NON-INVASIVE BIOMARKER TO IDENTIFY SUBJECT AT RISK OF PRETERM DELIVERY

• US 20180003713A1
• Filed: 09/19/2017
• Published: 01/04/2018
• Est. Priority Date: 10/24/2012
• Status: Active Grant

• Current Assignee: NYU Winthrop Hospital
• Original Assignee: Winthrop-University Hospital
• Inventors: RAGOLIA, Louis
• Granted Patent: US 10,408,838 B2
• Time in Patent Office: Days
• 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

1-21. -21. (canceled)

22. A pharmaceutical formulation comprising a therapeutic amount of a composition selected from the group consisting of at least one of a prostaglandin DP1 receptor antagonist, or a prostaglandin DP2 receptor antagonist, and a selective L-PGDS inhibitor, in an effective and non-teratogenic amount to delay preterm delivery in a pregnant human when administered in repeated doses without harming the fetus.

23. The pharmaceutical formulation according to claim 22, wherein the composition is 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)-I-(2-cyclohexyl-2-hydroxyethylamino)-hydantoin), S-5751 ((Z)-7-[(IR,2R,3S,5S)-2-(5-hydroxy benzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid), BAY-u3405 (Ramatroban, 3(R)-[[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid), and AT-56 (4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine).

24. A method for predicting and delaying preterm delivery of a fetus, comprising:

collecting a cervical vaginal secretion sample from a pregnant woman having an intact amniotic membrane, with a sponge treated with at least a protease inhibitor and a bacteriocide;

measuring lipocalin-type prostaglandin D2 synthase concentration and ratios of isoforms of lipocalin-type prostaglandin D2 synthase in the collected cervical vaginal secretion sample;

determining a likelihood of preterm delivery based on a comparison of the measured lipocalin-type prostaglandin D2 synthase concentration and ratios of the isoforms of lipocalin-type prostaglandin D2 synthase with population statistics with respect to the gestational age of the fetus; and

selectively applying a tocolytic therapy in dependence on the determined likelihood.

25. The method according to claim 24, wherein the tocolytic therapy comprises oral administration of a prostaglandin D2 receptor antagonist

26. A method for delaying preterm delivery of a human fetus, comprising:

collecting a cervical vaginal secretion sample from a pregnant woman having an intact amniotic membrane;

employing at least one antibody to measure lipocalin-type prostaglandin D2 synthase concentration and lipocalin-type prostaglandin D2 synthase isoform ratios in the collected cervical vaginal secretion sample;

comparing the measured lipocalin-type prostaglandin D2 synthase concentration and lipocalin-type prostaglandin D2 synthase isoform ratios in the collected cervical vaginal secretion sample with a relevant standard population, to determine a preterm delivery risk; and

selectively administering a therapeutic amount of at least one composition selected from the group consisting of a prostaglandin DP1 receptor antagonist, a prostaglandin DP2 receptor antagonist, and a selective L-PGDS inhibitor to the pregnant woman dependent on the determined preterm delivery risk.