COMPOSITIONS AND METHODS FOR MODULATING METABOLIC PATHWAYS

• US 20150342914A1
• Filed: 06/22/2015
• Published: 12/03/2015
• Est. Priority Date: 07/15/2011
• Status: Active Grant

• Current Assignee: Nusirt Sciences, Inc.
• Original Assignee: Nusirt Sciences, Inc.
• Inventors: Zemel, Michael, Grindstaff, E. Douglas II, Bruckbauer, Antje
• Granted Patent: US 9,198,883 B1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A23L 2/52 Adding ingredients adding preservatives A23L2/44
• CPC Class Codes: A23L 33/175 Amino acids
• CPC Class Codes: A23L 33/30 Dietetic or nutritional methods, e.g. for losing weight A23L33/10 takes precedence
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• 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 31/015 carbocyclic
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• 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 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• 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 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 36/87 : Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
• CPC Class Codes: A61K 38/22 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• 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 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications

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 can contain synergizing amounts of a sirtuin-pathway activators, including but not limited to resveratrol, in combination with beta-hydroxymethylbutyrate (HMB), keto isocaproic acid (KIC), leucine, or combinations of HMB, KIC and leucine.

Claims

1-30. -30. (canceled)

31. A method of administering a composition to a subject comprising:

a. administering to the subject at least about 500 mg of leucine and/or at least about 200 mg of one or more metabolites thereof, wherein the one or more leucine metabolites are selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and

b. administering to the subject an anti-diabetic agent comprising a biguanide and/or a thiazolidinedione, wherein the composition is substantially free of the individual amino acids alanine, glutamic acid, glycine, isoleucine, valine, and proline;

wherein when (a) is leucine, the molar ratio of (a) to (b) is greater than 2; and

wherein (a) and (b) are administered sequentially in any order or simultaneously.

32. The method of claim 31, wherein the composition comprises a subtherapeutic amount of the anti-diabetic agent.

33. The method of claim 31, wherein the anti-diabetic agent comprises at least about 25 mg to less than about 2000 mg of metformin.

34. The method of claim 31, wherein the anti-diabetic agent comprises at least about 50 mg of resveratrol and at least about 500 mg of metformin.

35. The method of claim 31, wherein the anti-diabetic agent comprises at least about 50 mg of metformin and less than about 500 mg of metformin.

36. The method of claim 31, wherein the anti-diabetic agent comprises rosiglitazone in an amount effective to achieve a circulating level of at least about 1 nM rosiglitazone in a subject.

37. The method of claim 31, wherein the composition further comprises resveratrol.

38. The method of claim 31, wherein (a) and (b) are administered sequentially in either order.

39. The method of claim 31, wherein each of (a) and (b) are formulated as a tablet, capsule, gel capsule, beverage, snack bar or a food composition.

40. The method of claim 31, wherein the subject has one or more symptoms of metabolic disorders.

41. The method of claim 40, wherein the metabolic disorder is selected from the group consisting of obesity, diabetes, hypertension, arteriosclerosis, high cholesterol, and hyperlipidemia.

42. The method of claim 31, wherein the insulin sensitivity in the subject is increased after said administering.

43. The method of claim 31, wherein the fat oxidation in the subject is increased or the inflammatory response in the subject is decreased.

44. The method of claim 31, wherein the composition is substantially free of an individual non-branched amino acid.

45. The method of claim 31, wherein the anti-diabetic agent comprises metformin and rosiglitazone.

46. A composition comprising:

a. at least about 500 mg of leucine and/or at least about 200 mg of one or more metabolites thereof, wherein the one or more leucine metabolites are selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and

b. an anti-diabetic agent comprising a thiazolidinedione.

47. The composition of claim 46, wherein the composition comprises a subtherapeutic amount of the anti-diabetic agent.

48. The composition of claim 46, wherein the anti-diabetic agent comprises rosiglitazone in an amount effective to achieve a circulating level of at least about 1 nM rosiglitazone in a subject.

49. The composition of claim 46, wherein the composition is substantially free of an individual non-branched amino acid.

50. The composition of claim 46, further comprising a sirtuin pathway activator that activates one or more of SIRT1, SIRT3, AMPK, and PGCla.

51. The composition of claim 46, further comprising a phosphodiesterase inhibitor.

52. The composition of claim 46, wherein the composition is formulated as a unit dose.

53. The composition of claim 46, wherein the composition comprises a therapeutic amount of the anti-diabetic agent.

54. The composition of claim 46, wherein the composition is formulated as a food composition, tablet, capsule, gel capsule, beverage, or snack bar.

55. A method for treating diabetes in a subject in need thereof comprising:

administering to the subject the composition of claim 46;

wherein the insulin sensitivity in the subject is increased.