Method of treating the syndrome of lipodystrophy

• US 6,846,831 B2
• Filed: 06/25/2002
• Issued: 01/25/2005
• 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:
  US10/179,993
• Publication Number:
  US 20030036546A1
• Time in Patent Office: 945 Days
• Field of Search: 514/282
• US Class Current: 514/282
• 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 31/4184 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 38/26 Glucagons
• CPC Class Codes: A61K 38/33 derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Methods of treating a human suffering from the Syndrome of Lipodystrophy or one or more HIV-related abnormalities included therein are provided. One method may include administering, by a pharmaceutically effective mode, a drug composition comprising an opioidergic agent, or alternatively, an opioidergic agent and an insulin secretagogue. The method may also include administering, by a pharmaceutically effective mode, a drug composition comprising an opiate agonist and opiate antagonist, or alternatively, an opiate agonist, opiate antagonist and an insulin secretagogue.

Claims

1. A method of treating a human suffering from the Syndrome of Lipodystrophy or one or more HIV-related abnormalities included therein, the method comprising:

administering, by a pharmaceutically effective mode, a drug composition comprising an opioidergic composition.

2. The method of claim 1, wherein the opioidergic composition includes at least one of an opiate antagonist, an opiate agonist and 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 drug composition comprises an opiate antagonist and the opiate antagonist has drug opiate antagonist IC₅₀ values, and the IC₅₀ values for the μ

, δ and

κ

opiate receptors have ratios such that;

{(IC₅₀κ

/IC₅₀μ

)<

10}, and {(IC₅₀κ

/IC₅₀δ

)<

10}.

6. The method of claim 2, wherein the opiate agonist comprises a single molecular entity.

7. The method of claim 2, wherein the opiate agonist comprises a combination of molecular entities.

8. The method of claim 1, wherein the opioidergic composition comprises a peripherally-acting μ

-agonist.

9. The method of claim 8, wherein the opioidergic composition comprises loperamide.

10. The method of claim 1, wherein the opioidergic composition comprises a centrally-acting μ

-agonist.

11. The method of claim 1, wherein the opioidergic composition comprises an opiate having mixed μ

-agonist and κ

antagonist activity.

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

-agonist and κ

antagonist activity is buprenorphine.

13. The method of claim 1 wherein the opioidergic composition 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) normorphine;

xvi) (D—

Ala²—

N—

Me—

Phe⁴—

Gly³—

ol)-Enkephalin (DAMGO);

xvii) oxycodone; and

xviii) tramadol.

14. The method of claim 1, wherein the opioidergic composition 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).

15. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is atherogenic dyslipidemia (AD).

16. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is hypertriglyceridemia (HTG).

17. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is elevated levels of cholesterol (Chol).

18. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is elevated levels of low-density-lipoprotein cholesterol (LDL).

19. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is low levels of high-density lipoprotein cholesterol (HDL).

20. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is insulin resistance (IR).

21. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is beta-cell dysfunction.

22. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is the loss of first phase insulin secretion.

23. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is impaired glucose tolerance (IGT).

24. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is Type 2 Diabetes.

25. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is elevated endogenous glucose production.

26. The method of claim 1, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is excessive gluconeogenesis.

27. The method of claim 1, further comprising a pre-treatment regimen comprising the daily administration of nalmefene in the range of 1-10 mg for a period of up to 6 weeks.

28. A method of treating a human suffering from the Syndrome of Lipodystrophy or one or more HIV-related abnormalities included therein, the method comprising:

administering, by a pharmaceutically effective mode, a drug composition comprising an opioidergic composition and at least one insulin secretagogue.

29. The method of claim 28, 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. muscarinic 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.

30. The method of claim 28, 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.

31. The method of claim 28, wherein the insulin secretagogue comprises sulphonylurea.

32. The method of claim 28, wherein the opioidergic composition includes at least one of an opiate antagonist, an opiate agonist and a combination thereof.

33. The method of claim 28, wherein the opiate antagonist comprises a single molecular entity.

34. The method of claim 28, wherein the opiate antagonist comprises a combination of molecular entities.

35. The method of claim 28, wherein the opioidergic composition 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) normorphine;

xv) (D—

Ala²—

N—

Me—

Phe⁴—

Gly³—

ol) -Enkephalin (DAMGO);

xvi) oxycodone; and

xvii) tramadol.

36. The method of claim 28, wherein the opioidergic composition 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).

37. The method of claim 28, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy includes at least one of atherogenic dyslipidemia (AD), hypertriglyceridemia (HTG), elevated levels of cholesterol (Chol), elevated levels of low-density-lipoprotein cholesterol (LDL), low levels of high-density lipoprotein cholesterol (HDL), insulin resistance (IR), beta-cell dysfunction, impaired or loss of first phase insulin secretion, impaired glucose tolerance (IGT), Type 2 Diabetes, elevated endogenous glucose production, and excessive gluconeogenesis.

38. The method of claim 28, wherein the drug composition is a single agent having opioidergic activity and insulinotropic activity.

39. A method of treating a human suffering from the Syndrome of Lipodystrophy or one or more HIV-related abnormalities included therein, the method comprising:

administering, by a pharmaceutically effective mode, a drug composition comprising

at least one opiate agonist; and

at least one opiate antagonist.

40. The method of claim 39, wherein the drug composition further comprises at least one insulin secretagogue.

41. The method of claim 39, 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. muscarinic 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.

42. The method of claim 40, 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.

43. The method of claim 40, wherein the insulin secretagogue includes sulphonylurea.

44. The method of claim 39, wherein the opiate agonist includes a μ

-agonist.

45. The method of claim 39, wherein the opiate agonist includes loperamide.

46. The method of claim 39, wherein the opiate agonist includes at least one of a centrally-acting μ

agonist and a peripherally-acting μ

agonist.

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

xviii) dihydromorphine;

xix) morphine;

xx) hydromorphone;

xxi) methadone;

xxii) fentanyl;

xxiii) sufentanyl;

xxiv) demorphine;

xxv) codeine;

xxvi) ethylmorphine;

xxvii) etonitazene;

xxviii) hydrocodone;

xxix) levorphanol;

xxx) norcodeine;

xxxi) normorphine;

xxxii) (D—

Ala²—

N—

Me—

Phe⁴—

Gly³—

ol)-Enkephalin (DAMGO);

xxxiii) oxycodone; and

xxxiv) tramadol.

48. The method of claim 39, wherein the HIV-related abnormality included in the Syndrome of Lipodystrophy is at least one of atherogenic dyslipidemia (AD), hypertriglyceridemia (HTG), elevated levels of cholesterol (Chol), elevated levels of low-density-lipoprotein cholesterol (LDL), low levels of high-density lipoprotein cholesterol (HDL), insulin resistance (IR), beta-cell dysfunction, impaired or loss of first phase insulin secretion, impaired glucose tolerance (IGT), Type 2 Diabetes, elevated endogenous glucose production, and excessive gluconeogenesis.