JP5213852B2 - 放射線肺障害の予防及び治療のためのピリドン系誘導体の使用 - Google Patents
放射線肺障害の予防及び治療のためのピリドン系誘導体の使用 Download PDFInfo
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- JP5213852B2 JP5213852B2 JP2009514614A JP2009514614A JP5213852B2 JP 5213852 B2 JP5213852 B2 JP 5213852B2 JP 2009514614 A JP2009514614 A JP 2009514614A JP 2009514614 A JP2009514614 A JP 2009514614A JP 5213852 B2 JP5213852 B2 JP 5213852B2
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- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000002640 oxygen therapy Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007119 pathological manifestation Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 229950009343 sivelestat Drugs 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- ZAIFANJZUGNYCK-UHFFFAOYSA-M sodium;2-[[2-[[4-(2,2-dimethylpropanoyloxy)phenyl]sulfonylamino]benzoyl]amino]acetate Chemical compound [Na+].C1=CC(OC(=O)C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NCC([O-])=O ZAIFANJZUGNYCK-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
- Toxicology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アルコキシ基(例えば、メトキシ基、エトキシ基)又はC1-6アルキルチオ基(例えば、メチルチオ基、エチルチオ基)である。]
又はその薬学的に許容される塩の使用を提供する。
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アルコキシ基又はC1-6アルキルチオ基である。]
又はその薬学的に許容される塩の使用を提供する。
前記哺乳動物に予防有効量の式Iの化合物:
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アルコキシ基又はC1-6アルキルチオ基である。]
又はその薬学的に許容される塩を使用する工程と、
その後、該哺乳動物に対して、放射線治療を行う工程と、
を含む方法を提供する。
(a)放射線治療の予定される放射線量がD0である、放射線治療が必要な哺乳動物対象に、式Iの化合物:
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アルコキシ基又はC1-6アルキルチオ基である。]
又はその薬学的に許容される塩を使用する工程と、
(b)放射線量D1(ここで、D1>D0である)で、前記哺乳動物に対して、放射線治療を行う工程と、
を含む方法を提供する。
(D1-D0)/D0> 20%
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アルコキシ基又はC1-6アルキルチオ基である。]
又はその薬学的に許容される塩を示す。
さらに、本発明は、放射線治療の放射線量を向上させる方法を提供する。該方法は、予定される放射線量D0の、放射線治療を行う患者に、予め予防有効量のピルフェニドンを使用し、その後放射線量D1で放射線治療を行うことを含む。ここで、D1>D0で、好ましくは、D1がD0より20%、より好ましくは、50%大きい。
ピルフェニドンの放射線肺障害に対する作用
(a) 照射方法:
照射源:Varian 600C線形加速器、6MV X線。
照射方法:覚醒状態でマウスを1列に6匹ずつ特製の有機ガラス容器内に固定し、線量ビルドアップ効果を補償するように、上に厚さ1.5cmの有機ガラス板を覆い、源-皮距離:100cm、照射野:2.5×18cmで、コリメーターの鉛板で頭部と腹部を遮り、マウスの胸部のみを照射した。照射は一回ずつ1200cGyであった。実験マウスが清潔動物室を出入りする場合、エアろ過付きの専用密閉転移箱が用いられる。
動物:10週齢のBALB/Cマウス
モデル対照組(60匹):照射のみで、治療しなかった。
予防投与組(60匹):照射の2日間前から所定の投与量の薬物を投与した。放射線照射の処理方法及び線量はモデル対照組と同じである。毎日1回ピルフェニドンを胃灌流投与し(投与量は200mg/kgで、0.5%のCMC-Naで溶解して0.1ml/10gの量で投与)、合計3ヶ月投与した。
治療投与組(60匹):照射当日から所定の投与量の薬物を投与した。放射線照射の処理方法及び線量はモデル対照組と同じで、照射は一回であった。毎日1回ピルフェニドンを胃灌流投与し(投与量は200mg/kgで、0.5%のCMC-Naで溶解して0.1ml/10gの量で投与)、合計3ヶ月投与した。
空白対照組(60匹):照射せず、毎日0.5%のCMC-Naを胃灌流投与し、合計3ヶ月投与した。
照射後、各組のマウスについて、毎日1回死亡が出現したかを観察した。実験処理後、定期的に洗浄液の細胞分類計数、コラーゲン含有量の測定(ヒドロキシプロリン)、病理形態学観察等を行った。
肺ヒドロキシプロリン含有量の測定:肺組織をとり、ヒドロキシプロリンキットの説明書に従って測定する。
組織の病理学検査:肺組織をとってホルマリンで固定し、脱水後パラフィン包埋し、HE染色及びマッソン・トリクローム染色を行う。評価基準は、Ashcroft間質肺線維化半定量評点基準を参照し、放射線肺障害を評価する。
実験によって、ピルフェニドンの予防及び治療はいずれも肺胞洗浄液における炎症性細胞の数を低下することができ、ピルフェニドンは放射線照射による肺部の炎症反応に対してある程度の抑制作用を持つことが明らかにされた。予防性投与の治療効果は、治療性投与よりも顕著であった(表1と図1)。
ピルフェニドンは放射線治療線量に対する耐性の向上が可能
(a)方法:実施例1と同様であった。
予防組(60匹):照射の2日間前から所定の投与量の薬物を投与した。薬物治療は2組に分かれ、ピルフェニドンを胃灌流投与し(投与量は200mg/kgで、0.5%のCMC-Naで溶解して0.1ml/10gの量で投与)、合計3ヶ月投与した。
12名の健康な被験者に400mgのピルフェニドンのカプセルを、1日当たり1回か3回経口投与し、5日間持続し、且つ毎日被験者の血中薬物濃度を測定した。結果、400mgで投与を持続した3日目に、既に定常状態になった。これは、体内の薬物濃度を定常状態にするように、予防でピルフェニドンを投与する(例えば、照射の2日間前に投与)ことにより、治療作用の発揮に有利であることを示唆した。
ピルフェニドンを含有する薬物組成物の製造
ピルフェニドン類似体の合成
式(I)において、R1は4位のメチル基であり、R2は4位のヒドロキシメチル基である類似体が、以下の反応により得られた。
5-メチル-1-(4-ヒドロキシフェニル)-2-(1H)-ピリドンの放射線肺障害に対する作用
ピルフェニドンの代わりに5-メチル-1-(4-ヒドロキシフェニル)-2-(1H)-ピリドン(F351)を使用し、一組あたりの動物を20匹とした以外、実施例1を繰り返した。
実験によって、化合物F351での予防と治療はいずれも肺胞洗浄液における炎症性細胞の数を低下することができ、且つ予防性投与の治療効果は、治療性投与よりも顕著であったことがわかった。
肺障害は胸部腫瘍の治療においてよくある問題で、早期と晩期の放射線肺障害の二種に分かれる。早期肺障害(放射線肺炎)は、通常放射線治療の過程で発生し、重篤な結果を導くことが多く、軽度の場合、クールを中断させ、腫瘍治療の効果に影響し、重度の場合、直接に患者を致死させる。肺部感染も肺臓の線維化を増加し、肺臓の晩期の放射線障害に対しては予防が主要な手段である。現在、臨床で特に放射線肺障害を治療する薬物もないし、放射線肺障害に対する予防性薬物もまだ報告されていない。
Claims (11)
- 放射線肺障害を予防する薬物の製造のための、式Iの化合物:
(式中、
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アル
コキシ基又はC1-6アルキルチオ基である。)
又はその薬学的に許容される塩の使用。 - 前記放射線肺障害は、放射線で肺がん、乳がん、食道がん、悪性リンパ腫又は他の胸部
の悪性腫瘍を治療するときに生じる障害であることを特徴とする請求項1に記載の使用。 - 前記化合物は、ピルフェニドンであることを特徴とする請求項1に記載の使用。
- 放射線治療の放射線量を向上させる薬物の製造のための、式Iの化合物:
(式中、
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アル
コキシ基又はC1-6アルキルチオ基である。)
又はその薬学的に許容される塩の使用。 - 前記放射線治療は、肺がん、乳がん、食道がん、悪性リンパ腫又は他の胸部の悪性腫瘍
に対して行われる放射線治療であることを特徴とする請求項4に記載の使用。 - 前記化合物は、ピルフェニドンであることを特徴とする請求項4に記載の使用。
- 哺乳動物の放射線肺障害を予防するための医薬組成物であって、
式Iの化合物:
(式中、
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アル
コキシ基又はC1-6アルキルチオ基である。)
又はその薬学的に許容される塩を含む、医薬組成物。 - 前記哺乳動物に対して、放射線治療を行う前に投与される、請求項7に記載の医薬組成物。
- 前記放射線治療は、肺がん、乳がん、食道がん、悪性リンパ腫又は他の胸部の悪性腫瘍
に対して行われる放射線治療である、請求項8に記載の医薬組成物。 - 哺乳動物の放射線治療の放射線量を向上させるための医薬組成物であって、
式Iの化合物:
(式中、
R1は、3、4、5又は6位の、メチル基、エチル基又はトリフルオロメチル基であり、
R2は、存在しないか、或いは、2、3又は4位の、ヒドロキシ基、メルカプト基、C1-6アル
コキシ基又はC1-6アルキルチオ基である。)
又はその薬学的に許容される塩を含み、
前記放射線治療で予定されていた放射線量がD 0 の場合に、前記哺乳動物に対して放射線量D1(ここで、D1>D0である)で放射線治療を行うために投与される、医薬組成物。 - 前記放射線量D1及びD0は下式:
(D1-D0)/D0 >20%
を満たすことを特徴とする請求項10に記載の医薬組成物。
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PCT/CN2006/002504 WO2007147297A1 (en) | 2006-06-15 | 2006-09-25 | The use of derviate of pyridone for preventing and treating radioactive injury of lungs |
