Compositions and methods of treating cardiac fibrosis with ifetroban
The present invention is directed to methods of treating, preventing, and/or ameliorating fibrosis syndrome, and in particular cardiac fibrosis, by administration of a therapeutically effective amount of ifetroban, or a pharmaceutically acceptable salt thereof.
1. A method of treating cardiac fibrosis in a mammal in need of treatment thereof, consisting of administering a therapeutically effective amount of a thromboxane A 2 receptor antagonist or a pharmaceutically acceptable salt thereof to the mammal.
2. The method of claim 1 , wherein the mammal is a human patient.
3. The method of claim 1 , wherein the thromboxane A 2 receptor antagonist is [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid (ifetroban), or a pharmaceutically acceptable salt thereof to the mammal.
4. The method of claim 3 , wherein the therapeutically effective amount of ifetroban reduces the rate of formation of fibrotic tissue in the mammal.
5. The method of claim 3 , wherein the ifetroban is administered in an amount effective to provide a plasma concentration of the ifetroban of about 1 ng/ml to about 10,000 ng/ml.
6. The method of claim 3 , wherein the thromboxane A 2 receptor antagonist is administered in an amount effective to provide a plasma concentration from about 1 ng/ml to about 100,000 ng/ml.
7. The method of claim 3 wherein the therapeutically effective amount is from about 10 mg to about 1000 mg per day.
8. The method of claim 7 , wherein the ifetroban is administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally, or transdermally.
9. The method of claim 7 , wherein the therapeutically effective amount of ifetroban slows the progression of myocardial fibrosis in the human patient.
10. The method of claim 7 , wherein the therapeutically effective amount of ifetroban improves the exercise capacity in the human patient.
11. The method of claim 7 , the therapeutically effective amount of ifetroban reduces RV fibrosis in the human patient.
12. The method of claim 7 , wherein the therapeutically effective amount of ifetroban reduces cardiomyocyte hypertrophy in the human patient.
13. The method of claim 7 , wherein the therapeutically effective amount of ifetroban provides an increased E/A wave ratio in the human patient.
14. The method of claim 7 , wherein the therapeutically effective amount of ifetroban improves or maintains a function selected from the group consisting of right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF), right ventricular diastolic function (RVDF), and left ventricular diastolic function (LVDF).
15. The method of claim 14 , wherein the therapeutically effective amount of ifetroban protects against increases in cardiomyocyte diameter in the human patient.
16. The method of claim 15 , wherein the therapeutically effective amount of ifetroban is cardioprotective against pressure overload, by moving the right heart towards adaptation rather than a maladaptive fibrosis, inflammation and cellular hypertrophy.
17. The method of claim 16 , wherein the therapeutically effective amount of ifetroban attenuates left heart failure in the human patient.
18. A method of treating cardiac fibrosis in a human in need of treatment thereof, consisting of administering ifetroban or a pharmaceutically acceptable salt thereof in a therapeutically effective amount from about 10 mg to about 1000 mg per day to a human patient in an amount effective to attenuate left heart failure, such that the therapeutically effective amount of ifetroban provides an increased E/A wave ratio in the human patient.
19. The method of claim 18 , wherein the therapeutically effective amount of ifetroban improves or maintains a function selected from the group consisting of right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary dynamics, right ventricular systolic pressure (RVSP), left ventricular systolic function (LVSF), right ventricular diastolic function (RVDF), and left ventricular diastolic function (LVDF).
20. The method of claim 18 , wherein the therapeutically effective amount of ifetroban protects against increases in cardiomyocyte diameter in the human patient.