Use of a ghrelin agonist to improve the catabolic effects of glucocorticoid treatment
A method and pharmaceutical composition for inhibiting the effect of glucocorticoids, particularly dexamethasone, which suppress growth hormone secretion, by administering ghrelin or a ghrelin analogue, for example, [Aib 2 , Glu 3 (NH-hexyl)]hGhrelin(1-28)-NH 2 (SEQ ID NO:2) or other suitable ghrelin agonist, to counteract the catabolic effects of said dexamethasone and other natural glucocorticoids.
1. A method to ameliorate the catabolic effects of excess glucocorticoids in a child in need of such treatment comprising administering to said child a therapeutically effective amount of a ghrelin agonist, wherein said excess glucocorticoids are the result of the long term administration of dexamethasone.
2. A method according to claim 1 , wherein said amelioration alleviates a reduction in growth in said child.
3. A method according to claim 1 , wherein said amelioration alleviates a reduction in growth rate in said child.
4. A method according to claim 1 , wherein said amelioration alleviates a reduction in body weight in said child.
5. A method according to claim 1 , wherein said amelioration alleviates a reduction in body weight due in part to a loss in lean body mass in said child.
6. A method according to claim 1 , wherein said amelioration alleviates a reduction in IGF-1 levels in said child.
7. A method according to claim 1 , wherein said amelioration alleviates a reduction in bone mass in said child.
8. A method according to claim 1 wherein said ghrelin agonist is [Aib 2 , Glu 3 (NH-hexyl)]hGhrelin(1-28)-NH 2 (SEQ ID NO:2).
9. A method according to claim 1 wherein said ghrelin agonist is selecting from the group consisting of:
(SEQ ID NO: 3)
(Dap 3 (octanesulfonyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 4)
(Aib 2 , A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 5)
(Aib 2,6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 6)
(Aib 2 , 3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 7)
(A5c 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 8)
(Act 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 9)
(Aib 2 , Act 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 10)
(Aib 2 , Abu 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 11)
(Aib 2 , 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 12)
(Aib 2 , Thz 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 13)
(Aib 2 , Pip 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 14)
(Aib 2 , Dhp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 15)
(Aib 2,8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 16)
(Aib 2 , 4-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 17)
(Aib 2 , Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 18)
(Aib 2,10 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 19)
(Aib 2 , Tic 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 20)
(A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 21)
(3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 22)
(Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 23)
(2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 24)
(Aib 2 , Cha 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 25)
(Aib 2 , Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 26)
((Aib 2,8 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 27)
(Aib 2 , Glu 3 (NH-hexyl), 3-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 28)
(Aib 2 , Glu 3 (NH-hexyl), 4-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 29)
(Aib 2 , Glu 3 (NH-hexyl), Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 30)
(Aib 2 , Glu 3 (NH-hexyl), 2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 31)
(Aib 2,10 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 32)
(Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 33)
(Glu 3 (NH-hexyl), Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 34)
(Aib 2,12 , Glu 3 (NH-hexyl), 4-Pal 9 , Orn 15 )hGhrelin
(1-28)-NH 2
(SEQ ID NO: 35)
(Glu 3 (O-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 36)
(Aib 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 37)
(Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 38)
(Ac-Gly 1 , Aib 2 )hGhrelin(1-28)-NH 2
and
(SEQ ID NO: 41)
(n-octanoyl-Gly 1 )hGhrelin(1-28)-NH 2 .
10. A method according to claim 1 , wherein the administration of said ghrelin agonist is selected from the group consisting of subcutaneous, intramuscular, intranasal, intraperitoneal, and intravenous administration.
11. A method for allowing the long term administration of therapeutic doses of dexamethasone to a child to treat a disease or condition, comprising alleviating the catabolic effects of the administration of said long term therapeutic doses of dexamethasone by the administration of a ghrelin agonist.
12. A method according to claim 11 , in which said ghrelin agonist is [Aib 2 , Glu 3 (NH-hexyl)]hGhrelin(1-28)-NH 2 (SEQ ID NO:2).
13. A method according to claim 11 , wherein said ghrelin agonist is selecting from the group consisting of:
(SEQ ID NO: 3)
(Dap 3 (octanesulfonyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 4)
(Aib 2 , A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 5)
(Aib 2,6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 6)
(Aib 2 , 3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 7)
(A5c 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 8)
(Act 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 9)
(Aib 2 , Act 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 10)
(Aib 2 , Abu 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 11)
(Aib 2 , 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 12)
(Aib 2 , Thz 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 13)
(Aib 2 , Pip 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 14)
(Aib 2 , Dhp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 15)
(Aib 2,8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 16)
(Aib 2 , 4-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 17)
(Aib 2 , Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 18)
(Aib 2,10 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 19)
(Aib 2 , Tic 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 20)
(A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 21)
(3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 22)
(Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 23)
(2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 24)
(Aib 2 , Cha 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 25)
(Aib 2 , Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 26)
((Aib 2,8 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 27)
(Aib 2 , Glu 3 (NH-hexyl), 3-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 28)
(Aib 2 , Glu 3 (NH-hexyl), 4-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 29)
(Aib 2 , Glu 3 (NH-hexyl), Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 30)
(Aib 2 , Glu 3 (NH-hexyl), 2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 31)
(Aib 2,10 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 32)
(Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 33)
(Glu 3 (NH-hexyl), Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 34)
(Aib 2,12 , Glu 3 (NH-hexyl), 4-Pal 9 , Orn 15 )hGhrelin
(1-28)-NH 2
(SEQ ID NO: 35)
(Glu 3 (O-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 36)
(Aib 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 37)
(Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 38)
(Ac-Gly 1 , Aib 2 )hGhrelin(1-28)-NH 2
and
(SEQ ID NO: 41)
(n-octanoyl-Gly 1 )hGhrelin(1-28)-NH 2 .
