Treatment or prevention of cardiovascular events via the administration of a colchicine derivative
A method for the treatment or prevention of a cardiovascular event in a subject with atherosclerotic vascular disease comprising the step of: b) administering a therapeutically effective amount of a compound of formula (I), a known colchicine derivative and/or a salt thereof wherein: R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11 and R 12 independently represent hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, halogen, C 1-4 haloalkyl, nitro, amino, C 2-4 acylamino, C 1-4 alkyl or dialkylamino, hydroxyl, C 1-4 alkoxy, C 1-4 alkylthio, a group of the formula —SO 2 N(R x ) 2 or SO 2 R x where R x is C 1-4 alkyl, C 1-4 acyloxy, or optionally substituted phenyl, optionally substituted phenoxy; R 7 and R 8 independently represent hydrogen, C 1-4 alkyl or C 1-4 acyl; and R 5 ′, R 5 ″, R 6 ′ and R 6 ″ independently represent hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, halogen, C 1-4 haloalkyl, nitro, amino, C 2-4 acylamino, hydroxyl, C 1-4 alkoxy or C 1-4 alkylthio a group of the formula —SO 2 N(R x ) 2 or SO 2 R x where R x is C 1-4 alkyl, C 1-4 acyloxy, or optionally substituted phenyl.
1. A method for treating and/or reducing the risk of a cardiovascular event in a subject in need thereof comprising: administering to the subject a therapeutically effective amount of a composition comprising no more than about 0.6 total mg of (i) colchicine, (ii) a salt of (i), or any combination of (i)-(ii), wherein the composition is administered once per day, thereby treating and/or reducing the risk of the cardiovascular event in the subject.
2. The method of claim 1 , wherein the composition is administered orally, topically, parenterally, intraorbitally, ophthalmically, intraventricularly, intracranially, intracapsularly, intraspinally, intracisternally, intraperitoneally, buccally, rectally, vaginally, intranasally, by aerosol administration and/or inhalation spray, or by an implanted reservoir.
3. The method of claim 1 , wherein the composition is administered in the form of a tablet, capsule, liquid dose, gel or powder.
4. The method of claim 1 , wherein the composition comprises about 0.5 mg of (i) colchicine, (ii) the salt of (i), or any combination of (i)-(ii).
5. The method of claim 1 , wherein the subject has atherosclerotic vascular disease.
6. The method of claim 5 , wherein the atherosclerotic vascular disease is a coronary disease.
7. The method of claim 6 , wherein the coronary disease is a clinically stable coronary disease.
8. The method of claim 1 , wherein the cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest or noncardioembolic ischemic stroke.
9. The method of claim 1 , further comprising co-administering to the subject a therapeutically effective amount of a second agent for the treatment and/or reduction of risk of the cardiovascular event in the subject.
10. The method of claim 9 , wherein the second agent is a colchicine-compatible statin.
11. The method of claim 10 , wherein the colchicine-compatible statin is selected from the group consisting of: (i) atorvastatin, (ii) fluvastatin, (iii) lovastatin, (iv) pitavastatin, (v) rosuvastatin, (vi) simvastatin, (vii), pravastatin, a salt of any of (i)-(vii), or any combination thereof.
12. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.
13. The method of claim 1 , wherein the composition reduces the risk of the subject having a cardiovascular event by a greater percentage than a composition that does not include (i)-(ii).
14. The method of claim 13 , wherein the risk of out-of-hospital cardiac arrest is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.
15. The method of claim 13 , wherein the risk of acute coronary syndrome is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.
16. The method of claim 13 , wherein the risk of noncardioembolic ischemic stroke is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.
17. The method of claim 1 , wherein administration of the compound also reduces the risk of an adverse gastrointestinal event in the subject.
18. The method of claim 17 , wherein the composition reduces the risk of an adverse gastrointestinal event in the subject as compared to administration of a composition that includes more than 1.0 total mg of (i) colchicine, (ii) a salt of (i), or any combination of (i)-(ii).
19. A method for treating and/or reducing the risk of a cardiovascular event in a subject in need thereof, that comprises:
administering to the subject a therapeutically effective amount of a composition comprising no more than about 0.6 total mg of (i) colchicine, (ii) a salt of (i), or any combination of (i)-(ii),
wherein the composition is administered once per day,
wherein the composition is in the form of a tablet,
wherein the cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke, and
wherein the composition is homogeneous.
20. The method of claim 19 , wherein the composition comprises about 0.5 mg of (i) colchicine, (ii) the salt of (i), or any combination of (i)-(ii).
21. The method of claim 19 , wherein the subject has atherosclerotic vascular disease.
22. The method of claim 21 , wherein the atherosclerotic vascular disease is a coronary disease.
23. The method of claim 22 , wherein the coronary disease is a clinically stable coronary disease.
24. The method of claim 19 , further comprising co-administering to the subject a therapeutically effective amount of a second agent for the treatment and/or reduction of risk of the cardiovascular event in the subject.