Treatment of the insulin resistance syndrome

• US 20030166662A1
• Filed: 02/19/2003
• Published: 09/04/2003
• Est. Priority Date: 08/11/2000
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Gibbs, Earl Michael, Fryburg, David Albert, Koppiker, Nandan Parmanand
• Application Number:
  US10/368,826
• Publication Number:
  US 20030166662A1
• Time in Patent Office: Days
• US Class Current: 514/252.16
• 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 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Use of a selective cGMP PDE5 inhibitor or a pharmaceutical composition thereof in the preparation of a medicament for the curative, palliative or prophylactic treatment of the insulin resistance syndrome wherein the insulin resistance syndrome means the concomitant existence in a subject of two or more of dyslipidemia; hypertension; type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes; hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal obesity wherein said use can occur alone or in combination with other agents to treat the insulin resistance syndrome or individual aspects of the insulin resistance syndrome.

Claims

1. A method of treating the insulin resistance syndrome in a mammal comprising administering to said mammal an effective amount of a selective cGMP PDE5 inhibitor or a pharmaceutically acceptable salt, solvate or composition thereof, wherein the insulin resistance syndrome means the concomitant existence in said mammal of two or more of:

dyslipidemia;

hypertension;

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

2. A method of claim 1 wherein said mammal has type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes and at least one or more of:

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

3. A method of claim 2 wherein said selective cGMP PDE5 inhibitor is sildenafil or sildenafil citrate.

4. A method of claim 1 wherein said mammal has type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes and at least two or more of:

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

5. A method of claim 1 wherein said mammal has type 2 diabetes mellitus, impaired glucose tolerance or a family history of diabetes and at least three or more of:

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

6. A method of claim 1 wherein said mammal has type 2 diabetes mellitus, impaired glucose tolerance or a family history of diabetes and at least four or more of:

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

7. A method of claim 1 wherein said mammal has type 2 diabetes mellitus, impaired glucose tolerance or a family history of diabetes and at least five or more of:

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

8. A method of claim 1 wherein said mammal has type 2 diabetes mellitus or impaired glucose tolerance;

dyslipidemia;

hypertension; and

truncal obesity.

9. A method of claim 1 wherein said mammal has three or more of:

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

10. A method of claim 1 wherein said mammal has four or more of:

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

11. A method of claim 1 wherein said mammal has five or more of:

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

dyslipidemia;

hypertension;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity.

12. A method of claim 1 wherein said mammal has dyslipidemia, hypertension, type 2 diabetes mellitus or impaired glucose tolerance (IGT) and truncal obesity.

13. A method of claim 1 wherein the selective cGMP PDE5 inhibitor is sildenafil, 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) pyrazino[2′

, 1′

;

6,1]pyrido[3,4-b]indole-1,4-dione;

2-[2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one or 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazolo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine or a pharmaceutically acceptable salt, solvate, pro-drug, polymorph or pharmaceutical composition thereof.

14. A method of claim 13 wherein the selective cGMP PDE5 inhibitor is sildenafil, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

15. A method of claim 14 wherein the selective cGMP PDE5 inhibitor is sildenafil citrate.

16. A method of claim 1 wherein said mammal has:

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

dyslipidemia;

hypertension; and

truncal obesity.

51. A method of claim 1 wherein said mammal is a polygenic mammal.

55. A method of claim 1 comprising administering said cGMP PDE5 inhibitor orally.

60. A method of claim 1 wherein said cGMP PDE5 inhibitor has an IC₅₀ against PDE5 of less than 100 nM and a selectivity ratio of PDE5 over PDE3 of more than 100.

17. A method of treating the insulin resistance syndrome in a mammal comprising administering to said mammal an effective amount of a selective cGMP PDE5 inhibitor or a pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof.

18. A method of claim 17 comprising daily dosing, wherein said dosing is in the form of single, multiple or divided doses.

19. A method of claim 18 comprising daily dosing for 5 or more days, wherein said daily dosing is in the form of single, multiple or divided doses.

20. A method of claim 17 comprising continuous dosing for 5 or more days, wherein said continuous dosing is in the form of single or multiple continuous release doses.

21. A method of treating the insulin resistance syndrome in a mammal comprising administering to said mammal an effective amount of a selective cGMP PDE5 inhibitor in combination with one or more further components selected from one or more of:

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents.

