Methods for treating disorders using plant extracts

• US 20030072822A1
• Filed: 08/30/2002
• Published: 04/17/2003
• Est. Priority Date: 08/31/2001
• Status: Active Grant

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Raskin, Ilya, Ribnicky, David M.
• Granted Patent: US 6,893,627 B2
• Time in Patent Office: Days
• US Class Current: 424/740
• 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 36/282 Artemisia, e.g. wormwood or sagebrush
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention provides materials and methods relating to mildly polar fluid extracts of plant materials, such as Artemisia plant species, useful in methods for treating diabetes and methods for modulating the activity of glucagon-like peptide-1 (GLP-1), and in methods for modulating phosphoenol pyruvate carboxykinase (PEPCK) activity in a diabetes-specific manner. The extracts are generally non-toxic and non-mutagenic and may be administered to diabetics with beneficial effect on blood glucose levels. The extracts may also be administered to non-diabetics without deleterious effect. The plants are easily grown with a minimum of time, labor, and cost. Extracts are inexpensively and quickly prepared without the need for fractionation to remove potentially deleterious compounds, and the extracts may be administered to mammals such as humans through various routes, in a variety of forms, and at convenient concentrations.

Claims

1. A method of modulating blood glucose level in a mammal comprising administration of an effective dose of a mildly polar extract of Artemisia.

2. The method according to claim 1 wherein the blood glucose level is decreased.

38. The method according to claims 1, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, 20, 21, or 28, wherein the Artemisia is Artemisia dracunculus.

39. The method according to claims 1, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, 20, 21, or 28, wherein the mildly polar extract is an alcoholic extract.

40. The method according to claim 39, wherein the alcoholic extract is an ethanolic extract.

41. The method according to claims 1, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, 20, 21, or 28, wherein the extract lacks detectable mutagenic activity.

42. The method according to claims 1, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, 20, 21, or 28, wherein the mammal is human.

43. The method according to claims 1, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, 20, 21, or 28, wherein the administration comprises oral delivery.

44. The method according to claims 1, 3, 5, 6, 7, 8, 9, 11, 13, 15, 17, 20, 21, or 28, wherein the extract has no acute oral toxicity at a dosage of up to 5000 milligram plant material per kilogram mammal body weight.

3. A method of modulating glucagon-like peptide-1 (GLP-1) activity in a mammal comprising administration of an effective dose of a mildly polar extract of Artemisia.

4. The method according to claim 3 wherein the GLP-1 activity is increased.

5. A method of altering the appetite of a mammal comprising administering an effective dose of a mildly polar extract of Artemisia to the mammal.

6. A method of promoting an ileal brake comprising administering an effective dose of a mildly polar extract of Artemisia to a mammal.

7. A method of modulating the binding between GLP-1 and the GLP-1 receptor comprising administering an effective dose of a mildly polar extract of Artemisia to a mammal.

8. A method of modulating α

-glucosidase activity in a mammal comprising administration of an effective dose of a mildly polar extract of Artemisia.

9. A method of modulating insulin resistance in a mammal comprising administering an effective dose of a mildly polar extract of Artemisia.

10. The method according to claim 9 wherein insulin resistance is decreased.

11. A method of modulating the in vivo conversion of glucose to glycogen in a mammal comprising administering an effective dose of a mildly polar extract of Artemisia.

12. The method according to claim 11 wherein the in vivo conversion of glucose to glycogen is increased.

13. A method of modulating the expression of insulin receptor substrate-2 (IRS-2) polypeptide in a mammal comprising administering an effective dose of a mildly polar extract of Artemisia.

14. The method according to claim 13 wherein the expression of IRS-2 polypeptide is increased.

15. A method of modulating insulin-stimulated glucose uptake in a mammal comprising administering an effective dose of a mildly polar extract of Artemisia.

16. The method according to claim 15 wherein the insulin-stimulated glucose uptake is increased.

17. A method of modulating hepatic glucose output in a mammal comprising administering an effective dose of a mildly polar extract of Artemisia.

18. The method according to claim 17 wherein the hepatic glucose output is decreased.

19. The method according to claim 17 wherein the mildly polar extract is an alcoholic extract that decreases phosphoenol pyruvate carboxykinase (PEPCK) expression.

20. A method of treating Type 2 diabetes in a mammal comprising administering an effective dose of a mildly polar extract of Artemisia.

21. A method of promoting increased cellular energy in non-adipose cells comprising administering an effective dose of a mildly polar extract of Artemisia.

