WO2022016751A1 - Formulation de diagnostic moléculaire et de traitement de l'endométriose, méthode de préparation associée et utilisation associée - Google Patents

Formulation de diagnostic moléculaire et de traitement de l'endométriose, méthode de préparation associée et utilisation associée Download PDF

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Publication number
WO2022016751A1
WO2022016751A1 PCT/CN2020/129877 CN2020129877W WO2022016751A1 WO 2022016751 A1 WO2022016751 A1 WO 2022016751A1 CN 2020129877 W CN2020129877 W CN 2020129877W WO 2022016751 A1 WO2022016751 A1 WO 2022016751A1
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polypeptide
endometriosis
product obtained
modification
molecular diagnosis
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PCT/CN2020/129877
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English (en)
Chinese (zh)
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赵华山
张键
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深圳先进技术研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/14—Peptides, e.g. proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
    • C07K14/445—Plasmodium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof

Definitions

  • the invention belongs to the field of medical cell biology, and relates to a molecular diagnosis and treatment preparation for endometriosis and a preparation method and application thereof.
  • Endometriosis is a common clinical gynecological intractable disease in which active endometrial tissue grows ectopic in a non-uterine environment.
  • pathogenesis of the disease is still unclear, there is still a lack of efficient and direct tools for the diagnosis and treatment of the disease.
  • Early detection is undoubtedly a prerequisite for the intervention and treatment of the disease.
  • the purpose of the present invention is to provide a molecular diagnosis and treatment preparation for endometriosis and its preparation method and application.
  • One aspect of the present invention provides a molecular diagnosis and treatment preparation for endometriosis, comprising: 1) an effector component, that is, a diagnostic compound and/or a drug for treating endometriosis; 2) a targeting component, that is, a target component To recognize the ability of the polypeptide;
  • the polypeptide includes one or more of the following sequences in combination, or a derivative of one or more of the following sequences in combination,
  • the polypeptide can be modified on a diagnostic and/or therapeutic carrier to achieve its specific recognition of the lesion tissue, thereby obtaining a disease intervention tool that can be used for diagnosis and treatment.
  • the derivative is the product obtained by the modification of the terminal or side chain of the polypeptide, or the product obtained by the labeling modification of the polypeptide by the fluorescent group, or the product obtained by the isotopic labeling of the polypeptide, or the polypeptide obtained by phosphorylation modification.
  • the modification of the terminal or side chain of the polypeptide includes but is not limited to N-terminal acetylation modification and C-terminal amination modification.
  • isotope used in isotopic labeling of the polypeptide includes, but is not limited to, 13C , and the modification is used for tracking purposes.
  • the phosphorylation modification of the polypeptide includes but is not limited to p-Ser, p-Thr, and p-Tyr.
  • polypeptide is labeled with biotin for the purpose of localization and detection, and the like.
  • polypeptide is modified with a photosensitizer to facilitate the preparation of a photosensitizer.
  • polypeptide is modified with azide, which is beneficial to the secondary ligation reaction.
  • polypeptide is modified with PEG for preparation of a drug carrier.
  • polypeptides can be synthesized independently by general organic chemistry laboratory conditions, or industrially synthesized by conventional commercial reagent companies, that is, the use of solid-phase method to synthesize polypeptides, and the condensation reaction between different amino acids on the resin to realize the synthesis of directional amino acid chains. .
  • the desired modification group is applied after the amino acid is linked.
  • the diagnostic compound includes a near-infrared region dye.
  • the near-infrared region dyes include but are not limited to Cy5, Cy7, and indocyanine green.
  • the near-infrared region dye is indocyanine green.
  • the drugs for treating endometriosis include therapeutic antibodies and existing therapeutic drugs for endometriosis.
  • the therapeutic drug for endometriosis is a drug with small molecular weight, suitable water solubility, and high biological safety and stability.
  • the therapeutic drug for endometriosis includes one or a combination of at least two of progestins, androgens, and gonadotropin-releasing hormone agonists;
  • the progestin drugs include puvera, progesterone, nemethon, and progesterone caproate;
  • the androgen drugs include danazol
  • the gonadotropin-releasing hormone agonist comprises goserelin.
  • Another aspect of the present invention provides a method for preparing a molecular diagnosis and treatment preparation for endometriosis.
  • the effector component and the targeting component are connected and assembled by conventional methods to obtain a molecular diagnosis and treatment preparation for endometriosis; the The molar ratio of the effector component and the targeting component is 1:0 ⁇ 1:1, excluding 1:0, preferably 1:0.5 ⁇ 1:1.
  • a kind of preparation method of endometriosis molecular diagnosis and treatment preparation comprises the following steps:
  • connection and assembly are carried out by conventional methods (such as EDC method, etc.), and the molar ratio of effector components and targeting components is 1:0 ⁇ 1:1 (excluding 1:0), preferably 1:0.5 ⁇ 1:1.
  • the effector component is also a polypeptide substance, a conventional polypeptide synthesis method can be used, and a suitable polypeptide linker structure is used between the two components to directly synthesize a complete diagnostic preparation. It is generally stored at 4°C for future use or ready-to-use.
  • the molecular diagnosis and treatment preparation for endometriosis provided by the present invention can be used for the diagnosis of endometriosis.
  • FIG. 1 is an effect diagram of in vivo imaging of indocyanine green in an embodiment of the present invention.
  • the present invention uses SEQ The polypeptide sequence described in ID No. 1 is exemplified.
  • Example 1 SEQ Preparation of the polypeptide sequence described in ID No. 1
  • the effector component was selected from indocyanine green dye, which was purchased from a commercial chemical reagent company, and was modified with a DBCO linker, so as to facilitate subsequent connection with the polypeptide sequence.
  • the polypeptide sequence prepared in Example 1 was selected. Mix the effector component and the targeting component at a molar ratio of 1:0.5, and store them at 4 °C after thorough mixing.
  • mice Male female mice were taken, sterilized and anesthetized, anteroposterior endometrial tissue was taken, cut into small pieces (2 mm ⁇ 2 mm), fixed and inoculated near the mesenteric blood vessels, and the wounds were sutured, and the mice rested and had free access to food and water for one month. After the vesicles grow, the modeling can be considered successful.
  • the diagnosis and treatment preparation prepared in Example 2 was injected into the tail vein of the successful model mice, and 24 hours later, the mice were subjected to respiratory anesthesia, and then placed in a small animal imager, and the fluorescence was observed in vivo under respiratory anesthesia.
  • the excitation wavelength of the fluorescence signal is between 600-900 nanometers.
  • the molecular diagnosis and treatment preparation for endometriosis provided by the present application can be used for the purpose of diagnosis and treatment of endometriosis.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Optics & Photonics (AREA)
  • Biomedical Technology (AREA)
  • Acoustics & Sound (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une formulation de diagnostic moléculaire et de traitement, une méthode de préparation associée et une utilisation associée. La formulation comprend : (1) un composant à effet, c'est-à-dire un composé de diagnostic et/ou un médicament pour le traitement de l'endométriose ; et (2) un composant de ciblage, c'est-à-dire un polypeptide ayant une capacité de reconnaissance de ciblage. Le polypeptide comprend un polypeptide qui est une ou une combinaison de plusieurs des séquences suivantes ou un dérivé du polypeptide qui est une ou une combinaison de plusieurs des séquences suivantes : SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5 et SEQ ID No.6. Ladite formulation est appropriée pour le diagnostic et/ou le traitement de maladies de l'endométriose chez l'humain, et peut également être utilisée en tant qu'outil de recherche pour un animal de laboratoire pour l'endométriose.
PCT/CN2020/129877 2020-07-21 2020-11-18 Formulation de diagnostic moléculaire et de traitement de l'endométriose, méthode de préparation associée et utilisation associée WO2022016751A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010706564.2A CN113952467A (zh) 2020-07-21 2020-07-21 一种子宫内膜异位症分子诊疗制剂及其制备方法和应用
CN202010706564.2 2020-07-21