22. A method of claim 21 wherein said selective cGMP PDE5 inhibitor is sildenafil, sildenafil citrate or a pharmaceutical composition thereof and wherein said mammal has:

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

dyslipidemia;

hypertension; and

truncal obesity.

50. A method of claim 21 wherein said selective cGMP PDE5 inhibitor is sildenafil citrate and said further components are selected from one or more of:

weight loss agents, sulfonyl ureas, insulin, Rezulin, Avandia, Actos, Glipizide, Metformin, Acarbose, rosiglitasone, pioglitazone, farglitazar, LY333531, CS011, PPAR-alpha agonists, and CP-470711.

56. A method of claim 21 comprising administering said cGMP PDE5 inhibitor orally.

61. A method of claim 21 wherein said cGMP PDE5 inhibitor has an IC₅₀ against PDE5 of less than 100 nM and a selectivity ratio of PDE5 over PDE3 of more than 100.

23. A method of treating type 2 diabetes mellitus in a mammal comprising administering to said mammal an effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

24. A method of claim 23 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil, 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt, solvate, pro-drug, polymorph or a pharmaceutical composition thereof.

25. A method of claim 24 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

26. A method of claim 24 wherein the selective cGMP PDE5 inhibitor is sildenafil or a pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof.

27. A method of claim 26 wherein the selective cGMP PDE5 inhibitor is sildenafil citrate.

28. A method of claim 26 comprising daily dosing, wherein said dosing is in the form of single, multiple or divided doses.

29. A method of claim 28 comprising daily dosing for 5 or more days, wherein said daily dosing is in the form of single, multiple or divided doses.

30. A method of claim 26 comprising continuous dosing for 5 or more days, wherein said continuous dosing is in the form of single or multiple continuous release doses.

57. A method of claim 23 comprising administering said cGMP PDE5 inhibitor orally.

62. A method of claim 23 wherein said cGMP PDE5 inhibitor has an IC₅₀ against PDE5 of less than 100 nM and a selectivity ratio of PDE5 over PDE3 of more than 100.

31. A method of treating type 2 diabetes mellitus in a mammal comprising administering to said mammal an effective amount of sildenafil citrate in combination with one or more further components selected from one or more of:

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors one or more insulin sensitising agents; and

one or more hypoglycaemic agents.

52. A method of claim 31 wherein said selective cGMP PDE5 inhibitor is sildenafil citrate and said further components are selected from one or more of:

weight loss agents, sulfonyl ureas, insulin, Rezulin, Avandia, Actos, Glipizide, Metformin, Acarbose, rosiglitasone, pioglitazone, farglitazar, LY333531, CS011, PPAR-alpha agonists, and CP-470711.

32. A method of treating impaired glucose tolerance (IGT) in a mammal comprising administering to said mammal an effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor or a pharmaceutical composition thereof.

33. A method of claim 32 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil, 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt, solvate, pro-drug, polymorph or a pharmaceutical composition thereof.

34. A method of claim 33 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

35. A method of claim 33 wherein said selective cGMP PDE5 inhibitor is sildenafil, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

36. A method of claim 35 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil citrate.

37. A method of claim 36 comprising daily dosing, wherein said dosing is in the form of single, multiple or divided doses.

38. A method of claim 37 comprising daily dosing for 5 or more days, wherein said daily dosing is in the form of single, multiple or divided doses.

39. A method of claim 36 comprising continuous dosing for 5 or more days, wherein said continuous dosing is in the form of single or multiple continuous release doses.

58. A method of claim 32 comprising administering said cGMP PDE5 inhibitor orally.

63. A method of claim 32 wherein said cGMP PDE5 inhibitor has an IC₅₀ against PDE5 of less than 100 nM and a selectivity ratio of PDE5 over PDE3 of more than 100.

40. A method of treating of impaired glucose tolerance (IGT) in a mammal comprising administering to said mammal an effective amount of sildenafil citrate in combination with one or more further components selected from one or more of:

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents.

53. A method of claim 40 wherein said selective cGMP PDE5 inhibitor is sildenafil citrate and said further components are selected from one or more of:

weight loss agents, sulfonyl ureas, insulin, Rezulin, Avandia, Actos, Glipizide, Metformin, Acarbose, rosiglitasone, pioglitazone, farglitazar, LY333531, CS011, PPAR-alpha agonists, and CP-470711.