22. The method according to claim 21 wherein the increased cellular energy provides increased muscle cell strength.

23. The method according to claim 21 wherein the increased cellular energy provides increased muscle cell endurance.

24. The method according to claim 21 wherein the increased cellular energy prevents or reduces physiological distress.

25. The method according to claim 21 wherein the increased cellular energy prevents or reduces fatigue.

26. The method according to claim 21 wherein the increased cellular energy prevents or reduces a nutritional deficiency.

27. The method according to claim 21 wherein the non-adipose cells are selected from the group consisting of muscle cells and neurons.

28. A method of preparing a mildly polar extract of Artemisia comprising the steps of:

(a) contacting Artemisia with an elicitor; and

(b) extracting the Artemisia with a mildly polar fluid.

29. The method according to claim 28 wherein the mildly polar fluid comprises at least 60% ethanol.

30. The method according to claim 28 wherein the Artemisia comprises a stem:

leaf biomass ratio of at least 1.0.

31. The method according to claim 28, further comprising disrupting Artemisia.

32. The method according to claim 28 wherein the Artemisia is immature.

33. The method according to claim 28 wherein the extract comprises a compound selected from the group consisting of capillarisin, tetrahydroxy-methoxy flavanone, umbelliferone, sakuranin, a trihydroxy-methoxy flavanone and a trihydroxy flavanone.

34. The method according to claim 28 wherein the elicitor is selected from the group consisting of chitosan and Trichoderma.

35. The method according to claim 28 wherein the elicitor is about 0.1% chitosan.

36. The method according to claim 28 wherein the elicitor is Trichoderma harzianum.

37. The method according to claim 28, further comprising drying the extract at an elevated temperature to reduce methyl eugenol concentration.

45. A pharmaceutical composition comprising an effective dose of a mildly polar extract of Artemisia.

46. The composition according to claim 45 wherein the Artemisia is Artemisia dracunculus.

47. The composition according to claim 45 wherein the mildly polar extract is an alcoholic extract.

48. The composition according to claim 47 wherein the alcoholic extract is an ethanolic extract.

49. The composition according to claim 45 wherein the extract lacks detectable mutagenic activity.

51. The use of the composition according to claim 49, wherein the use is selected from the group consisting of modulating glucose level in a mammal, altering the appetite of a mammal, promoting an ileal brake, modulating the binding between GLP-1 and the GLP-1 receptor, modulating alpha-glucosidase activity in a mammal, modulating insulin resistance in a mammal, modulating the in vivo conversion of glucose to glycogen in a mammal, modulating the expression of insulin receptor substrate-2 (IRS-2) polypeptide in a mammal, modulating insulin-stimulated glucose uptake in a mammal, modulating hepatic glucose level in a mammal, treating type 2 diabetes in a mammal and promoting increased cellular energy in non-adipose cells.

50. A pharmaceutical composition comprising an effective dose of a compound selected from the group consisting of capillarisin, tetrahydroxy-methoxy flavanone, umbelliferone, sakuranin, trihydroxy-methoxy flavanone and trihydroxy flavanone.

52. A formulation for treating diabetes in a mammal comprising an Artemisia extract and at least one compound selected from the group consisting of gymnema sylvestre, fenugreek, bitter melon, alpha-lipoic acid, alpha-lipoic acid salts, corosolic acid, ursolic acid, D-pinitol, aloe vera, chromium picolinate, banaba leaf, yacou root, momordica charantia, olive leaf extract, pterocarpus marsupium, salacia reticulata, garlic, hawthorn, phosphatidylserine, omega 3 fatty acids, and resistant starch.

53. A formulation for weight control in a mammal comprising an Artemisia extract and at least one compound selected from the group consisting of pyruvic acid, pyruvic acid salts, L-carnitine, hydroxycitric acid, ephedrine, caffeine, conjugated linoleic acid, aspirin, alpha-lipoic acid, and alpha-lipoic acid salts.

54. A formulation for promoting increased cellular energy in non-adipose cells in a mammal comprising an Artemisia extract and at least one compound selected from the group consisting of creatine, creatine monohydrate, a creatine salt, creatine citrate, creatine pyruvate, phosphocreatine, caffeine, alpha-lipoic acid, glucosamine, chondroitin, hydrolyzed collagen, methylsulfonyl-methane, Whey protein, L-glutamine, phosphatidylcholine, choline, a choline salt, phosphatidylserine, beta-hydroxy beta-methylbutyrate, pyruvic acid, pyruvic acid salts, L-carnitine, D-ribose, an amino acid, a branched chain amino acid, S-Adenosylmethionine, taurine, conjugated linoleic acid, alpha-lipoic acid, alpha-lipoic acid salts, and glycerin.