COMPOSITIONS AND METHODS FOR INCREASING ENERGY METABOLISM

• US 20160279130A1
• Filed: 11/13/2013
• Published: 09/29/2016
• Est. Priority Date: 11/13/2012
• Status: Active Grant

• Current Assignee: Nusirt Sciences, Inc.
• Original Assignee: Nusirt Sciences, Inc.
• Inventors: ZEMEL, Michael, BRUCKBAUER, Antje, BAGGETT, Brooke
• Granted Patent: US 9,943,517 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 31/05 Phenols cannabinoids A61K31/658
• 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 31/4415 Pyridoxine, i.e. Vitamin B6 pyridoxal phosphate A61K31/675
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compositions and methods useful for inducing an increase in fatty acid oxidation or mitochondrial biogenesis, reducing weight gain, inducing weight loss, or increasing Sirt1, Sirt3, or AMPK activity are provided herein. Such compositions comprise a combination of a PDE 5 inhibitor, such as sildenafil or icariin, and resveratrol, and a branched amino acid such as leucine, or its metabolite.

Claims

1. A composition effective for enhancing energy metabolism comprising:

a) a phosphodiesterase 5 (PDE

     5) inhibitor; and

b) leucine and/or a leucine metabolite.

2. The composition of claim 1, wherein the composition enhances energy metabolism in the subject to a greater degree as compared to administering to the subject component (a) or component (b) alone.

3. The composition of claim 2, wherein the enhanced energy metabolism is measured by an increase in fatty acid oxidation of an adipocyte by at least about 300%, an increase in glucose utilization of an adipocyte by at least 150%, an increase in glucose utilization of an adipocyte by a change of at least 60%, or an increase in mitochondrial biomass by at least about 15%.

4. The composition of claim 2, wherein the enhanced energy metabolism is measured by a reduction in postprandial blood glucose of at least 20%, a reduction in postprandial insulin by at least 30%, a reduction in fasting blood glucose by at least 40%, a reduction in fasting insulin by at least 40%, a reduction in blood glucose response to glucose load by at least 15%, a two-fold improvement in insulin tolerance results, or a reduction in inflammatory stress by at least 20%.

5. The composition of claim 4, wherein the reduction in blood glucose in response to glucose load is evidenced by an area under a glucose tolerance curve.

6. The composition of claim 1, wherein the PDE 5 inhibitor is avanafil, iodenafil, mirodenafil, sildenafil, tadalafil, icariin, vardenafil, udenafil, or zaprinst.

7. The composition of claim 1, wherein the PDE 5 inhibitor is sildenafil or icariin.

8. The composition of claim 1, wherein the PDE 5 inhibitor is icariin.

9. The composition of claim 1, wherein component (b) is HMB.

10. The composition of claim 1, wherein component (b) is free leucine.

11. The composition of claim 1, further comprising a non-selective PDE inhibitor.

12. The composition of claim 1, further comprising vitamin B6.

13. The composition of claim 1, further comprising a pharmaceutically active agent other than the PDE 5 inhibitor.

14. The composition of claim 1, wherein the composition is substantially free of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine in free amino acid form.

15. The composition of claim 1, wherein the composition is substantially free of isoleucine and valine in free amino acid form.

16. The composition of claim 1, wherein the composition is formulated for oral consumption.

17. The composition of claim 1, wherein the composition is a unit dosage comprising a sub-therapeutic amount of component (a).

18. The unit dosage of claim 17, wherein the sub-therapeutic amount of component (a) is between about 0.1 and about 20 mg of sildenafil.

19. The unit dosage of claim 17, wherein the sub-therapeutic amount of component (a) is between about 0.1 and about 10 mg of sildenafil.