14. A method according to claim 11 , wherein said therapeutic doses of dexamethasone are administered to a child to treat respiratory distress of prematurity and said catabolic effects of said long term administration of therapeutic doses of dexamethasone are alleviated by the administration of a ghrelin agonist.
15. A method according to claim 14 , in which said ghrelin agonist is [Aib 2 , G 1 u 3 (NH-hexyl)]hGhrelin(1-28)-NH 2 (SEQ ID NO:2).
16. A method according to claim 14 , wherein said ghrelin agonist is selecting from the group consisting of:
(SEQ ID NO: 3)
(Dap 3 (octanesulfonyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 4)
(Aib 2 , A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 5)
(Aib 2,6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 6)
(Aib 2 , 3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 7)
(A5c 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 8)
(Act 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 9)
(Aib 2 , Act 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 10)
(Aib 2 , Abu 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 11)
(Aib 2 , 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 12)
(Aib 2 , Thz 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 13)
(Aib 2 , Pip 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 14)
(Aib 2 , Dhp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 15)
(Aib 2,8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 16)
(Aib 2 , 4-Pal 9 )hGhrelin(1-28)-NH
(SEQ ID NO: 17)
(Aib 2 , Taz 9 )hGhrelin(1-28)-NH
(SEQ ID NO: 18)
(Aib 2,10 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 19)
(Aib 2 , Tic 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 20)
(A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 21)
(3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 22)
(Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 23)
(2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 24)
(Aib 2 , Cha 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 25)
(Aib 2 , Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 26)
((Aib 2,8 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 27)
(Aib 2 , Glu 3 (NH-hexyl), 3-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 28)
(Aib 2 , Glu 3 (NH-hexyl), 4-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 29)
(Aib 2 , Glu 3 (NH-hexyl), Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 30)
(Aib 2 , Glu 3 (NH-hexyl), 2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 31)
(Aib 2,10 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 32)
(Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 33)
(Glu 3 (NH-hexyl), Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 34)
(Aib 2,12 , Glu 3 (NH-hexyl), 4-Pal 9 , Orn 15 )hGhrelin
(1-28)-NH 2
(SEQ ID NO: 35)
(Glu 3 (O-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 36)
(Aib 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 37)
(Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 38)
(Ac-Gly 1 , Aib 2 )hGhrelin(1-28)-NH 2
and
(SEQ ID NO: 41)
(n-octanoyl-Gly 1 )hGhrelin(1-28)-NH 2 .
17. A method according to claim 11 , wherein said therapeutic doses of dexamethasone are administered to a child to treat asthma and said catabolic effects of said long term administration of therapeutic doses of dexamethasone are alleviated by the administration of a ghrelin agonist.
18. A method according to claim 17 , in which said ghrelin agonist is [Aib 2 , G 1 u 3 (NH-hexyl)]hGhrelin(1-28)-NH 2 (SEQ ID NO:2).
19. A method according to claim 17 , wherein said ghrelin agonist is selecting from the group consisting of:
(SEQ ID NO: 3)
(Dap 3 (octanesulfonyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 4)
(Aib 2 , A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 5)
(Aib 2,6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 6)
(Aib 2 , 3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 7)
(A5c 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 8)
(Act 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 9)
(Aib 2 , Act 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 10)
(Aib 2 , Abu 6 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 11)
(Aib 2 , 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 12)
(Aib 2 , Thz 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 13)
(Aib 2 , Pip 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 14)
(Aib 2 , Dhp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 15)
(Aib 2,8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 16)
(Aib 2 , 4-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 17)
(Aib 2 , Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 18)
(Aib 2,10 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 19)
(Aib 2 , Tic 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 20)
(A6c 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 21)
(3-Pal 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 22)
(Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 23)
(2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 24)
(Aib 2 , Cha 5 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 25)
(Aib 2 , Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 26)
((Aib 2,8 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 27)
(Aib 2 , Glu 3 (NH-hexyl), 3-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 28)
(Aib 2 , Glu 3 (NH-hexyl), 4-Pal9)hGhrelin(1-28)-NH 2
(SEQ ID NO: 29)
(Aib 2 , Glu 3 (NH-hexyl), Taz 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 30)
(Aib 2 , Glu 3 (NH-hexyl), 2-Thi 9 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 31)
(Aib 2,10 , Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 32)
(Glu 3 (NH-hexyl), 4-Hyp 7 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 33)
(Glu 3 (NH-hexyl), Aib 8 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 34)
(Aib 2,12 , Glu 3 (NH-hexyl), 4-Pal 9 , Orn 15 )hGhrelin
(1-28)-NH 2
(SEQ ID NO: 35)
(Glu 3 (O-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 36)
(Aib 2 )hGhrelin(1-28)-NH 2
(SEQ ID NO: 37)
(Glu 3 (NH-hexyl))hGhrelin(1-28)-NH 2
(SEQ ID NO: 38)
(Ac-Gly 1 , Aib 2 )hGhrelin(1-28)-NH 2
and
(SEQ ID NO: 41)
(n-octanoyl-Gly 1 )hGhrelin(1-28)-NH 2 .
20. A method according to claim 11 , wherein said administration of said ghrelin agonist is selected from the group consisting of subcutaneous, intramuscular, intranasal, intraperitoneal, and intravenous administration.