Use of phosphodiesterase antagonists to treat insulin resistance

• US 20030181461A1
• Filed: 01/24/2003
• Published: 09/25/2003
• Est. Priority Date: 01/25/2002
• Status: Abandoned Application

• Current Assignee: Diamedica Inc.
• Original Assignee: University of Manitoba
• Inventors: Lautt, Wilfred Wayne, Macedo, Paula
• Application Number:
  US10/350,070
• Publication Number:
  US 20030181461A1
• 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 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• 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 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

A phosphodiesterase antagonist is used to reduce insulin resistance, and to amplify the effect of nitric oxide on skeletal muscle insulin-mediated glucose uptake in a mammal. In some instances, the antagonist is targeted to the liver. In some instances, the insulin resistance is hepatic insulin sensitizing substance (“HISS”) dependant insulin resistance.

Claims

1. A method of reducing insulin resistance in a mammalian patient comprising administering a suitable phosphodiesterase antagonist.

2. The method of claim 1 wherein the insulin resistance is HISS-dependent insulin resistance.

3. The method of claim 2 wherein the antagonist is at least one of vinpocetine, zaprinast and dipyridamole, sildenafil, theophylline, aminophylline, isobutylmethyl xanthine anagrelide, tadalafil, dyphylline, vardenafil, cilostazol and caffeine.

4. The method of claim 2 wherein the phosphodiesterase antagonist is antagonist of at least one of phosphodiesterase of subtype 3 and 5.

5. The method of claim 2 wherein the phosphodiesterase antagonist is preferentially targeted to the liver.

6. The method of claim 5 wherein the phosphodiesterase antagonist is targeted to the liver using albumin.

7. The method of claim 5 wherein the phosphodiesterase antagonist is targeted to the liver using a plurality of liposomes.

8. The method of claim 1 wherein the phosphodiesterase antagonist is administered by intravenous administration.

9. The method of claim 1 wherein the phosphodiesterase antagonist is administered by transdermal administration.

10. The method of claim 1 wherein the phosphodiesterase antagonist is administered by oral administration.

11. The method of claim 1 wherein the phosphodiesterase antagonist is administered by intra peritoneal administration.

12. The method of claim 1 wherein the phosphodiesterase antagonist is administered by portal vein injection.

14. The method of claim 1 wherein the phosphodiesterase antagonist is administered intravenously at a dose of between about 5 and 500 μ

g/kg body weight.

15. The method of claim 1 wherein the patient is a human.

13. The method of claim I wherein the phosphodiesterase antagonist is administered orally at a dose of between about 2 and 300 mg/kg body weight.

16. A method of amplifying the effect of nitric oxide on skeletal muscle insulin sensitivity comprising administering a phosphodiesterase antagonist.

17. The method of claim 16 wherein the phosphodiesterase antagonist is at least one of vinpocetine, zaprinast and dipyridamole, sildenafil, theophylline, aminophylline, isobutylmethyl xanthine anagrelide, tadalafil, dyphylline, vardenafil, cilostazol and caffeine.

18. A kit comprising:

a phosphodiesterase antagonist in a pharmaceutically acceptable carrier; and

instructions for the administration of the phosophodiesterase antagonist to reduce insulin resistance in a mammalian patient.

19. The kit of claim 18 further comprising means to administer the phosphodiesterase antagonist.

20. A pharmaceutical composition comprising a phosphodiesterase antagonist and at least one other drug used in the treatment of diabetes.

21. The pharmaceutical composition of claim 20 further including a pharmaceutically acceptable liver-targeting substance.

22. A method of increasing glucose uptake by skeletal muscle of a patient, comprising administering a phosphodiesterase antagonist.

23. The method of claim 22 wherein the phosphodiesterase antagonist is preferentially targeted to the liver.

24. The method of claim 22 wherein the phosphodiesterase antagonist includes at least one of vinpocetine, zaprinast, dipyridamole, sildenafil, theophylline, aminoptiylline, isobutylmethyl xanthine and caffeine.

25. The method of claim 22 wherein the patient suffers from at least one of chronic liver disease, chronic hypertension, type II diabetes, fetal alcohol syndrome, gestational diabetes, obesity, age-related insulin resistance, and hepatic nerve damage.

26. The method of claim 25 wherein the patient is a human.

27. The method of claim 24 wherein the phosphodiesterase antagonist is administered orally at a dose of between about 2 and 300 mg/kg body weight.

28. The method of claim 25 wherein the phosphodiesterase antagonist is administered intravenously at a dose of between about 5 and 500 μ

g/kg body weight.