20. The unit dosage of claim 17, wherein the sub-therapeutic amount of component (a) is between about 0.5-about 50 mg of avanafil, about 0.05-about 10 mg of iodenafil, about 0.25-about 25 mg of mirodenafil, about 0.01-about 1.25 mg of tadalafil, about 0.01-about 1.25 mg of vardenafil, about 0.5-about 50 mg of udenafil, about 0.5-about 50 mg of zaprinst, or about 0.05-about 100 mg of icariin.

21. The unit dosage of claim 17, wherein component (b) comprises about 50 to about 1000 mg of free leucine.

22. The unit dosage of claim 17, wherein component (b) comprises about 500 to about 700 mg of free leucine.

23. The unit dosage of claim 17, wherein component (b) comprises at least about 500 mg of free leucine.

24. The unit dosage of claim 17, wherein component (b) comprises at least about 200 mg of HMB.

30. A method of regulating energy metabolism in a subject in need thereof comprising administering to the subject a composition of any one of the preceding claims.

31. The method of claim 30, wherein the composition is administered orally.

32. A method of regulating energy metabolism comprising:

a) identifying a subject having or prone to obesity or diabetes; and

b) administering to the subject a composition of any one of claims 1-29.

36. A method for increasing energy metabolism in a subject comprising:

administering to said subject the composition any of claims 1-29 at a selected dosing level, wherein the selected dosing level induces a circulating level of about 1 nM sildenafil and about 0.5 mM leucine in the subject.

47. A kit comprising a multi-day supply of unit dosages of the composition any of claims 1-29 and instructions directing the administration of said multi-day supply over a period of multiple days.

25. A composition effective for enhancing energy metabolism comprising:

a) a PDE 5 inhibitor; and

b) a polyphenol,

wherein the composition enhances energy metabolism in the subject to a greater degree as compared to administering to the subject component (a) or component (b) alone.

26. The composition of claim 25, wherein the polyphenol is resveratrol.

27. The composition of claim 25, wherein the polyphenol is a stilbene or hydroxycinnamic acid.

28. The composition of claim 25, wherein the polyphenol is chlorogenic acid, resveratrol, caffeic acid, piceatannol, ellagic acid, epigallocatechin gallate (EGCG), grape seed extract, or any analog thereof.

29. The composition of claim 25, further comprising leucine and/or a leucine metabolite.

33. A method of regulating energy metabolism in a subject in need thereof comprising administering to the subject a unit dosage comprising a subtherapeutic amount of a PDE 5 inhibitor and, at least about 500 mg of leucine or about 200 mg of HMB.

34. The method of claim 33, wherein the subtherapeutic amount of the PDE 5 inhibitor is less than about 10 mg/day.

35. The method of claim 33, wherein the PDE 5 inhibitor is sildenafil.

37. A method of treating diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective composition comprising:

a) a PDE inhibitor; and

b) a branched-chain amino acid in free amino acid form or a free metabolite thereof.

38. The method of claim 37, wherein the branched chain amino acid is free leucine.

39. The method of claim 37, wherein the metabolite is HMB.

40. The method of claim 37, wherein the PDE inhibitor is a PDE5 inhibitor.

41. The method of claim 37, PDE 5 inhibitor is avanafil, iodenafil, mirodenafil, sildenafil, tadalafil, icariin, vardenafil, udenafil, or zaprinst.

42. The method of claim 37, comprising administering the therapeutically effective composition orally.

43. The method of claim 37, comprising administering the therapeutically effective composition for at least one, two or six weeks.

44. The method of claim 37, wherein the administering improves a symptom of diabetes in the subject.

45. The method of claim 44, wherein the improvement of the diabetes symptom is measured by a reduction in postprandial blood glucose of at least 20%, a reduction in postprandial insulin by at least 30%, a reduction in fasting blood glucose by at least 40%, a reduction in fasting insulin by at least 40%, a reduction in blood glucose response to glucose load by at least 15%, a two-fold improvement in insulin tolerance results, or a reduction in inflammatory stress by at least 20%.

46. The method of claim 45, wherein the reduction in blood glucose response to glucose load is evidenced by an area under a glucose tolerance curve.