JP5733601B2 - 劇症型炎症の予防および/または治療剤 - Google Patents
劇症型炎症の予防および/または治療剤 Download PDFInfo
- Publication number
- JP5733601B2 JP5733601B2 JP2010159031A JP2010159031A JP5733601B2 JP 5733601 B2 JP5733601 B2 JP 5733601B2 JP 2010159031 A JP2010159031 A JP 2010159031A JP 2010159031 A JP2010159031 A JP 2010159031A JP 5733601 B2 JP5733601 B2 JP 5733601B2
- Authority
- JP
- Japan
- Prior art keywords
- fulminant
- inflammation
- therapeutic agent
- preventive
- administration
- 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
Links
- 239000003814 drug Substances 0.000 title claims description 32
- 229940124597 therapeutic agent Drugs 0.000 title claims description 26
- 206010061218 Inflammation Diseases 0.000 title description 36
- 230000004054 inflammatory process Effects 0.000 title description 36
- 230000003449 preventive effect Effects 0.000 title description 21
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 claims description 31
- 229960004144 josamycin Drugs 0.000 claims description 31
- 241000712461 unidentified influenza virus Species 0.000 claims description 29
- 206010035664 Pneumonia Diseases 0.000 claims description 21
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 claims description 18
- 239000004187 Spiramycin Substances 0.000 claims description 18
- 239000004480 active ingredient Substances 0.000 claims description 18
- 229960001294 spiramycin Drugs 0.000 claims description 18
- 229930191512 spiramycin Natural products 0.000 claims description 18
- 235000019372 spiramycin Nutrition 0.000 claims description 18
- XJSFLOJWULLJQS-UHFFFAOYSA-N leucomycin A3 Natural products COC1C(OC(C)=O)CC(=O)OC(C)CC=CC=CC(O)C(C)CC(CC=O)C1OC1C(O)C(N(C)C)C(OC2OC(C)C(OC(=O)CC(C)C)C(C)(O)C2)C(C)O1 XJSFLOJWULLJQS-UHFFFAOYSA-N 0.000 claims description 15
- 230000009385 viral infection Effects 0.000 claims description 13
- 230000002265 prevention Effects 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 description 49
- 210000004072 lung Anatomy 0.000 description 24
- 210000000440 neutrophil Anatomy 0.000 description 20
- 239000003120 macrolide antibiotic agent Substances 0.000 description 19
- 241000700605 Viruses Species 0.000 description 18
- 102000003896 Myeloperoxidases Human genes 0.000 description 17
- 108090000235 Myeloperoxidases Proteins 0.000 description 17
- 102000019034 Chemokines Human genes 0.000 description 14
- 108010012236 Chemokines Proteins 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 206010022000 influenza Diseases 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 208000037816 tissue injury Diseases 0.000 description 9
- 102000004127 Cytokines Human genes 0.000 description 8
- 108090000695 Cytokines Proteins 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- -1 fumarate ion Chemical class 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 210000000952 spleen Anatomy 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010052015 cytokine release syndrome Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 210000004969 inflammatory cell Anatomy 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 206010050685 Cytokine storm Diseases 0.000 description 5
- 208000001940 Massive Hepatic Necrosis Diseases 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 238000003753 real-time PCR Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000009525 Myocarditis Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000008595 infiltration Effects 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 201000004193 respiratory failure Diseases 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 description 2
- 208000027932 Collagen disease Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010058858 Meningococcal bacteraemia Diseases 0.000 description 2
- 208000034486 Multi-organ failure Diseases 0.000 description 2
- 208000010718 Multiple Organ Failure Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 2