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US7767700B2 (en) | 2006-12-18 | 2010-08-03 | Intermune, Inc. | Method of providing pirfenidone therapy to a patient |
US8304413B2 (en) | 2008-06-03 | 2012-11-06 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
EP2389227A4 (en) * | 2009-01-26 | 2012-08-08 | Intermune Inc | METHODS OF TREATING ACUTE MYOCARDIAL INFARCTION AND RELATED DISORDERS |
MX2011007675A (es) * | 2011-07-19 | 2012-07-11 | Cell Therapy And Technology S A De C V | Procedimiento para la fabricacion de una composicion farmaceutica en forma de tabletas de liberacion prolongada conteniendo pirfenidona y su aplicacion en la regresion de la insuficiencia renal cronica, contractura capsular mamaria y fibrosis hepatica humanas. |
AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
US9682071B2 (en) | 2013-03-15 | 2017-06-20 | Intermune, Inc. | Methods of improving microvascular integrity |
US9763992B2 (en) | 2014-02-13 | 2017-09-19 | Father Flanagan's Boys' Home | Treatment of noise induced hearing loss |
CA2943363A1 (en) | 2014-04-02 | 2015-10-08 | Intermune, Inc. | Anti-fibrotic pyridinones |
US10251871B2 (en) * | 2015-02-05 | 2019-04-09 | Memorial Sloan Kettering Cancer Center | Compositions and methods for treatment of edema |
US20210008052A1 (en) * | 2019-05-13 | 2021-01-14 | Bio Med Sciences, Inc. | Active ingredient woundcare and scar management products, process of manufacture and useful articles thereof |
CN115429802A (zh) * | 2021-06-04 | 2022-12-06 | 北京康蒂尼药业股份有限公司 | 包含羟尼酮与右美沙芬的药物组合物及其治疗肺纤维化的应用 |
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CA1049411A (en) | 1972-12-18 | 1979-02-27 | Affiliated Medical Research | N-substituted pyridone and general method for preparing pyridones |
AU5427080A (en) | 1979-01-08 | 1980-07-17 | Margolin, B. | Pirfenidone in the treatment of pulmonary interstitial fibrosis |
JPH02215719A (ja) | 1989-02-15 | 1990-08-28 | Yamauchi Akitomo | 線維化病変組織の修復並びに線維化病変の阻止剤 |
ES2183839T3 (es) | 1993-05-07 | 2003-04-01 | Solomon B Margolin | Composiciones y procedimiento de reparacion y de prevencion de lesiones del tipo de fibrosis. |
US5789426A (en) | 1995-01-20 | 1998-08-04 | Cornell Research Foundation, Inc. | Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation |
US6114353A (en) * | 1995-03-03 | 2000-09-05 | Margolin; Solomon B. | Compositions and method for treatment of lymphomas, leukemias, and leiomyomas |
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