Modification of feeding behavior

• US 20060014678A1
• Filed: 01/10/2003
• Published: 01/19/2006
• Est. Priority Date: 06/28/2002
• Status: Active Grant

• Current Assignee: Imperial Innovations Limited (Imperial College London), Oregon Health & Science University
• Original Assignee: Imperial College Innovations Ltd. (Imperial College London)
• Inventors: Small, Caroline Jane, Butler, Andrew, Bloom, Stephen Robert, Cowley, Michael, Cone, Roger, Batterham, Rachel Louise, Ghatei, Mohammed Ali, Low, Malcolm James Duncan
• Granted Patent: US 8,058,233 B2
• Time in Patent Office: Days
• US Class Current: 514/4.900
• 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 38/1709 from mammals
• 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 38/2271 Neuropeptide Y
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Methods are disclosed for decreasing calorie intake, food intake, and appetite in a subject. The methods include peripherally administering PYY or an agonist thereof and GLP-1 or an agonist thereof to the subject, simultaneously or sequentially, thereby decreasing the calorie intake of the subject.

Claims

1. A method for decreasing appetite, reducing hunger or sensations of hunger, increasing satiety or sensations of satiety, decreasing food intake, decreasing calorie intake, reducing nutrient availability, increasing energy expenditure, preventing, reducing or treating weight gain, inducing or promoting weight loss, maintaining a desired body weight or a desired Body Mass Index, or reducing or preventing obesity in a subject, which comprises peripherally administering a therapeutically effective amount of PYY or an agonist thereof and a therapeutically effective amount of GLP-1 or an agonist thereof to the subject.

2. A method as claimed in claim 1, wherein said method prevents weight gain, induces weight loss, maintains a desired body weight or a desired Body Mass Index or reduces obesity in said subject as measured by the Body Mass Index.

3. A method as claimed in claim 1, wherein said method decreases appetite, reduces hunger or sensations of hunger, or increases satiety or sensations of satiety in said subject.

4. A method as claimed in claim 1, wherein a therapeutically effective amount of PYY is administered to said subject.

5. A method as claimed in claim 1, wherein a therapeutically effective amount of GLP-1 is administered to said subject.

6. A method as claimed in claim 1, wherein a therapeutically effective amount of PYY and a therapeutically effective amount of GLP-1 is administered to said subject.

7. A method as claimed in claim 1, wherein said method improves the lipid profile in said subject.

8. A method as claimed in claim 1, wherein said method alleviates a condition or disorder in said subject that can be alleviated by reducing nutrient availability.

9. A method as claimed in claim 1, wherein the PYY or agonist thereof and the GLP-1 or agonist thereof are administered to said subject sequentially.

10. A method as claimed in claim 9, wherein the PYY or agonist thereof and the GLP-1 or agonist thereof are administered to said subject via different routes.

11. A method as claimed in claim 1, wherein the subject is overweight.

12. A method as claimed in claim 1, wherein the subject is obese.

13. A method as claimed in claim 1, wherein the subject is diabetic.

14. A method as claimed in claim 1, wherein peripheral administration comprises subcutaneous, intravenous, intramuscular, intranasal, transdermal, intracistemal, intravaginal. intraperitoneal, oral, topical, transmucosal, rectal or sublingual administration or pulmonary inhalation.

15. A method as claimed in claim 70, wherein peripherally administering PYY or the agonist thereof comprises administering about 45 to about 135 pmol of PYY or the agonist thereof per kilogram body weight of the subject.

16. A method as claimed in claim 15, wherein peripherally administering PYY or the agonist thereof comprises administering about 72 pmol of PYY or the agonist thereof per kilogram body weight of the subject.

17. A method as claimed in claim 1, wherein the PYY or the agonist thereof or the GLP-1 or agonist thereof is peripherally administered to the subject at least 30 minutes prior to a meal.

18. A method as claimed in claim 1, wherein the PYY or the agonist thereof or the GLP-1 or agonist thereof is peripherally administered to the subject in multiple or divided doses.

19. A method as claimed in claim 1, wherein the PYY or the agonist thereof and the GLP-1 or agonist thereof is administered in an amount sufficient to decrease calorie intake in said subject for a period of at least about 2 hours.

20. A method as claimed in claim 19, wherein the PYY or the agonist thereof and the GLP-1 or agonist thereof is administered in an amount sufficient to decrease calorie intake in said subject for a period of about 2 to 24 hours.

21. A method as claimed in claim 1, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 0.1 nmoles per kg body weight up to 3.2 nmoles per kg body weight of the subject.

22. A method as claimed in or claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of nmoles per kg body weight up to 3.0 nmoles per kg body weight of the subject.

23. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 0.1 nmoles per kg body weight of the subject.

24. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 0.2 nmoles per kg body weight of the subject.

25. A method as claimed in claim 35, wherein the PYY agonist comprises a molecule that specifically binds the Y2 receptor.

26. A method as claimed in claim 25, wherein the PYY agonist increases the expression of c-fos in a section of an arcuate nucleus contacted with the PYY agonist.

27. A method as claimed in claim 35, wherein the PYY agonist specifically binds to a neuropeptide Y neuron and inhibits an activity of a neuropeptide Y neuron.

28. A method as claimed in claim 27, wherein the PYY agonist decreases the action potential firing rate of the neuropeptide Y neuron.

29. A method as claimed in claim 27, wherein the neuropeptide Y neuron synapses with a proopiomelanocortin neuron, and wherein binding of the PYY agonist to the neuropeptide Y neuron results in an increased activity of the proopiomelanocortin neuron.

30. A method as claimed in claim 29, wherein the decreased activity of the neuropeptide Y neuron results in an increase in action potential firing on the proopiomelanocortin neuron.

31. A method as claimed in claim 36, wherein the GLP-1 agonist is exendin-4 or a derivative thereof that is a GLP-1 agonist.

32. A method as claimed in claim 73, further comprising administering a therapeutically effective amount of amfepramone (diethylpropion), phentermine, mazindol, phenylpropanolamine, fenfluramine, dexfenfluramine, or fluoxetine to said subject.

33. A method as claimed in claim 1, wherein the subject is human.

34. A method as claimed in claim 1, wherein the PYY or agonist thereof and the GLP-1 or agonist thereof are administered to said subject substantially simultaneously.

35. A method as claimed in claim 1, wherein a therapeutically effective amount of a PYY agonist is administered to said subject.

36. A method as claimed in claim 1, wherein a therapeutically effective amount of a GLP-1 agonist is administered to said subject.

37. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 0.4 nmoles per km body weight of the subject.

38. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 0.6 nmoles per kg body weight of the subject.

39. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 0.8 nmoles per kg body weight of the subject.

40. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 1.0 nmoles per kg body weight of the subject.

41. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 1.2 nmoles per kg body weight of the subject.

42. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 1.4 nmoles per kg body weight of the subject.

43. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 1.6 nmoles per kg body weight of the subject.

51. A method as claimed in claim 1, which comprises administering PYY or an agonist thereof to the subject subcutaneously at a dose of 10 nmoles, 20 nmoles, 30 nmoles or, 40 nmoles.

52. A method as claimed in claim 1, which comprises administering PYY or an agonist thereof to the subject subcutaneously at a dose of 20 to 60 nmoles, or 35 to 45 nmoles.

58. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 1.8 nmoles per kg body weight of the subject.

59. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 2.0 nmoles per kg body weight of the subject.

60. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 2.2 nmoles per kg body weight of the subject.

61. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 2.4 nmoles per kg body weight of the subject.

62. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 2.6 nmoles per kg body weight of the subject.

63. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 2.8 nmoles per kg body weight of the subject.

64. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 3.0 nmoles per kg body weight of the subject.

65. A method as claimed in claim 21, wherein the PYY or agonist thereof and/or the GLP-1 or agonist thereof is administered peripherally at a dose of 3.2 nmoles per kg body weight of the subject.

66. A method as claimed in claim 4, wherein a therapeutically effective amount of PYY_3-36 is administered to said subject.

67. A method as claimed in claim 14, wherein peripheral administration comprises subcutaneous administration.

68. The method of claim 1, wherein peripheral administration comprises peripheral injection in a pulse dose.

69. The method of claim 1, wherein peripheral administration comprises administration in a slow, sustained or controlled release preparation or from a pump or implantable drug infusion device.