- 210000001132 alveolar macrophage Anatomy 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- PRQROPMIIGLWRP-BZSNNMDCSA-N chemotactic peptide Chemical compound CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-BZSNNMDCSA-N 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000012261 overproduction Methods 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940061367 tamiflu Drugs 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009192 Circulatory collapse Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 238000002738 Giemsa staining Methods 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010065042 Immune reconstitution inflammatory syndrome Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108010008211 N-Formylmethionine Leucyl-Phenylalanine Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000004078 Snake Bites Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 108010019701 influenza virus M-protein Proteins 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000023499 negative regulation of neutrophil degranulation Effects 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960002194 oseltamivir phosphate Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 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
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940061374 relenza Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(1)2つの既知化合物が、未知の属性として、劇症型炎症に対する治療効果を示すこと;および、
(2)上記(1)に記載の治療効果が、上記化合物の有する、好中球からのミエロペルオキシダーゼ(MPO;Myeloperoxidase)の放出を阻害する作用(MPO放出阻害作用;こちらも未知の属性である)に基づくものであること、
の2つの知見を得て、これらの知見に基づき、本発明を完成させるに至った。
劇症型炎症の予防および/または治療剤の製造における、スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の使用;
劇症型炎症の予防および/または治療における、スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の使用;
スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の有効量を、必要とする患者に投与することを含む、劇症型炎症の予防および/または治療方法。
1056種のマクロライド系化合物の合成分子について、以下の手法により、ヒトおよびマウスのそれぞれの好中球からのMPO放出阻害活性をスクリーニングした。具体的には、ヒトまたはマウスの好中球(1×106細胞/mL)に対し、それぞれの化合物(被験化合物)を5μg/mLの濃度で添加し、サイトカラシンB(5μg/mL)およびfMetLeuPhe(ホルミルメチオニルロイシルフェニルアラニン;走化性因子)(ヒト:10−6M、マウス:10−5M)の存在下、37℃にて10minインキュベートした際の好中球の脱顆粒の阻害活性を、MPO放出活性を測定することにより評価した。被験化合物を添加しないものを0%阻害率とし、被験化合物の阻害活性の「%阻害」により評価した。
2−1:実験動物
BALB/cマウスは、SPF環境下(国立感染症研究所の動物室管理室−感染区)で飼育し、インフルエンザウイルスの感染実験に供した。実験に使用するマウスの管理・処置は、千葉大学の動物実験ガイドラインおよび国立感染症研究所の動物実験ガイドラインの動物愛護の規定に基づいて行った。
インフルエンザウイルスのPR8(H1N1)株の溶液を1%FBS−DMEMを用いて調製し、上記BALB/cマウスに30μL経鼻投与した(投与されたウイルス量は0.75LD50=321.42pfu/マウスであった)。次いで、上述した3種のマクロライド系化合物をそれぞれ、ウイルス投与日から1日一回(ウイルス投与日を含む)、PBS−エタノール溶液として5日間連続投与(腹腔内注射、33mg/Kg(マクロライド系化合物換算))し(計6回投与)、肺炎の劇症化抑制効果を判定した(実験群)。なお、コントロール(陰性対照群)としては、マクロライド系化合物に代えて同量のPBS−エタノールを投与したマウスを用いた(各群:N=6)。
上記「2−2」に記載の実験群および比較対照群のマウスについて、生存率を評価した。これに基づいて作成した生存曲線を図1に示す。
上記で調製した肺サンプルについて、光学顕微鏡を用いて検鏡し、実験群と比較対照群との間で肺組織傷害の程度の差異を評価した。比較対照群およびM1を投与した実験群についての顕微鏡観察写真を図2に示す。なお、図2に示す写真は、インフルエンザウイルス投与から7日後に調製した肺サンプルの観察写真である。
上記で調製したBALFサンプルをCytofuge2(IRIS)にて1000rpm×2minでサイトスピンすることにより細胞をスライドガラスに接着させ、Diff−quick(シスメックス)にて当該細胞を染色した。なお、ここで用いた「Diff−quick」は、ギムザ染色と同様な染色が得られる迅速な鑑別用染色液セットである。また、必要に応じて、抗体による染色も実施した。そして、染色後のサンプルについて、光学顕微鏡を用いて検鏡し、実験群M1と比較対照群との間で浸潤炎症細胞の数を比較した。結果を図3に示す。
上記で調製した血漿サンプルおよびBALFサンプルについて、以下の手法により、23種類のサイトカイン・ケモカインのレベルの挙動を同時にかつ網羅的に測定・解析した。この際、血漿サンプルおよびBALFサンプル中のサイトカイン・ケモカインレベルの測定・解析には、Bio−PlexTMSuspension Array System(バイオラッド)を用いた。具体的には、サンプリングしたプレートを、シール・遮光し、1100rpm×30sec、300rpm×30min振とう、吸引ろ過にて3回洗浄し、二次抗体を各ウェルに25μLずつ添加した後、プレートをシール・遮光し、1100rpm×30sec、300rpm×30min振とう、吸引ろ過にて3回洗浄した。その後、ストレプトアビジン−PE溶液を各ウェルに50μLずつ添加し、プレートをシール・遮光し、1100rpm×30sec、300rpm×10min振とう、吸引ろ過にて3回洗浄した。ASSAY BUFFERを各ウェルに125μLずつ添加し、プレートをシールし、1100rpm×30sec振とう後、シールを剥がし、Bio−Plex Array Readerにて測定した。
上記で調製した肺サンプルおよび脾臓サンプルについて、リアルタイムPCR法により、インフルエンザウイルスMタンパク質のmRNA量を定量することにより、インフルエンザウイルス抗原の検出を行った。
上記の各試験において劇症型肺炎の治療効果を示した2種のマクロライド系化合物(M1およびM3)について、NMR(核磁気共鳴)法によりその化学構造を確認した。その結果、2種のいずれも16員環マクロライド系化合物であることが判明した。また、2種のいずれも既に抗菌薬として市販されている化合物と同一の構造を有していた。そこで、構造解析および抗菌活性の比較を行い、既知化合物と同一の化合物であることを確認した。具体的には、「M1」はスピラマイシンと同一の化合物であり、「M3」はジョサマイシン(ロイコマイシンA3)と同一の化合物であった。
Claims (3)
- スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩を有効成分として含有する、インフルエンザウイルスの感染による劇症型肺炎の予防および/または治療剤。
- 前記インフルエンザウイルスが、H5N1型またはH1N1型である、請求項1に記載
の剤。 - インフルエンザウイルスの感染による劇症型肺炎の予防および/または治療剤の製造における、スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の使用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010159031A JP5733601B2 (ja) | 2010-07-13 | 2010-07-13 | 劇症型炎症の予防および/または治療剤 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010159031A JP5733601B2 (ja) | 2010-07-13 | 2010-07-13 | 劇症型炎症の予防および/または治療剤 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2012020953A JP2012020953A (ja) | 2012-02-02 |
