Synthetic triterpenoids and methods of use in the treatment of disease
View Patent ↗The present invention concerns methods for treating and preventing renal/kidney disease, insulin resistance/diabetes, fatty liver disease, and/or endothelial dysfunction/cardiovascular disease using synthetic triterpenoids, optionally in combination with a second treatment or prophylaxis.
1. A method of improving kidney function in a subject in need thereof comprising administering to the subject a compound of the formula,
in an amount sufficient to improve kidney function.
2. The method of claim 1 , where the subject has chronic kidney disease (CKD) or exhibits one or more symptoms of CKD.
3. The method of claim 2 , where the subject has been identified as having CKD.
4. The method of claim 2 , where the CKD is characterized by a serum creatinine level of 1.3-3.0 mg/DL where the subject is a human female or a serum creatinine level of 1.5-3.0 mg/DL where the subject is a human male.
5. The method of claim 2 , where the CKD is stage 4.
6. The method of claim 1 , where the subject has diabetic nephropathy (DN) or exhibits one or more symptoms of DN.
7. The method of claim 6 , where the subject has been identified as having DN.
8. The method of claim 1 , where the administering results in an improvement in estimated glomerular filtration rate (eGFR) of the subject.
9. The method of claim 8 , where the administering reduces the level of serum creatinine in the subject.
10. The method of claim 9 , where the level of serum creatinine in the blood of the subject has been measured.
11. The method of claim 1 , where the level of blood urea nitrogen (BUN) in the subject has been measured.
12. The method of claim 1 , where the level of Adiponectin in the blood of the subject has been measured.
13. The method of claim 1 , where the level of Angiotensin II in the subject has been measured.
14. The method of claim 1 , where the subject has insulin resistance or exhibits one or more symptoms of insulin resistance.
15. The method of claim 14 , where the subject has been identified as having insulin resistance.
16. The method of claim 14 , where the level of hemoglobin Alc in the subject has been measured.
17. The method of claim 14 , where a blood sugar level of the subject has been measured.
18. The method of claim 14 , where the administering reduces the level of hemoglobin Alc or fasting blood glucose in the subject.
19. The method of claim 17 , where a fasting glucose level of the subject has been measured.
20. The method of claim 14 , where the insulin sensitivity of the subject has been measured by a hyperinsulinemic euglycemic clamp test.
21. The method of claim 14 , where a glucose disposal rate (GDR) in the subject has been measured.
22. The method of claim 1 , where the subject has cardiovascular disease (CVD) or exhibits one or more symptoms of CVD.
23. The method of claim 22 , where the subject has been identified as having CVD.
24. The method of claim 22 , where the level of a marker of CVD in the subject has been measured.
25. The method of claim 22 , where the number of circulating endothelial cells (CFCs) in the blood of the subject has been measured.
26. The method of claim 25 , where the CECs are iNOS-positive circulating endothelial cells.
27. The method of claim 22 , where the administering reduces the level of circulating endothelial cells in the subject.
28. The method of claim 27 , where the administering reduces the level of hemoglobin Alc or fasting blood glucose in the subject.
29. The method of claim 1 , wherein the subject is a human.
30. The method of claim 1 , wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4 °2θ.
31. The method of claim 30 , wherein the X-ray diffraction pattern (CuKα) is substantially as shown in FIG. 12A or FIG. 12B .
32. The method of claim 30 , wherein the pharmaceutically effective amount is a daily dose of about 10 mg to about 200 mg of the compound.
33. The method of claim 1 , wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a halo peak at approximately 13.5 °2θ, substantially as shown in FIG. 12C , and a T g from about 120 ° C. to about 135 °C.
34. The method of claim 33 , wherein the T g is from about 125 ° C. to about 130 ° C.
35. The method of claim 33 , wherein the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 30 mg of the compound.
36. The method of claim 1 , where the compound is administered orally, intraarterially or intravenously.
37. The method of claim 1 , where the compound is formulated as a hard or soft capsule or a tablet.
38. The method of claim 1 , wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.
39. The method of claim 38 , wherein the excipient is a methacrylic acid-ethyl acrylate copolymer (1:1).
40. A method of improving kidney function in a subject comprising administering to the subject a compound of the formula,
in an amount sufficient to improve kidney function, wherein:
(a) at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a halo peak at approximately 13.5 °2θ, substantially as shown in FIG. 12C , and a T g from about 120 ° C. to about 135 ° C.; and
(b) where the subject has been identified as having chronic kidney disease (CKD).