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WO2018199849A1 - Métabolites caractéristiques dans des fausses couches - Google Patents

Métabolites caractéristiques dans des fausses couches Download PDF

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Publication number
WO2018199849A1
WO2018199849A1 PCT/SG2018/050208 SG2018050208W WO2018199849A1 WO 2018199849 A1 WO2018199849 A1 WO 2018199849A1 SG 2018050208 W SG2018050208 W SG 2018050208W WO 2018199849 A1 WO2018199849 A1 WO 2018199849A1
Authority
WO
WIPO (PCT)
Prior art keywords
miscarriage
metabolite
control
decrease
concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SG2018/050208
Other languages
English (en)
Inventor
Thiam Chye TAN
Chee Wai KU
Nguan Soon Tan
Zhen Wei TAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanyang Technological University
Singapore Health Services Pte Ltd
Original Assignee
Nanyang Technological University
Singapore Health Services Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanyang Technological University, Singapore Health Services Pte Ltd filed Critical Nanyang Technological University
Priority to SG11201909977P priority Critical patent/SG11201909977PA/en
Priority to CN201880042548.9A priority patent/CN110785664A/zh
Publication of WO2018199849A1 publication Critical patent/WO2018199849A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/493—Physical analysis of biological material of liquid biological material urine

Definitions

  • the present invention refers to a method of identifying the risk of a miscarriage comprising detecting and measuring the concentration of at least one metabolite in a sample obtained from a subject, wherein absence or presence of the metabolite, compared to the control group identifies an increased risk of miscarriage, wherein the metabolite is selected from the group consisting of tetrahydrocortisone, propionylcarnitine, isovalerylcarnitine, 3-methylglutarylcarnitine, hexanoylcarnitine and 3 ⁇ ,20 ⁇ -dihydroxy-5 -pregnane-3-glucuronide.
  • the method disclosed herein comprises detecting the absence or presence of at least four metabolites. In another example, the method disclosed herein comprises detecting the absence or presence of four metabolites. In yet another example, an increased or a decreased metabolite concentration or fold change of metabolite concentration indicates an increased risk of miscarriage.
  • This study outlined herein compares urine metabolites between pregnant women with and without spontaneous miscarriage. These findings contribute to the assembly of metabolic profiles of women with healthy pregnancies and women with spontaneous miscarriages, whereby leading better understanding of the interactions of the derivatives of urine metabolites, thereby improving the understanding of the pathophysiology behind spontaneous miscarriage. It is shown that the metabolites disclosed herein can serve as a predictive and diagnostic tool for the risk and likelihood of miscarriage. Through the screening and comparison of urine metabolite profiles, significant differences in six urine metabolites were found amongst pregnant women with and without spontaneous miscarriages.
  • Progesterone triggers the expression of Progesterone-induced-blocking factor (PIBF).
  • PIBF Progesterone-induced-blocking factor
  • the fetal presence in the maternal body triggers an immune response as it contains cells from the paternal side as well. A successful pregnancy would thus require suppression of the maternal immune response against the fetus.
  • Progesterone-induced-blocking factor (PIBF) has been shown to modulate the cytokine production from a pro-inflammatory Thl response to that of an anti-inflammatory Th2 response.
  • PIBF directly modulates the cytotoxic effect of decidual lymphocytes, protecting the fetus from these immune cells. It has been shown that lower PIBF levels result in pathological pregnancies such as pre-term birth or pre -eclampsia. Thus, the indispensability of progesterone in pregnancy aligns well with the finding of low progesterone metabolites in the urine of women who miscarry.
  • one of the metabolites is propionylcarnitine.
  • the metabolite is urinary or serum propionylcarnitine.
  • the metabolite is propionylcarnitine.
  • a change in the concentration of propionylcarnitine is indicative of an increased risk of miscarriage.
  • a decrease in the concentration of propionylcarnitine is indicative of an increased risk of miscarriage.
  • a decrease of propionylcarnitine compared to the control is a decrease of at least 0.41 (or -0.41) fold change in concentration compared to the control.
  • two metabolites are used in the method as disclosed herein, wherein two metabolites are selected from the group consisting of tetrahydrocortisone, propionylcarnitine, isovalerylcarnitine, 3-methylglutarylcarnitine, hexanoylcarnitine and 3a,20a-dihydroxy-5 -pregnane-3- glucuronide.
  • the two metabolites are selected from the group consisting of tetrahydrocortisone and propionylcarnitine; tetrahydrocortisone and isovalerylcarnitine; tetrahydrocortisone and 3-methylglutarylcarnitine; tetrahydrocortisone and hexanoylcarnitine; tetrahydrocortisone and 3a,20a-dihydroxy-5 -pregnane-3-glucuronide; propionylcarnitine and isovalerylcarnitine; propionylcarnitine and 3-methylglutarylcarnitine; propionylcarnitine and hexanoylcarnitine; propionylcarnitine and 3a,20a-dihydroxy-5 -pregnane-3-glucuronide; isovalerylcarnitine and 3-methylglutarylcarnitine; isovalerylcarnitine and 3-methylglutarylcarnitine; isovalerylcarnitine and he
  • spectroscopy-based assay examples include surface enhanced Raman spectroscopy (SERS), nuclear magnetic resonance (NMR), NMR spectroscopy, proton nuclear magnetic resonance ('H-NMR) and Raman spectroscopy.
  • the subject is to be administered dydrogesterone (also known as duphaston, isopregnenone, dehydroprogesterone, didrogesteron, 6-dehydroretroprogesterone, or 9 , 10a-pregna-4,6-diene-3,20-dione) or progesterone (also known as pregn-4-ene-3,20-dione, prometrium, utrogestan, endometrin or crinone).
  • dydrogesterone also known as duphaston, isopregnenone, dehydroprogesterone, didrogesteron, 6-dehydroretroprogesterone, or 9 , 10a-pregna-4,6-diene-3,20-dione
  • progesterone also known as pregn-4-ene-3,20-dione, prometrium, utrogestan, endometrin or crinone
  • the subject can be required to be administered a treatment once, twice, or three times a day.
  • the subject can be administered a drug immediately after having been determined to be at risk of miscarriage.
  • the drug can be administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, or 24 hours after having been determined to be at risk of a miscarriage.
  • the drug is to be administered during the day.
  • the drug is to be administered at night.
  • This amount can be per administration, or as a treatment total over a specific period of time.
  • the subject is to be administered 10 mg of the drug.
  • the subject is to be administered 40 mg of the drug.
  • the subject is to be administered 200 mg of the drug.
  • Profile data were collected from 50 to 1 ,200 m/z for both the positive and negative ionization mode with a scan time of 0.15 seconds over a 12 minute analysis.
  • Leucine enkephalin at a concentration of 200 ng/ml, was used as the lock mass with a flow rate of 5 ⁇ /min. It had a m/z of 556.2771 and 554.2615 in the positive and negative ionization mode respectively.
  • MassLynx software from Waters was used to control the system and data acquisition.
  • the UPLC-MS analysis in this study employed a QC strategy that was previously described. Firstly, to condition the column, QC sample was run 10 times before initiating the runs for the actual samples.
  • T-tests were used for statistical comparison of differences in maternal characteristics and metabolite levels between the miscarriage and full-term birth groups. Analysis of co-variances was used to determine if metabolite levels were linked to gestation age.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Endocrinology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

La présente invention concerne des procédés d'identification du risque de fausse couche chez un sujet, comprenant la détection et la mesure de la concentration d'au moins un métabolite dans un échantillon obtenu à partir du sujet. Spécifiquement, une augmentation de la concentration de tétrahydrocortisone, et une diminution de la concentration de propionylcarnitine, d'isovalérylcarnitine, de 3-méthylglutarylcarnitine, d'hexanoylcarnitine ou de 3α,20α-dihydroxy-5β-prégnane-3-glucuronide dans un échantillon de sérum ou d'urine sont associées à une fausse couche spontanée dans le premier trimestre d'une grossesse. L'invention concerne en outre des trousses pour déterminer le risque de fausse couche chez un sujet.
PCT/SG2018/050208 2017-04-28 2018-04-30 Métabolites caractéristiques dans des fausses couches Ceased WO2018199849A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SG11201909977P SG11201909977PA (en) 2017-04-28 2018-04-30 Characteristic metabolites in miscarriages
CN201880042548.9A CN110785664A (zh) 2017-04-28 2018-04-30 流产中的特征性代谢物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SG10201703502T 2017-04-28
SG10201703502T 2017-04-28

