Methods for prophylaxis or treatment of conditions associated with cortical spreading depression
The present invention is directed to the use of a class of peptide compounds for the prophylaxis and treatment of chronic headache, particularly migraines.
1. A method for treating a condition associated with cortical spreading depression (CSD) in a subject, comprising administering to the subject, in an amount effective to suppress CSD, a compound having the Formula (IIb)
wherein
Ar is phenyl which is unsubstituted or substituted with at least one halo group;
R 3 is CH 2 -Q, wherein Q is lower alkoxy containing 1-3 carbon atoms; and
R 1 is lower alkyl containing 1-3 carbon atoms,
or a pharmaceutically acceptable salt thereof, wherein the condition associated with CSD is a chronic headache selected from a group consisting of a muscle contraction headache, a toxic headache, a cluster headache, a traction headache, and an inflammatory headache.
2. The method of claim 1 , wherein the compound is
(R)-2-acetamido-N-benzyl-3-methoxypropionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; or
O-methyl-N-acetyl-D-serine-p-fluorobenzylamide.
3. The method of claim 1 wherein, in the compound of Formula (IIb), Ar is unsubstituted phenyl.
4. The method of claim 1 wherein, in the compound of Formula (IIb), halo is fluoro.
5. The method of claim 1 wherein, in the compound of Formula (IIb), R 3 is CH 2 -Q, wherein Q is alkoxy containing 1-3 carbon atoms and Ar is unsubstituted phenyl.
6. The method of claim 1 , wherein the compound is substantially enantiopure.
7. The method of claim 1 , wherein the compound of Formula (IIb) is (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
8. The method of claim 7 , wherein the compound is substantially enantiopure.
9. The method of claim 1 , wherein the compound is administered at a dose of at least 100 mg/day.
10. The method of claim 1 , wherein the compound is administered at a dose of at a maximum 1 g/day.
11. The method of claim 1 , wherein the compound is administered at increasing daily doses until a predetermined daily dose is reached which is maintained during further treatment.
12. The method of claim 1 , wherein the compound is administered in at most three doses per day.
13. The method of claim 1 , wherein administration of the compound results in a plasma concentration of 7 to 8 μg/ml (trough) and 9 to 12 μg/ml (peak).
14. The method of claim 1 , wherein the compound is administered for at least one week.
15. The method of claim 1 , wherein the compound is administered orally.
16. The method of claim 1 , further comprising administering to the subject a further active agent effective for prevention or treatment of a headache or a CSD-associated condition.
17. The method of claim 16 , wherein the compound of Formula (IIb) and the further active agent are present in a single dose form.
18. The method of claim 1 , wherein the subject is a mammal.
19. The method of claim 18 , wherein the subject is human.
20. The method of claim 16 , wherein the compound of Formula (IIb) and the further active agent are present in separate dose forms.
21. The method of claim 1 , wherein the compound is administered at a dose of at a maximum 1 g/day.
22. The method of claim 1 , wherein the compound is administered at a dose of at a maximum 400 mg/day.
23. A method of suppressing CSD to prevent or treat a CSD-initiated headache in a subject in need thereof, the CSD-initiated headache selected from the group consisting of a muscle contraction headache, a toxic headache, a cluster headache, a traction headache, and an inflammatory headache, the method comprising administering to the subject an oral effective amount of (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
24. The method of claim 23 , wherein the headache is cluster headache.
25. The method of any one of claims 23 to 24 , further comprising administering to the subject a triptan.
26. The method of claim 25 , wherein the triptan is sumatriptan.
27. The method of claim 23 , comprising orally administering to the subject about 100 mg/day to about 400 mg/day (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
28. The method of claim 16 , wherein the further active agent is effective for treatment of a CSD-associated condition selected from the group consisting of head injury, transient global amnesia, and intracranial hemorrhage.
29. A method of treating in a subject a CSD-associated condition selected from the group consisting of a head injury, transient global amnesia, and intracranial hemorrhage, the method comprising administering to the subject an effective amount of (R)-2-acetamido-N-benzyl-3-methoxypropionamide.