Methods and compositions for the use of D-malic acid to decrease serum triglyceride, cholesterol and lipoprotein levels

• US 20040110803A1
• Filed: 09/15/2003
• Published: 06/10/2004
• Est. Priority Date: 09/13/2002
• Status: Abandoned Application

• Current Assignee: Samford University
• Original Assignee: Samford University
• Inventors: Jenkins, Ronald L., Dovlatabadi, Hossein
• Application Number:
  US10/662,654
• Publication Number:
  US 20040110803A1
• Time in Patent Office: Days
• US Class Current: 514/355
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

Compositions, methods and uses are provided for treating or preventing cardiovascular disease, including by decreasing serum cholesterol, triglyceride and lipoprotein cholesterol levels in a host that include administering an effective amount of D-malic acid or its pharmaceutically acceptable salt, prodrug or pharmaceutically acceptable derivative.

Claims

1. A method for treating cardiovascular disease in a host comprising administering an effective amount of a compound of the following formula:

2. The method of claim 1, wherein the compound is in substantially pure form.

3. The method of claim 1, wherein the compound is D-malic acid.

4. The method of claim 1, wherein the compound is D,L-malic acid.

25. The method of claim 1, further comprising administering a compound in combination or alternation selected from the group consisting of statins, IBAT inhibitors, MTP inhibitors, cholesterol absorption antagonists, phytosterols, CETP inhibitors, fibric acid derivatives and antihypertensive agents.

26. The method of claim 25, further comprising the administration of the compound (−

)-(2R,4S)-4-Amino-2-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or its salts.

27. The method of claim 25, wherein the fibric acid derivative is selected from the group consisting of clofibrate, fenofibrate, ciprofibrate, bezafibrate and gemfibrozil.

5. A method for decreasing the serum lipoprotein cholesterol level in a host comprising administering an effective amount of a compound of the following formula:

6. The method of claim 5, wherein the compound is in substantially pure form.

7. The method of claim 5, wherein the compound is D-malic acid.

8. The method of claim 5, wherein the compound is D,L-malic acid.

9. A method for decreasing the low density lipoprotein cholesterol level in a host comprising administering an effective amount of a compound of the following formula:

10. The method of claim 9, wherein the compound is in substantially pure form.

11. The method of claim 9, wherein the compound is D-malic acid.

12. The method of claim 9, wherein the compound is D,L-malie acid.

13. A method for decreasing the very low density lipoprotein cholesterol level in a host comprising administering an effective amount of a compound of the following formula:

14. The method of claim 13, wherein the compound is in substantially pure form.

15. The method of claim 13, wherein the compound is D-malic acid.

16. The method of claim 13, wherein the compound is D,L-malic acid.

17. A method for decreasing the serum triglyceride level in a host comprising administering an effective amount of a compound of the following formula:

18. The method of claim 17, wherein the compound is in substantially pure form.

19. The method of claim 17, wherein the compound is D-malic acid.

20. The method of claim 18, wherein the compound is D,L-malic acid.

21. A method for decreasing the total serum cholesterol level in a host comprising administering an effective amount of a compound of the following formula:

22. The method of claim 21, wherein the compound is in substantially pure form.

23. The method of claim 21, wherein the compound is D-malic acid.

24. The method of claim 21, wherein the compound is D,L-malic acid.

28. A pharmaceutical composition for decreasing the serum lipoprotein cholesterol level in a host consisting essentially of a compound of the following formula:

29. The pharmaceutical composition of claim 28, wherein the compound is in substantially pure form.

30. The pharmaceutical composition of claim 28, wherein the compound is D-malic acid.

31. The pharmaceutical composition of claim 28, wherein the compound is D,L-malic acid.

32. The pharmaceutical composition of claim 28, wherein the serum lipoprotein is selected from LDL, VLDL and HDL.

41. The pharmaceutical composition of claim 28, further comprising a compound selected from the group consisting of statins, JBAT inhibitors, MTP inhibitors, cholesterol absorption antagonists, phytosterols, CETP inhibitors, fibric acid derivatives and antihypertensive agents.

42. The pharmaceutical composition of claim 41, further comprising the compound (−

)-(2R,4S)-4-Amino-2-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or its salts.

43. The composition of claim 41, wherein the fibric acid derivative is selected from the group consisting of clofibrate, fenofibrate, ciprofibrate, bezafibrate and gemfibrozil.

33. A pharmaceutical composition for decreasing the serum total cholesterol level in a host consisting essentially of a compound of the following formula:

34. The pharmaceutical composition of claim 33, wherein the compound is in substantially pure form.

35. The pharmaceutical composition of claim 33, wherein the compound is D-malic acid.

36. The pharmaceutical composition of claim 33, wherein the compound is D,L-malic acid.

37. A pharmaceutical composition for decreasing the serum triglyceride level in a host consisting essentially of a compound of the following formula:

38. The pharmaceutical composition of claim 37, wherein the compound is in substantially pure form.

39. The pharmaceutical composition of claim 37, wherein the compound is D-malic acid.

40. The pharmaceutical composition of claim 37, wherein the compound is D,L-malic acid.

44. A method for treating hyperlipidemia comprising administering to a host an effective amount of a compound of the following formula:

45. The method of claim 44, wherein the compound is in substantially pure form.

46. The pharmaceutical composition of claim 44, wherein the compound is D-malic acid.

47. The pharmaceutical composition of claim 44, wherein the compound is D,L-malic acid.