JP2012020953A5 JP2012020953A5 (ja) | 2013-09-05 |
JP5733601B2 true JP5733601B2 (ja) | 2015-06-10 |
Family
ID=45775519
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010159031A Active JP5733601B2 (ja) | 2010-07-13 | 2010-07-13 | 劇症型炎症の予防および/または治療剤 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP5733601B2 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4292593A1 (en) | 2021-02-15 | 2023-12-20 | Kinki University | Pharmaceutical composition for preventing cytokine storm |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60027015T2 (de) * | 2000-08-17 | 2006-10-05 | The Kitasato Institute | Pseudoerythromycin-derivate |
-
2010
- 2010-07-13 JP JP2010159031A patent/JP5733601B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
JP2012020953A (ja) | 2012-02-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Honce et al. | Obesity-related microenvironment promotes emergence of virulent influenza virus strains | |
Moskophidis et al. | Contribution of virus-specific CD8+ cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model | |
Englund et al. | Common emergence of amantadine-and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults | |
Pociask et al. | γδ T cells attenuate bleomycin-induced fibrosis through the production of CXCL10 | |
Ahangari et al. | Saracatinib, a selective src kinase inhibitor, blocks fibrotic responses in preclinical models of pulmonary fibrosis | |
Moore et al. | Respiratory syncytial virus disease mechanisms implicated by human, animal model, and in vitro data facilitate vaccine strategies and new therapeutics | |
Fislova et al. | Multiorgan distribution of human influenza A virus strains observed in a mouse model | |
JP2023520580A (ja) | コロナウイルス誘発炎症状態の処置方法 | |
US20220362272A1 (en) | Medicament for prevention or treatment of rhinovirus infection | |
Bochner et al. | Advances in mechanisms of allergy | |
WO2012102793A2 (en) | Mammalian genes involved in toxicity and infection | |
EP3317290A1 (en) | Compositions and methods for the treatment of viral infection | |
Iturra et al. | Progression of type 2 helper T Cell–type inflammation and airway remodeling in a rodent model of naturally acquired subclinical primary pneumocystis infection | |
Hayden et al. | Human influenza: Pathogenesis, clinical features, and management | |
JP5733601B2 (ja) | 劇症型炎症の予防および/または治療剤 | |
BR112021000060A2 (pt) | Derivados de 1,3,5-tris(6-metilpiridin-2-iloxi)benzeno e compostos relacionados como ligantes nlrx1 para tratar doenças inflamatórias | |
US11065301B2 (en) | Pharmaceutical composition for ameliorating the symptoms and disease of the respiratory infection caused by human metapneumovirus (HMPV), which comprises at least one agent that neutralizes the function of TSLP and/or TSLPR and/or OX40L and/or CD177 molecules, and a pharmaceutically acceptable excipient, and use thereof | |
Andres et al. | Hospitalization due to respiratory syncytial virus infection in patients under 2 years of age with hemodynamically significant congenital heart disease | |
Qi et al. | Avian influenza A (H7N9) virus infection in pregnant woman, China, 2013 | |
Aoki | Oseltamivir | |
JP2023529025A (ja) | 抗ウイルス処置としてのアゼラスチン | |
CN116249520A (zh) | 使用WNT/β-连环蛋白通路抑制剂阻断SARS-COV-2和其他致病病毒的复制 | |
WO2011004843A1 (ja) | Sirsまたは強毒性インフルエンザ感染症処置のための医薬組成物 | |
US20220062357A1 (en) | Method and composition against virus infections with activated innate lymphoid cells (ilcs) | |
KR101627623B1 (ko) | 이종 인플루엔자 바이러스에 대한 백신 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130712 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20130712 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20130712 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131008 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131128 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131219 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140805 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141006 |
|
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: 20150303 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150402 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5733601 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 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |