Method of treating the syndrome of coronary heart disease risk factors in humans

• US 6,919,310 B2
• Filed: 03/03/2003
• Issued: 07/19/2005
• Est. Priority Date: 08/15/2000
• Status: Expired due to Term

• Current Assignee: Neurendo Pharma, LLC
• Original Assignee: CPD, LLC
• Inventors: Clemens, Anton H.
• Primary Examiner(s): Henley, III, Raymond J.
• Application Number:
  US10/377,838
• Publication Number:
  US 20030149076A1
• Time in Patent Office: 869 Days
• Field of Search: 514/282, 514/2, 514/331, 514/592, 514/647
• US Class Current: 514/6.9
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• 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 38/2278 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 9/00 Drugs for disorders of the cardiovascular system

Abstract

The invention provides an improved method of treating a human suffering from one or more conditions included within the Coronary Heart Disease Risk Factor (CHDRF) syndrome. The method includes administering, by a pharmaceutically effective mode, a drug composition having an opioidergic agent including an opiate antagonist, opiate having μ-agonist activity or combination thereof, and an insulin secretagogue.

Claims

1. A method for treating one or more conditions of metabolic syndrome of Coronary Heart Disease Risk Factors (CHDRF) comprising at least one of Insulin Resistance, BetaCell Dysfunction, Impaired Glucose Tolerance, Type 2 Diabetes, overweightness, obesity and dyslipidemia in a patient suffering therefrom, the method comprising administering to said patient, by a pharmaceutically effective mode, a drug composition comprising:

an opioidergic agent; and

an insulin secretagogue.

2. The method of claim 1, wherein the opioidergic agent is an opiate antagonist, an opiate having μ

-agonist activity or a combination thereof.

3. The method of claim 2, wherein the opiate antagonist comprises a single molecular entity.

4. The method of claim 2, wherein the opiate antagonist comprises a combination of molecular entities.

5. The method of claim 2, wherein the opiate having μ

-agonist activity comprises a single molecular entity.

6. The method of claim 2, wherein the opiate having μ

-agonist activity comprises a combination of molecular entities.

7. The method of claim 2, wherein the drug composition comprises a peripherally acting μ

-agonist.

8. The method of claim 7, wherein the drug composition comprises loperamide.

9. The method of claim 2, wherein the drug composition comprises a centrally acting μ

-agonist.

10. The method of claim 2, wherein the drug composition further comprises an opiate having mixed μ

-agonist and κ

antagonist activity.

11. The method of claim 10, wherein the opiate having mixed μ

-agonist and κ

antagonist activity is buprenorphine.

12. The method of claim 2 wherein the opioidergic agent includes at least one of the following:

i) dihydromorphine;

ii) morphine;

iii) hydromorphone;

iv) methadone;

v) fentanyl;

vi) sufentanyl;

vii) buprenorphine;

viii) demorphine;

ix) codeine;

x) ethylmorphine;

xi) etonitazene;

xii) hydrocodone;

xiii) levorphanol;

xiv) norcodeine;

xv) normophine;

xvi) (D-Ala²-N-Me-Phe⁴-Gly³-ol)-Enkephalin (DAMGO); and

xvii) oxycodone.

13. The method of claim 2, wherein the opioidergic agent includes at least one of the following:

i) nalmefene;

ii) naltrexone;

iii) nor-binaltorphimine;

iv) (−

)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomorphan (MR

     2266);

v) a triethylenedioxy derivative of B-naltrexamine (TENA); and

vi) guanidylated naltrindole (GNTI).

14. The method of claim 2, wherein the condition included within the CHDRF Syndrome is Insulin Resistance (IR).

15. The method of claim 2, wherein the condition included within the CHDRF Syndrome is Beta-Cell Dysfunction.

16. The method of claim 2, wherein the condition included within the CHDRF Syndrome is Impaired Glucose Tolerance (IGT).

17. The method of claim 2, wherein the condition included within the CHDRF Syndrome is Type 2 Diabetes.

18. The method of claim 2, wherein the condition included within the CHDRF syndrome is overweight.

19. The method of claim 2, wherein the condition included within the CHDRF syndrome is obesity.

20. The method of claim 2, wherein the condition included within the CHDRF syndrome is dyslipidemia.

21. The method of claim 1, wherein the insulin secretagogue includes at least one of the following:

i. sulphonylureas;

ii. tolbutamide;

iii. chlorpropamide;

iv. glimepiride;

v. glipizide;

vi. glyburide;

vii. meglitinides;

viii. repaglinide;

ix. pramlintide;

x. morphilinoguanide;

xi. acetylcholine;

xii. muscannic agonists;

xiii. carbachol;

xiv. bethanechol;

xv. beta-L-glucose pentaacetate;

xvi. chiro-inositol;

xvii. myo-inositol;

xviii. GIP;

xix. GLP-1; and

xx. Extendin-4.

22. The method of claim 1, wherein the insulin secretagogue is a non-glucose dependent insulin secretagogue, the method producing insulin release patterns capable of attaining glucose dependent, bi-phasic release characteristics with reduced likelihood of producing hypoglycemia.

23. The method of claim 22, wherein the insulin secretagogue is sulphonylurea.

56. The method of claim 2, wherein opiate agonist comprises tramadol.

57. The method of claim 2, wherein the drug composition comprises at least one of CHMMO, diprenorphine, and a combination thereof.

58. The method of claim 2, wherein the opiate antagonist has IC₅₀ levels for the μ

, δ

, and κ

opiate receptors, the IC₅₀ levels being {(IC₅₀κ

/IC₅₀μ

)<

3} and {(IC₅₀κ

/IC₅₀δ

)<

3}.

59. The method of claim 2, wherein the opiate antagonist has IC₅₀ levels for the μ

, δ

, and κ

opiate receptors, the IC₅₀ levels being {(IC₅₀κ

/IC₅₀μ

)<

10} and {(IC₅₀κ

/IC₅₀δ

)<

10}.

60. The method of claim 1, wherein the drug composition is administered in a daily dose comprising less than about 10 μ

g/kg opioidergic agent and equal to or less than about 10 μ

g/kg of insulin secretagogue for monotherapy.

24. A method for treating one or more conditions of metabolic syndrome of Coronary Heart Disease Risk Factors (CHDRF) comprising at least one of Insulin Resistance, BetaCell Dysfunction, Impaired Glucose Tolerance, Type 2 Diabetes, overweightness, obesity and dyslipidemia in a patient suffering therefrom, the method comprising administering to said patient, by a pharmaceutically effective mode, a drug composition comprising:

an opiate antagonist; and

an insulin secretagogue.

25. The method of claim 24, wherein the opiate antagonist comprises a single molecular entity.

26. The method of claim 24, wherein the opiate antagonist comprises a combination of molecular entities.

27. The method of claim 24, wherein the opiate antagonist includes at least one of the following:

i) nalmefene

ii) naltrexone;

iii) nor-binaltorphimine;

iv) (−

)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomorphan (MR

     2266);

v) a triethylenedioxy derivative of B-naltrexamine (TENA); and

vi) guanidylated naltrindole (GNTI).

28. The method of claim 24, wherein the condition included within the CHDRF Syndrome is Insulin Resistance.

29. The method of claim 24, wherein the condition included within the CHDRF Syndrome is Beta-Cell Dysfunction.

30. The method of claim 24, wherein the condition included within the CHDRF syndrome is Impaired Glucose Tolerance (IGT).

31. The method of claim 24, wherein the condition included within the CHDRF syndrome is Type 2 Diabetes.

32. The method of claim 24, wherein the condition included within the CHDRF syndrome is overweight.

33. The method of claim 24, wherein the condition included within the CHDRF syndrome is obesity.

34. The method of claim 24, wherein the condition included within the CHDRF syndrome is dyslipidemia.

35. The method of claim 24 wherein the opiate antagonist has IC₅₀ levels for the μ

, δ

, and κ

opiate receptors, the IC₅₀ levels being {(IC₅₀κ

/IC₅₀μ

)<

3} and {(IC₅₀κ

/IC₅₀δ

)<

3}.

