of the arginine amino acid entity of (b) in the composition is greater than the wt. % of the leucine amino acid entity of (a); or
(4) a combination of two or three of (1)-(3).
17. The method of claim 8 , wherein (a)-(d) are each a free amino acid or a salt thereof, and wherein the composition further comprises L-isoleucine or a salt thereof and L-valine or a salt thereof.
18. The method of claim 17 , wherein a ratio of the L-leucine or a salt thereof of (a), the L-isoleucine or a salt thereof, the L-valine or a salt thereof, the L-arginine or a salt thereof of (b), the L-glutamine or a salt thereof of (c), and the NAC or a salt thereof of (d) is, respectively, 1+/−15%:0.5+/−15%:0.5+/−15%:1.5+/−15%:2+/−15%:0.15+/−15%.
19. The method of claim 17 , wherein the composition further comprises a L-serine, and wherein a ratio of the L-leucine or a salt thereof of (a), the L-isoleucine or a salt thereof, the L-valine or a salt thereof, the L-arginine or a salt thereof of (b), the L-glutamine or a salt thereof of (c), the NAC or a salt thereof of (d), and the L-serine is, respectively, 12+/−15%:6+/−15%:3+/−15%:9+/−15%:12+/−15%:2.7+/−15%:18+/−15%.
20. A method for treating liver dysfunction or liver disease in a human, wherein the method comprises administering to a human subject in need thereof an effective amount of a pharmaceutical composition consisting essentially of:
(a) L-leucine or a salt thereof;
(b) L-arginine or a salt thereof;
(c) L-glutamine or a salt thereof;
(d) N-acetylcysteine (NAC) or a salt thereof;
(e) L-isoleucine or a salt thereof;
(f) L-valine or a salt thereof; and
(g) one or more pharmaceutically acceptable excipients.