41. A method of treating insulin resistance (IR) in a mammal comprising administering to said mammal an effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor or a pharmaceutical composition thereof.

42. A method of claim 41 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil, 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt, solvate, pro-drug, polymorph or a pharmaceutical composition thereof.

43. A method of claim 42 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

44. A method of claim 42 wherein said selective cGMP PDE5 inhibitor is sildenafil, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

45. A method of claim 44 wherein the selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil citrate.

46. A method of claim 44 comprising daily dosing, wherein said dosing is in the form of single, multiple or divided doses.

47. A method of claim 46 comprising daily dosing for 5 or more days, wherein said daily dosing is in the form of single, multiple or divided doses.

48. A method of claim 44 comprising continuous dosing for 5 or more days, wherein said continuous dosing is in the form of single or multiple continuous release doses.

59. A method of claim 41 comprising administering said cGMP PDE5 inhibitor, orally.

64. A method of claim 41. wherein said cGMP PDE 5 inhibitor has an IC₅₀ against PDE5 of less than 100 nM and a selectivity ratio of PDE5 over PDE3 of more than 100.

49. A method of treating of insulin resistance (IR) in a mammal comprising administering to said mammal an effective amount of sildenafil citrate in combination with one or more further components selected from one or more of:

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents.

54. A method of claim 49 wherein said selective cGMP PDE5 inhibitor is sildenafil citrate and said further components are selected from one or more of:

weight loss agents, sulfonyl ureas, insulin, Rezulin, Avandia, Actos, Glipizide, Metformin, Acarbose, rosiglitasone, pioglitazone, farglitazar, LY333531, CS011, PPAR-alpha agonists, and CP-470711.

65. A kit containing a treatment for the insulin resistance syndrome, wherein the insulin resistance syndrome means the concomitant existence in said mammal of two or more of:

dyslipidemia;

hypertension;

type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes;

hyperuricaemia and/or gout;

a pro-coagulant state;

atherosclerosis;

or truncal obesity comprising;

a) a therapeutically effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor and a pharmaceutically acceptable carrier in a first unit dosage form;

b) a therapeutically effective amount of one or more further components selected from one or more of;

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents nd a pharmaceutically acceptable carrier in a second unit dosage form; and

c) a container for containing said first and second dosage forms.

66. A kit of claim 65 wherein said selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil or sildenafil citrate.

67. A kit containing a treatment for type 2 diabetes mellitus comprising:

a) a therapeutically effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor and a pharmaceutically acceptable carrier in a first unit dosage form;

b) a therapeutically effective amount of one or more further components selected from one or more of;

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents nd a pharmaceutically acceptable carrier in a second unit dosage form; and

c) a container for containing said first and second dosage forms.

68. A kit of claim 67 wherein said selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil or sildenafil citrate.

69. A kit containing a treatment for impaired glucose tolerance (IGT) comprising:

a) a therapeutically effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor and a. pharmaceutically acceptable carrier in a first unit dosage form;

b) a therapeutically effective amount of one or more further components selected from one or more, of;

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents nd a pharmaceutically acceptable carrier in a second unit dosage form; and

c) a container for containing said first and second dosage forms.

70. A kit of claim 69 wherein said selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil or sildenafil citrate.

71. A kit containing a treatment for insulin resistance comprising:

a) a therapeutically effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor and a pharmaceutically acceptable carrier in a first unit dosage form;

b) a therapeutically effective amount of one or more further components selected from one or more of;

protein kinase inhibitors; and

or one or more activators or AMP-activated protein kinase; and

/or one or more weight loss agents; and

/or insulin; and

/or one or more PPAR-gamma agonists; and

/or one or more PPAR-alpha agonists; and

/or one or more dual PPAR-alpha/PPAR-gamma agonists;

one or more sorbitol dehydrogenase inhibitors;

one or more aldose reductase inhibitors;

one or more insulin sensitising agents; and

one or more hypoglycaemic agents nd a pharmaceutically acceptable carrier in a second unit dosage form; and

c) a container for containing said first and second dosage forms.

72. A kit of claim 71 wherein said selective pyrazolopyrimidinone cGMP PDE5 inhibitor is sildenafil or sildenafil citrate.