Synthetic triterpenoids and methods of use in the treatment of disease
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 preventing end-stage renal disease (ESRD) in a patient suffering from stage 4 chronic kidney disease (CKD), comprising administering to the patient a compound of the formula
in an amount sufficient to prevent ESRD.
2. The method of claim 1 , where the CKD is characterized by a serum creatinine level of 1.3-3.0 mg/DL where the patient is a human female or a serum creatinine level of 1.5-3.0 mg/DL where the patient is a human male.
3. The method of claim 1 , where the level of serum creatinine in the blood of the patient has been measured.
4. The method of claim 1 , where the level of blood urea nitrogen (BUN) in the patient has been measured.
5. The method of claim 1 , where the level of adiponectin in the blood of the patient has been measured.
6. The method of claim 1 , where the level of angiotensin II in the patient has been measured.
7. The method of claim 1 , where the patient has insulin resistance or exhibits one or more symptoms of insulin resistance.
8. The method of claim 7 , where the patient has been identified as having insulin resistance.
9. The method of claim 7 , where the level of hemoglobin A1c in the patient has been measured.
10. The method of claim 7 , where a blood sugar level of the patient has been measured.
11. The method of claim 10 , where a fasting glucose level of the patient has been measured.
12. The method of claim 7 , where the insulin sensitivity of the patient has been measured by a hyperinsulinemic euglycemic clamp test.
13. The method of claim 7 , where a glucose disposal rate (GDR) in the patient has been measured.
14. The method of claim 1 , where the patient has cardiovascular disease (CVD) or exhibits one or more symptoms of CVD.
15. The method of claim 14 , where the patient has been identified as having CVD.
16. The method of claim 14 , where the level of a marker of CVD in the patient has been measured.
17. The method of claim 14 , where the number of circulating endothelial cells (CECs) in the blood of the patient has been measured.
18. The method of claim 17 , where the CECs are iNOS-positive circulating endothelial cells.
19. The method of claim 1 , wherein the patient is a human.
20. 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.
21. The method of claim 20 , wherein the X-ray diffraction pattern (CuKα) is substantially as shown in FIG. 12A or FIG. 12B .
22. The method of claim 20 , wherein the pharmaceutically effective amount is a daily dose of about 10 mg to about 200 mg of the compound.
23. 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° 20, substantially as shown in FIG. 12C , and a T g from about 120° C. to about 135° C.
24. The method of claim 23 , wherein the T g is from about 125° C. to about 130° C.
25. The method of claim 23 , wherein the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 30 mg of the compound.
26. The method of claim 1 , where the compound is administered orally, intraarterially or intravenously.
27. The method of claim 1 , where the compound is formulated as a hard or soft capsule or a tablet.
28. The method of claim 1 , wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.
29. The method of claim 28 , wherein the excipient is a methacrylic acid-ethyl acrylate copolymer.
30. A method of preventing end-stage renal disease (ESRD) in a patient suffering from stage 4 chronic kidney disease (CKD), comprising administering to the patient a compound of the formula
in an amount sufficient to prevent ESRD, 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 patient has been identified as having chronic kidney disease (CKD).