JP6895963B2 - 多発性嚢胞腎のバイオマーカーおよびその使用 - Google Patents

多発性嚢胞腎のバイオマーカーおよびその使用 Download PDF

Info

Publication number
JP6895963B2
JP6895963B2 JP2018525768A JP2018525768A JP6895963B2 JP 6895963 B2 JP6895963 B2 JP 6895963B2 JP 2018525768 A JP2018525768 A JP 2018525768A JP 2018525768 A JP2018525768 A JP 2018525768A JP 6895963 B2 JP6895963 B2 JP 6895963B2
Authority
JP
Japan
Prior art keywords
pkd
level
ambp
sample
patient
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.)
Active
Application number
JP2018525768A
Other languages
English (en)
Japanese (ja)
Other versions
JP2019502902A5 (enExample
JP2019502902A (ja
Inventor
ニコライ・バカノフ
サラ・モレノ
ティモシー・イー・ウェーデン
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.)
Genzyme Corp
Original Assignee
Genzyme Corp
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 Genzyme Corp filed Critical Genzyme Corp
Publication of JP2019502902A publication Critical patent/JP2019502902A/ja
Publication of JP2019502902A5 publication Critical patent/JP2019502902A5/ja
Application granted granted Critical
Publication of JP6895963B2 publication Critical patent/JP6895963B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4728—Details alpha-Glycoproteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
JP2018525768A 2015-11-18 2016-11-15 多発性嚢胞腎のバイオマーカーおよびその使用 Active JP6895963B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562257089P 2015-11-18 2015-11-18
US62/257,089 2015-11-18
PCT/US2016/062075 WO2017087409A1 (en) 2015-11-18 2016-11-15 Biomarker of polycystic kidney disease and uses thereof

Publications (3)

Publication Number Publication Date
JP2019502902A JP2019502902A (ja) 2019-01-31
JP2019502902A5 JP2019502902A5 (enExample) 2019-12-26
JP6895963B2 true JP6895963B2 (ja) 2021-06-30

Family

ID=57539614

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2018525768A Active JP6895963B2 (ja) 2015-11-18 2016-11-15 多発性嚢胞腎のバイオマーカーおよびその使用

Country Status (12)

Country Link
US (2) US11116755B2 (enExample)
EP (1) EP3377908B1 (enExample)
JP (1) JP6895963B2 (enExample)
KR (1) KR20180083902A (enExample)
CN (1) CN108700594B (enExample)
AU (1) AU2016357720A1 (enExample)
BR (1) BR112018009879A2 (enExample)
CO (1) CO2018006126A2 (enExample)
EA (1) EA201891170A1 (enExample)
MX (1) MX2018006250A (enExample)
WO (1) WO2017087409A1 (enExample)
ZA (1) ZA201803035B (enExample)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116755B2 (en) 2015-11-18 2021-09-14 Genzyme Corporation Biomarker of polycystic kidney disease and uses thereof
PL3920912T3 (pl) * 2019-02-04 2025-11-12 Genzyme Corporation Leczenie ciliopatii przy użyciu inhibitorów syntazy glukozyloceramidowej (gcs)
KR102859441B1 (ko) * 2019-11-22 2025-09-12 서울대학교산학협력단 Opn 검출용 제제를 포함하는, 다낭신의 진단용 조성물 및 이의 이용
JPWO2023145898A1 (enExample) * 2022-01-27 2023-08-03