36. The method of claim 24, wherein the insulin secretagogue includes at least one of the following:

i. sulphonylureas;

ii. tolbutamide;

iii. chlorpropamide;

iv. glimepiride;

v. glipizide;

vi. glyburide;

vii. meglitinides;

viii. repaglinide;

ix. pramlintide;

x. morphilinoguanide;

xi. acetylcholine;

xii. muscannic agonists;

xiii. carbachol;

xiv. bethanechol;

xv. beta-L-glucose pentaacetate;

xvi. chiro-inositol;

xvii. myo-inositol;

xviii. GIP;

xix. GLP-1; and

xx. Extendin-4.

37. The method of claims 24, wherein the insulin secretagogue is a non-glucose dependent insulin secretagogue, the method producing insulin release patterns capable of attaining glucose dependent, bi-phasic release characteristics with reduced likelihood of producing hypoglycemia.

38. The method of claim 37, wherein the insulin secretagogue is sulphonylurea.

62. The method of claim 24, wherein the drug composition comprises at least one of CHMMO, diprenorphine, and a combination thereof.

63. The method of claim 24, wherein the opiate antagonist has IC₅₀ levels for the μ

, δ

, and κ

opiate receptors, the IC₅₀ levels being {(IC₅₀κ

/IC₅₀μ

)<

10} and {(IC₅₀κ

/IC₅₀δ

)<

10}.

39. A method for treating one or more conditions of metabolic syndrome of Coronary Heart Disease Risk Factors (CHDRF) comprising at least one of Insulin Resistance, BetaCell Dysfunction, Impaired Glucose Tolerance, Type 2 Diabetes, overweightness, obesity and dyslipidemia in a patient suffering therefrom, the method comprising administering to said patient, by a pharmaceutically effective mode, a drug composition comprising:

an opiate agonist; and

an insulin secretagogue.

40. The method of claim 39, wherein the opiate agonist comprises a single molecular entity.

41. The method of claim 39, wherein the opiate agonist comprises a combination of molecular entities.

42. The method of claim 39, wherein the opiate agonist is a peripherally acting μ

-agonist.

43. The method of claim 42, wherein the opiate agonist is loperamide.

44. The method of claim 39, wherein the opiate agonist is a centrally acting μ

agonist.

45. The method of claim 39, wherein the opiate agonist includes at least one of the following:

i) dihydromorphine;

ii) morphine;

iii) hydromorphone;

iv) methadone;

v) fentanyl;

vi) sufentanyl;

vii) demorphine;

viii) codeine;

ix) ethylmorphine;

x) etonitazene;

xi) hydrocodone;

xii) levorphanol;

xiii) norcodeine;

xiv) normophine;

xv) (D-Ala²-N-Me-Phe⁴-Gly³-ol)-Enkephalin (DAMGO); and

xvi) oxycodone.

46. The method of claim 39, wherein the condition included within the CHDRF Syndrome is Insulin Resistance.

47. The method of claim 39, wherein the condition included within the CHDRF Syndrome is Beta-Cell Dysfunction.

48. The method of claim 39, wherein the condition included within the CHDRF syndrome is Impaired Glucose Tolerance (IGT).

49. The method of claim 39, wherein the condition included within the CHDRF syndrome is Type 2 Diabetes.

50. The method of claim 39, wherein the condition included within the CHDRF syndrome is overweight.

51. The method of claim 39, wherein the condition included within the CHDRF syndrome is obesity.

52. The method of claim 39, wherein the condition included within the CHDRF syndrome is dyslipidemia.

53. The method of claim 39, wherein the insulin secretagogue includes at least one of the following:

i. suipnonylureas;

ii. tolbutamide;

iii. chlorpropamide;

iv. glimepiride;

v. glipizide;

vi. glyburide;

vii. meglitinides;

viii. repaglinide;

ix. pramlintide;

x. morphilinoguanide;

xi. acetylcholine;

xii. muscarimc agonists;

xiii. carbachol;

xiv. bethanechol;

xv. beta-L-glucose pentaacetate;

xvi. chiro-inositol;

xvii. myo-inositol;

xviii. GIP;

xix. GLP-1; and

xx. Extendin-4.

54. The method of claims 39, wherein the insulin secretagogue is a non-glucose dependent insulin secretagogue, the method producing insulin release patterns capable of attaining glucose dependent, bi-phasic release characteristics with reduced likelihood of producing hypoglycemia.

55. The method of claim 39, wherein the insulin secretagogue is sulphonylurea.

61. The method of claim 39, wherein opiate agonist comprises tramadol.