Publications (1)

Publication Number Publication Date
WO2018199849A1 true WO2018199849A1 (fr) 2018-11-01

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Family Applications (1)

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PCT/SG2018/050208 Ceased WO2018199849A1 (fr) 2017-04-28 2018-04-30 Métabolites caractéristiques dans des fausses couches

Country Status (3)

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CN (1) CN110785664A (fr)
SG (1) SG11201909977PA (fr)
WO (1) WO2018199849A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12162243B2 (en) 2018-01-15 2024-12-10 Nanyang Technological University Superhydrophobic platform for sensing urine metabolites and toxins

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034287A1 (fr) * 1995-04-28 1996-10-31 Quidel Corporation Dosages et dispositifs permettant de determiner si une grossesse est normale ou anormale
US20140221236A1 (en) * 2013-02-01 2014-08-07 Kristi S. Borowski Metabolomic markers for preterm birth
US20150094227A1 (en) * 2013-10-02 2015-04-02 Spd Swiss Precision Diagnostics Gmbh Pregnancy test device and method
US20150090010A1 (en) * 2013-09-27 2015-04-02 Chang Gung University Method for diagnosing heart failure

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034287A1 (fr) * 1995-04-28 1996-10-31 Quidel Corporation Dosages et dispositifs permettant de determiner si une grossesse est normale ou anormale
US20140221236A1 (en) * 2013-02-01 2014-08-07 Kristi S. Borowski Metabolomic markers for preterm birth
US20150090010A1 (en) * 2013-09-27 2015-04-02 Chang Gung University Method for diagnosing heart failure
US20150094227A1 (en) * 2013-10-02 2015-04-02 Spd Swiss Precision Diagnostics Gmbh Pregnancy test device and method

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AL-MEMAR M. ET AL.: "Urine metabolomic changes by gestational age in early pregnancy and differences in the metabolome between viable pregnancies and those that miscarry", ULTRASOUND OBSTET GYNECOL, vol. 48, no. 1, 8 September 2016 (2016-09-08), pages 23 - 24, XP055528967, [retrieved on 20180723] *
KU C.W. ET AL.: "How can we better predict the risk of spontaneous miscarriage among women experiencing threatened miscarriage?", GYNECOLOGICAL ENDOCRINOLOGY, vol. 31, no. 8, 2 June 2015 (2015-06-02), pages 647 - 651, [retrieved on 20180723] *
KU C.W. ET AL.: "Spontaneous miscarriage in first trimester pregnancy is associated with altered urinary metabolite profile", BBA CLINICAL, vol. 8, 19 August 2017 (2017-08-19), pages 48 - 55, XP055528971, [retrieved on 20180723] *
LONG C.A. ET AL.: "First-trimester rapid semiquantitative assay for urine pregnanediol glucuronide predicts gestational outcome with the same diagnostic accuracy as serial human chorionic gonadotropin measurements", AM J OBSTET GYNECOL, vol. 170, no. 6, June 1994 (1994-06-01), pages 1822 - 1825, [retrieved on 20180723] *
NEPOMNASCHY P.A. ET AL.: "Cortisol levels and very early pregnancy loss in humans", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 103, no. 10, 22 February 2006 (2006-02-22), pages 3938 - 3942, XP055528969, [retrieved on 20180723] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12162243B2 (en) 2018-01-15 2024-12-10 Nanyang Technological University Superhydrophobic platform for sensing urine metabolites and toxins

Also Published As

Publication number Publication date
SG11201909977PA (en) 2019-11-28
CN110785664A (zh) 2020-02-11

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