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6710227B1 (en) 1998-09-16 2004-03-23 Cropdesign N.V. Cyclin-dependent kinase inhibitors and uses thereof
US6703395B2 (en) 1998-03-04 2004-03-09 Institute Of Experimental Botany Of The Academy Of Sciences Of The Czech Republic Cyclin dependent kinase inhibitor
US20040006074A1 (en) 1998-04-28 2004-01-08 The Government Of The United States Of America Cyclin dependent kinase (CDK)4 inhibitors and their use for treating cancer
CA2256121A1 (en) 1998-06-08 1999-12-08 Hong Wang Cyclin-dependent kinase inhibitors as plant growth regulators
ATE318818T1 (de) 1998-06-16 2006-03-15 Us Gov Health & Human Serv Annellierte azepinone als inhibitoren cyclin- abhängiger kinasen
US6559152B2 (en) 1998-10-13 2003-05-06 Dupont Pharmaceuticals Company 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones useful as cyclin dependent kinase inhibitors
JP2003500418A (ja) 1999-05-24 2003-01-07 エイブイアイ バイオファーマ， インコーポレイテッド 多発性嚢胞腎疾患の処置のためのｃ−ｍｙｃに対するアンチセンス
US6593356B2 (en) 1999-10-20 2003-07-15 Bristol-Myers Squibb Pharma Company Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents
US20040048844A1 (en) 1999-10-20 2004-03-11 Bristol-Myers Squibb Pharma Company Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents
WO2001081348A1 (en) 2000-04-25 2001-11-01 Bristol-Myers Squibb Company USE OF 5-THIO-, SULFINYL- AND SULFONYLPYRAZOLO[3,4-b]-PYRIDINES AS CYCLIN DEPENDENT KINASE INHIBITORS
US20050004007A1 (en) 2000-09-12 2005-01-06 Steven Grant Promotion of adoptosis in cancer cells by co-administration of cyclin dependent kinase inhibitiors and cellular differentiation agents
AU2509602A (en) 2000-12-20 2002-07-01 Sod Conseils Rech Applic Cyclin-dependent kinase (CDK) and glycolene synthase kinase-3 (GSK-3) inhibitors
GB0101686D0 (en) 2001-01-23 2001-03-07 Cancer Res Campaign Tech Cyclin dependent kinase inhibitors
GB0113041D0 (en) 2001-05-30 2001-07-18 Astrazeneca Ab Chemical compounds
WO2003063764A2 (en) 2001-07-10 2003-08-07 Bristol-Myers Squibb Pharma Company 6-SUBSTITUTED PYRAZOLO [3,4-d] PYRIMIDIN-4-ONES USEFUL AS CYCLIN DEPENDENT KINASE INHIBITORS
GB0218625D0 (en) 2002-08-10 2002-09-18 Astex Technology Ltd Pharmaceutical compounds
US7205308B2 (en) 2002-09-04 2007-04-17 Schering Corporation Trisubstituted 7-aminopyrazolopyrimidines as cyclin dependent kinase inhibitors
MXPA05002573A (es) 2002-09-04 2005-09-08 Schering Corp Pirazolopirimidinas como inhibidores de cinasa dependientes de ciclina.
MXPA05002572A (es) 2002-09-04 2005-09-08 Schering Corp Compuestos pirazolo[1,5-a]pirimidinas como inhibidores de cinasa depentes de ciclina.
NZ539164A (en) 2002-09-04 2006-04-28 Schering Corp Pyrazolopyrimidines as cyclin dependent kinase inhibitors
US7196078B2 (en) 2002-09-04 2007-03-27 Schering Corpoartion Trisubstituted and tetrasubstituted pyrazolopyrimidines as cyclin dependent kinase inhibitors
CN1694705A (zh) 2002-09-04 2005-11-09 先灵公司 用作依赖细胞周期蛋白激酶抑制剂的吡唑并嘧啶
US7196092B2 (en) 2002-09-04 2007-03-27 Schering Corporation N-heteroaryl pyrazolopyrimidines as cyclin dependent kinase inhibitors
US7119200B2 (en) 2002-09-04 2006-10-10 Schering Corporation Pyrazolopyrimidines as cyclin dependent kinase inhibitors
CA2499639C (en) 2002-09-19 2011-11-08 Schering Corporation Imidazopyridines as cyclin dependent kinase inhibitors
CA2499593C (en) 2002-09-19 2011-08-16 Michael P. Dwyer Pyrazolopyridines as cyclin dependent kinase inhibitors
JP2006503838A (ja) 2002-09-23 2006-02-02 シェーリング　コーポレイション サイクリン依存性キナーゼインヒビターとしての新規イミダゾピラジン
ATE377600T1 (de) 2002-09-23 2007-11-15 Schering Corp Imidazopyrazine als cdk-inhibitoren
US7576085B2 (en) 2002-09-23 2009-08-18 Schering Corporation Imidazopyrazines as cyclin dependent kinase inhibitors
GB0313677D0 (en) 2003-06-13 2003-07-16 Oxford Glycosciences Uk Ltd Novel compound
US9006181B2 (en) 2004-07-21 2015-04-14 The Administrators Of The Tulane Educational Fund Treatment of renal dysfunction and multiple myeloma using PACAP compounds
EP1808694A1 (en) 2006-01-17 2007-07-18 Universitätsklinikum Freiburg Method for diagnosing polycystic kidney disease
EP2594562B1 (en) 2007-05-31 2016-07-20 Genzyme Corporation 2-acylaminopropanol-type glucosylceramide synthase inhibitors
JP5661457B2 (ja) 2007-06-06 2015-01-28 シーメンス・ヘルスケア・ダイアグノスティックス・インコーポレーテッドＳｉｅｍｅｎｓ Ｈｅａｌｔｈｃａｒｅ Ｄｉａｇｎｏｓｔｉｃｓ Ｉｎｃ． 腎疾患の予測診断
US8389517B2 (en) 2008-07-28 2013-03-05 Genzyme Corporation Glucosylceramide synthase inhibition for the treatment of collapsing glomerulopathy and other glomerular disease
CN107935983A (zh) 2008-10-03 2018-04-20 简詹姆公司 2‑酰胺基丙醇型葡糖神经酰胺合酶抑制剂
US20120077263A1 (en) 2009-06-05 2012-03-29 Mayo Foundation For Medical Education And Research Methods and materials for isolating exosomes
CN102858985A (zh) * 2009-07-24 2013-01-02 西格马-奥尔德里奇有限责任公司 基因组编辑方法
CN102018702B (zh) 2009-09-16 2012-07-18 北京大学 银杏内酯b的一种用途
NZ625712A (en) 2009-11-27 2016-02-26 Genzyme Corp An amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
US20110195903A1 (en) 2009-12-15 2011-08-11 Adra Chaker N Methods and compositions for detecting recessive familial fsgs and uses thereof
US20140079769A1 (en) 2010-10-01 2014-03-20 Fabiola Terzi Methods for predicting the progression and treating a chronic kidney disease in a patient
US20130276513A1 (en) * 2010-10-14 2013-10-24 The Regents Of The University Of California Methods for diagnosing and assessing kidney disease
JP6021021B2 (ja) 2010-11-05 2016-11-02 国立大学法人京都大学 多発性嚢胞腎の検査方法および治療剤のスクリーニング方法
SG11201401222WA (en) 2011-10-03 2014-09-26 Celmatix Inc Methods and devices for assessing risk to a putative offspring of developing a condition
WO2013059119A1 (en) 2011-10-17 2013-04-25 The Regents Of The University Of Michigan Glucosylceramide synthase inhibitors and therapeutic methods using the same
CN102590491B (zh) 2012-02-06 2014-12-10 中国人民解放军第三军医大学第一附属医院 一种用于早期筛查或辅助诊断泌尿系统疾病的检测试剂盒、检测方法及其用途
ES2982997T3 (es) 2012-07-03 2024-10-21 Fond Centro San Raffaele 2-desoxiglucosa para uso en el tratamiento de la enfermedad renal poliquística dominante autosomal o enfermedad hepática poliquística
JOP20130273B1 (ar) * 2012-09-11 2021-08-17 Genzyme Corp مثبطات انزيم (سينثاز) غلوكوسيل سيراميد
JP6730252B2 (ja) 2014-08-04 2020-07-29 ジェンザイム・コーポレーション 多発性嚢胞腎のバイオマーカーおよびその使用
US11116755B2 (en) 2015-11-18 2021-09-14 Genzyme Corporation Biomarker of polycystic kidney disease and uses thereof