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WO2022016751A1 true WO2022016751A1 (fr) 2022-01-27

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CN115404274A (zh) * 2022-11-01 2022-11-29 广东省生殖科学研究所(广东省生殖医院) 一种甲基化位点在子宫内膜异位症诊断和分型中的应用

Citations (3)

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WO2015095952A1 (fr) * 2013-12-27 2015-07-02 The Centre For Drug Research And Development Conjugués var2csa-médicament
CN109387627A (zh) * 2018-10-16 2019-02-26 中国科学院深圳先进技术研究院 一种基于胎盘样硫酸软骨素a的癌症筛查和早期诊断的试剂方法
CN109568597A (zh) * 2017-09-28 2019-04-05 中国科学院深圳先进技术研究院 靶向胎盘样硫酸软骨素a的多肽药物偶联物及其制备方法和应用

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WO2015095952A1 (fr) * 2013-12-27 2015-07-02 The Centre For Drug Research And Development Conjugués var2csa-médicament
CN109568597A (zh) * 2017-09-28 2019-04-05 中国科学院深圳先进技术研究院 靶向胎盘样硫酸软骨素a的多肽药物偶联物及其制备方法和应用
CN109387627A (zh) * 2018-10-16 2019-02-26 中国科学院深圳先进技术研究院 一种基于胎盘样硫酸软骨素a的癌症筛查和早期诊断的试剂方法

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LI, MENG ET AL.: "Research Progress on Pregnancy-Associated Malaria", JOURNAL OF TROPICAL MEDICINE, vol. 8, no. 12, 31 December 2008 (2008-12-31), pages 1287 - 1293, XP055889072 *
PROFESSIONAL COMMITTEE OF GYNECOLOGY AND OBSTETRICS, CHINESE ASSOCIATION OF INTEGRATIVE MEDICINE: "Guidelines for Endometriosis by Integrated Traditional Chinese and Western Medicine", CHINESE JOURNAL OF INTEGRATED TRADITIONAL AND WESTERN MEDICINE, vol. 39, no. 10, 31 October 2019 (2019-10-31), pages 1169 - 1176, XP055889325 *

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