Non-invasive biomarker to identify subject at risk of preterm delivery

• US 9,797,903 B2
• Filed: 10/24/2013
• Issued: 10/24/2017
• Est. Priority Date: 10/24/2012
• Status: Active Grant

• Current Assignee: NYU Winthrop Hospital
• Original Assignee: Winthrop-University Hospital
• Inventors: Ragolia, Louis
• Primary Examiner(s): Heyer, Dennis
• Application Number:
  US14/438,110
• Publication Number:
  US 20150285800A1
• Time in Patent Office: 1,461 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: G01N 2333/99 Isomerases (5.)
• CPC Class Codes: G01N 2800/368 Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

Methods for diagnosis to allow prediction of the likelihood of preterm birth based upon the concentration of lipocalin-type prostaglandin D2 synthase (L-PGDS) in cervical vaginal secretions. In addition, specific prostaglandin D2 receptor antagonists may represent novel tocolytic therapeutics.

Claims

1. A method for assessing the likelihood of preterm delivery for a pregnant woman with an intact amniotic membrane, the method comprising:

receiving a cervical vaginal secretion sample collected from a pregnant woman, the cervical vaginal secretion sample being collected with an absorptive media and treated with a protease inhibitor to reduce proteolysis;

measuring lipocalin-type prostaglandin D2 synthase (L-PGDS) concentration from the cervical vaginal secretion sample;

and

administering to the pregnant woman, selectively in dependence on the measured lipocalin-type prostaglandin D2 synthase (L-PGDS) concentration of at least 1.8 μ

g/ml, an effective amount of a therapeutic composition to avoid or mitigate preterm delivery, comprising at least one compound selected from the group consisting of;

a prostaglandin DP1 receptor antagonist,

a prostaglandin DP2 receptor antagonist, and

a selective L-PGDS inhibitor.

2. The method of claim 1, wherein the cervical vaginal secretion is collected with a sponge.

3. The method of claim 1, wherein the prostaglandin DP1 receptor antagonist is administered in an effective amount as a tocolytic agent.

4. The method of claim 1, wherein the prostaglandin DP2 receptor antagonist is administered in an effective amount as a tocolytic agent.

5. The method of claim 1, wherein the selective L-PGDS inhibitor is administered in an effective amount as a tocolytic agent.

6. The method of claim 1, wherein the L-PGDS concentration is determined using an antibody sandwich Enzyme-Linked ImmunoSorbent Assay (ELISA).

7. The method of claim 1, wherein the L-PGDS concentration is normalized to protein levels in the cervical vaginal secretions for analysis.

8. The method according to claim 1, wherein the therapeutic composition comprises one or more compounds selected from the group consisting of AM156 ({2′

-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′

-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt), and AM206 (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt), MK-0524 ([(3R)-4-(4-Chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid), AM-853 (2-(4-(4-(tert-butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenyl sulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid), BW868C (3-benzyl-5-(6-carbohexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)-hydantoin), S-5751 ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxy benzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid), and BAY-u3405 (Ramatroban, 3(R)-[[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid).

9. The method according to claim 1, wherein the therapeutic composition comprises AT-56 (4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine).

10. The method according to claim 1, wherein the therapeutic composition is administered orally.

11. The method according to claim 1, wherein the therapeutic composition is administered by at least one of the group consisting of by inhalation, through a mucous membrane, transdermally, topically and rectally.

12. The method according to claim 1, wherein the therapeutic composition is administered parenterally.

13. The method according to claim 1, wherein the therapeutic composition is administered to achieve concurrent therapeutic effect with a coadminstered tocolytic agent which is not a prostaglandin D2 receptor antagonist and is not an L-PGDS inhibitor.

14. The method according to claim 13, wherein the coadministered tocolytic agent comprises a β

2 receptor agonist.

15. The method according to claim 13, wherein the β

2 receptor agonist is at least one compound selected from the group consisting of terbutaline, Ritodrine, Fenoterol, and Salbutamol.

16. The method according to claim 13, wherein the coadministered tocolytic agent comprises a non-steroidal anti-inflammatory drug cyclooxygenase inhibitor.

17. The method of claim 1, wherein the therapeutic composition comprises a DP2 receptor antagonist.

18. The method of claim 1, wherein the therapeutic composition comprises a DP1 receptor antagonist.

19. The method of claim 1, wherein the therapeutic composition comprises a selective L-PGDS inhibitor.