70. A method as claimed in claim 1, wherein peripherally administering PYY or the agonist thereof comprises administering about 0.5 to about 135 pmol of PYY or the agonist thereof per kilogram body weight of the subject.

71. A method as claimed in claim 18, wherein PYY or the agonist thereof is peripherally administered to the subject in a multitude of doses, wherein each dose in the multitude of doses comprises administration of about 0.5 to about 135 pmol of said PYY or agonist thereof per kilogram of body weight at least about 30 minutes prior to a meal.

72. A method as claimed in claim 20, wherein the PYY or the agonist thereof and the GLP-1 or agonist thereof is administered in an amount sufficient to decrease calorie intake in said subject for a period of about 2 to 12 hours.

73. A method as claimed in claim 1, further comprising administering a therapeutically effective amount of an additional appetite suppressant to said subject.

74. A method as claimed in claim 1, further comprising administering a food intake-reducing agent, plasma glucose-lowering agent or plasma lipid-altering agent to said subject.

44. A pharmaceutical composition comprising a therapeutically effective amount of PYY or an agonist thereof and a therapeutically effective amount of GLP-1 or an agonist thereof, in admixture or conjunction with a pharmaceutically suitable carrier.

45. A pharmaceutical composition comprising a therapeutically effective amount of PYY or an agonist thereof in admixture with a pharmaceutically suitable carrier, for subcutaneous administration.

46. A pharmaceutical composition as claimed in claim 45, which comprises 10 nmoles, 20 nmoles, 30 nmoles or, 40 nmoles of PYY or an agonist thereof.

47. A pharmaceutical composition as claimed in claim 45, which comprises from 20 to 60 nmoles, or 35 to 45 nmoles of PYY or an agonist thereof.

48. A pharmaceutical composition as claimed in claim 45, which comprises PYY or an agonist thereof in an amount suitable for subcutaneous administration of 0.1 nmoles up to 3.2 nmoles per kg body weight.

49. A pharmaceutical composition as claimed in claim 45, which comprises PYY or an agonist thereof in an amount suitable for subcutaneous administration 0.2 nmoles up to 3.0 nmoles per kg body weight.

50. A pharmaceutical composition as claimed in claim 45, in unit dosage form.

53. A method for decreasing appetite, reducing hunger or sensations of hunger, increasing satiety or sensations of satiety, decreasing food intake, decreasing calorie intake, reducing nutrient availability, increasing energy expenditure, preventing, reducing or treating weight gain, inducing or promoting weight loss, maintaining a desired body weight or a desired Body Mass Index, or reducing or preventing obesity in a subject, which comprises administering to said subject a therapeutically effective amount of PYY or an agonist thereof by subcutaneous administration.

54. A method as claimed in claim 53, which comprises administering PYY or an agonist thereof to the subject subcutaneously at a dose of 10 nmoles, 20 nmoles, 30 nmoles or 40 nmoles.

55. A method as claimed in claim 53, which comprises administering PYY or an agonist thereof to the subject subcutaneously at a dose of 20 to 60 nmoles, or 35 to 45 nmoles.

56. A method as claimed in claim 53, which comprises administering PYY or an agonist thereof to the subject subcutaneously at a dose of 0.1 nmoles up to 3.2 nmoles per kg body weight.

57. A method as claimed in claim 53, which comprises administering PYY or an agonist thereof to the subject subcutaneously at a dose of 0.2 nmoles up to 3.0 nmoles per kg body weight.

75. A method for decreasing appetite, reducing hunger or sensations of hunger, increasing satiety or sensations of satiety, decreasing food intake, decreasing calorie intake, reducing nutrient availability, increasing energy expenditure, preventing, reducing or treating weight gain, inducing or promoting weight loss, maintaining a desired body weight or a desired Body Mass Index, or reducing or preventing obesity in a subject, which comprises peripherally administering a therapeutically effective amount of PYY and a therapeutically effective amount of GLP-1 to the subject.

76. A method for decreasing appetite, food intake or calorie intake in a subject, comprising peripherally administering to said subject an amount of PYY and an amount of GLP-1 effective to decrease appetite, food intake or calorie intake in said subject.