Also Published As

Publication number Publication date
US20210379031A1 (en) 2021-12-09
EP3377908A1 (en) 2018-09-26
US11116755B2 (en) 2021-09-14
MX2018006250A (es) 2018-09-05
KR20180083902A (ko) 2018-07-23
US12150938B2 (en) 2024-11-26
CN108700594B (zh) 2021-06-29
US20180338961A1 (en) 2018-11-29
AU2016357720A1 (en) 2018-07-05
JP2019502902A (ja) 2019-01-31
ZA201803035B (en) 2019-02-27
WO2017087409A1 (en) 2017-05-26
EP3377908B1 (en) 2020-08-05
CN108700594A (zh) 2018-10-23
EA201891170A1 (ru) 2018-11-30
CO2018006126A2 (es) 2018-07-10
BR112018009879A2 (pt) 2018-11-13

Similar Documents

Publication Publication Date Title
US12150938B2 (en) Biomarker of polycystic kidney disease and uses thereof
Zucchi et al. One year in review 2019: systemic lupus erythematosus
Djudjaj et al. Macrophage migration inhibitory factor mediates proliferative GN via CD74
EP2753931B1 (en) Autoimmune and inflammatory disorder therapy
US10545134B2 (en) RAC1 inhibitors for the treatment of Alport glomerular disease
RU2580626C2 (ru) Применение ингибиторов vap-1 для лечения фиброзных болезней
JP7005695B2 (ja) 多発性嚢胞腎のバイオマーカーおよびその使用
Han et al. CXCR4-targeted PET imaging in rheumatoid arthritis: a novel approach for monitoring disease activity and therapeutic response
JP2017081870A (ja) 椎間板変性症に対する治療薬ｊａｋ‐ｓｔａｔ３阻害剤
TW202112368A (zh) 用於治療有關dux4表現之疾病的抑制劑組合
JP2022501388A (ja) 関節リウマチにおけるｐｔｐｒｓ及びプロテオグリカン
JP2019502902A5 (enExample)
Park et al. Regulation of phosphorylation of glycogen synthase kinase 3α and the correlation with sperm motility in human
Guerra-Torres A case report of tuberous sclerosis and autosomal dominant polycystic kidney disease in the era of Tolvaptan
Lokau et al. Transforming growth factor beta induces interleukin-11 expression in osteoarthritis
US20250170129A1 (en) Senotherapeutic agents and alpha-klotho polypeptides
Easterday Skeletal Muscle Derived CD81+ Extracellular Vesicles as a Potential Therapeutic for Insulin Resistance in Adipocytes
Wen et al. A paradigm shift of PD-L1 immunotherapy based on a tracking-to-triggering immunoediting effect of 2-[18F] FDG
WO2022122889A1 (en) Methods and compositions for detecting the activation of mtor pathway
EP3946337A1 (en) Compositions and methods to treat non-alcoholic fatty liver diseases (nafld)
EA045040B1 (ru) Способы и композиции для лечения нарушений, ассоциированных со старением

Legal Events

Date Code Title Description
A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20191112

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20191112

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20200730

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20210105

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20210402

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20210511

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20210608

R150 Certificate of patent or registration of utility model

Ref document number: 6895963

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250