Compositions and methods for stimulating gastrointestinal motility
The present invention relates to a method of treating a transient impairment of the motility of the gastrointestinal system resulting from postoperative ileus in a patient wherein said method includes the step of administering a therapeutically effective amount of a peptidyl analog of ghrelin to said patient.
1. A method of stimulating the motility of the gastrointestinal system in a patient, said method comprising administering a peptidyl analog of ghrelin to a patient in need thereof
wherein said peptidyl analog of ghrelin comprises the following formula (II):
R 1 - A 1 - A 2 - A 3 - A 4 - A 5 - R 2 (II)
wherein:
A 1 is Aib, Apc or Inp;
A 2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), or D-Trp;
A 3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), or D-Trp;
A 4 is 2-Fua, Orn, 2-Pal, 3-Pal, 4-Pal, Pff, Phe, Pim, Taz, 2-Thi, 3-Thi, Thr(Bzl);
A 5 is Apc, Dab, Dap, Lys, Orn, or deleted;
R 1 is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and
R 2 is OH or NH 2 ;
provided that when A 5 is Dab, Dap, Lys, or Orn, then:
A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 3 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 4 is 2-Thi, 3-Thi, Taz, 2-Fua, 2-Pal, 3-Pal, 4-Pal, Orn, Thr(Bzl), or Pff;
when A 5 is deleted, then:
A 3 is D-Bip, D-Bpa, or D-Dip; or
A 4 is 2-Fua, Pff, Taz, or Thr(Bzl); or
A 1 is Apc when
A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 3 is D-Bip, D-Bpa, D-Dip or D-Bal; or
A 4 is 2-Thi, 3-Thi, Orn, 2-Pal, 3-Pal or 4-Pal;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein said patient is experiencing postoperative ileus following gastrointestinal surgery.
3. The method of either claim 1 or claim 2 , wherein said patient is either concurrently being administered or has previously been administered opioid analgesics.
4. The method of claim 3 , wherein said peptidyl analog is H-Inp-D-Bal-D-Trp-Phe-Apc-NH 2 .
5. The method according to claim 1 , wherein said patient is a human.
6. The A method according to claim 1 , wherein said patient in need of gastrointestinal stimulation is experiencing gastroesophageal reflux disease, ileus, emesis, gastroparesis, IBS, constipation, or colonic pseudo-obstruction.
7. The method according to claim 6 , wherein said patient is experiencing ileus, emesis or gastroparesis.
8. The method according to claim 7 , wherein said patient is experiencing ileus.
9. The method according to claim 8 , wherein said ileus is postoperative ileus.
10. The method according to claim 9 , wherein said postoperative ileus follows abdominal surgery.
11. The method according to claim 10 , wherein said ileus is of the stomach, small intestine, or large intestine.
12. The method according to claim 8 , wherein said ileus is caused by a factor other than abdominal surgery.
13. The method according to claim 12 , wherein said ileus is of the stomach, small intestine or large intestine.
14. The method according to claim 1 , wherein said therapeutically effective amount of said pharmaceutical composition comprising a peptidyl analog of ghrelin or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, is administered intravenously, subcutaneously, orally, or by implantation of a sustained release formulation.
15. A method of stimulating the motility of the gastrointestinal system in a patient wherein said method comprises identifying a patient suffering from or at risk for gastroesophageal reflux disease, ileus, emesis, gastroparesis, IBS, constipation, or colonic pseudo-obstruction, and administering to said patient a therapeutically effective amount a pharmaceutical composition comprising a peptidyl analog of ghrelin or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, according to claim 1 .
16. A method of preventing post-operative ileus in a patient in need thereof, wherein said method comprises administering to said patient a therapeutically effective amount a pharmaceutical composition comprising a peptidyl analog of ghrelin or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, according to claim 1 , before, during or after a surgery, or a combination thereof.
17. The method of according to claim 16 , wherein said administration is before said surgery.
18. The method of according to claim 16 , wherein said administration is during said surgery.
19. The method of according to claim 16 , wherein said administration is after said surgery.
20. A method of preventing post-operative ileus, gastroesophageal reflux disease, emesis, gastroparesis, IBS, constipation, or colonic pseudo-obstruction in a patient in need thereof by administering to said patient a therapeutically effective amount a pharmaceutical composition comprising a peptidyl analog of ghrelin or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, according to claim 1 , wherein said administration is intravenous, subcutaneous, oral, or by implantation of a sustained release formulation.
21. The method according to claim 20 , wherein said administration is intravenous.
22. The method according to claim 20 , wherein said administration is subcutaneous.
23. The method according to claim 20 , wherein said administration is oral.
24. The method according to claim 20 , wherein said administration is by implantation of a sustained release formulation.
25. A method of eliciting a response from a ghrelin receptor in a patient in need thereof which comprises administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising a peptidyl analog of ghrelin or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, according to claim 1 .