CN103747784B - 败血症的预防剂和/或治疗剂 - Google Patents
败血症的预防剂和/或治疗剂 Download PDFInfo
- Publication number
- CN103747784B CN103747784B CN201280037274.7A CN201280037274A CN103747784B CN 103747784 B CN103747784 B CN 103747784B CN 201280037274 A CN201280037274 A CN 201280037274A CN 103747784 B CN103747784 B CN 103747784B
- Authority
- CN
- China
- Prior art keywords
- iron
- compound
- ala
- septicemia
- ferrous
- 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.)
- Expired - Fee Related
Links
- 206010040047 Sepsis Diseases 0.000 title abstract description 96
- 208000013223 septicemia Diseases 0.000 title abstract description 87
- 239000003814 drug Substances 0.000 title abstract description 76
- 229940124597 therapeutic agent Drugs 0.000 title abstract description 55
- 230000000069 prophylactic effect Effects 0.000 title abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- PRZPUYBFEJPNPF-UHFFFAOYSA-J tetrasodium 3-carboxy-3,5-dihydroxy-5-oxopentanoate 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Na+].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[Na+].[Na+].[Na+].C(CC(O)(C(=O)O)CC(=O)O)(=O)[O-] PRZPUYBFEJPNPF-UHFFFAOYSA-J 0.000 claims abstract description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 86
- 229910052742 iron Inorganic materials 0.000 claims description 44
- 150000002506 iron compounds Chemical class 0.000 claims description 29
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 108090001005 Interleukin-6 Proteins 0.000 claims description 17
- 108090001007 Interleukin-8 Proteins 0.000 claims description 17
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 102000008857 Ferritin Human genes 0.000 claims description 7
- 108050000784 Ferritin Proteins 0.000 claims description 7
- 238000008416 Ferritin Methods 0.000 claims description 7
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000011640 ferrous citrate Substances 0.000 claims description 6
- 235000019850 ferrous citrate Nutrition 0.000 claims description 6
- 229960003330 pentetic acid Drugs 0.000 claims description 6
- FJXWZGKHZFDDPQ-UHFFFAOYSA-N 1-[carboxy(methyl)amino]propane-1,1,3-tricarboxylic acid Chemical compound C(=O)(O)C(N(C)C(=O)O)(CCC(=O)O)C(=O)O FJXWZGKHZFDDPQ-UHFFFAOYSA-N 0.000 claims description 5
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 5
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 5
- DQMUQFUTDWISTM-UHFFFAOYSA-N O.[O-2].[Fe+2].[Fe+2].[O-2] Chemical compound O.[O-2].[Fe+2].[Fe+2].[O-2] DQMUQFUTDWISTM-UHFFFAOYSA-N 0.000 claims description 5
- 239000011706 ferric diphosphate Substances 0.000 claims description 5
- 235000007144 ferric diphosphate Nutrition 0.000 claims description 5
- VEPSWGHMGZQCIN-UHFFFAOYSA-H ferric oxalate Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O VEPSWGHMGZQCIN-UHFFFAOYSA-H 0.000 claims description 5
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 claims description 5
- 229940036404 ferric pyrophosphate Drugs 0.000 claims description 5
- 239000011773 ferrous fumarate Substances 0.000 claims description 5
- 235000002332 ferrous fumarate Nutrition 0.000 claims description 5
- 229960000225 ferrous fumarate Drugs 0.000 claims description 5
- 150000003278 haem Chemical class 0.000 claims description 5
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 5
- AEDLILNWEXDEHC-UHFFFAOYSA-M sodium;butanedioic acid;3-carboxy-3,5-dihydroxy-5-oxopentanoate Chemical compound [Na+].OC(=O)CCC(O)=O.OC(=O)CC(O)(C(O)=O)CC([O-])=O AEDLILNWEXDEHC-UHFFFAOYSA-M 0.000 claims description 5
- 230000001629 suppression Effects 0.000 claims description 5
- 229960001124 trientine Drugs 0.000 claims description 5
- 238000004073 vulcanization Methods 0.000 claims description 5
- GMNYICKUXVITKU-UHFFFAOYSA-L CC([O-])=O.CC([O-])=O.CC(O)=O.CC(O)=O.CC(O)=O.NCCNCCN.N.[Fe+2] Chemical compound CC([O-])=O.CC([O-])=O.CC(O)=O.CC(O)=O.CC(O)=O.NCCNCCN.N.[Fe+2] GMNYICKUXVITKU-UHFFFAOYSA-L 0.000 claims description 4
- 229920001353 Dextrin Polymers 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
- MDXRFOWKIZPNTA-UHFFFAOYSA-L butanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)CCC([O-])=O MDXRFOWKIZPNTA-UHFFFAOYSA-L 0.000 claims description 4
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].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 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 claims description 4
- OGMQNMUHVLRDRT-UHFFFAOYSA-J disodium;3-[20-(carboxylatomethyl)-18-(dioxidomethylidene)-8-ethenyl-13-ethyl-3,7,12,17-tetramethyl-2,3-dihydroporphyrin-23-id-2-yl]propanoate;hydron;iron(2+) Chemical compound [H+].[Na+].[Na+].[Fe+2].C1=C([N-]2)C(CC)=C(C)C2=CC(C(=C2C)C=C)=NC2=CC(C(C2CCC([O-])=O)C)=NC2=C(CC([O-])=O)C2=NC1=C(C)C2=C([O-])[O-] OGMQNMUHVLRDRT-UHFFFAOYSA-J 0.000 claims description 4
- 229960002413 ferric citrate Drugs 0.000 claims description 4
- 239000004222 ferrous gluconate Substances 0.000 claims description 4
- 235000013924 ferrous gluconate Nutrition 0.000 claims description 4
- 229960001645 ferrous gluconate Drugs 0.000 claims description 4
- 229960001604 ferrous succinate Drugs 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- ATEAWHILRRXHPW-UHFFFAOYSA-J iron(2+);phosphonato phosphate Chemical compound [Fe+2].[Fe+2].[O-]P([O-])(=O)OP([O-])([O-])=O ATEAWHILRRXHPW-UHFFFAOYSA-J 0.000 claims description 4
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 claims description 4
- 229940057531 saccharated iron oxide Drugs 0.000 claims description 4
- RZTXLBSUYPIGSE-UHFFFAOYSA-L CN(C(CCC(O)=O)(C([O-])=O)C(O)=O)C([O-])=O.N.[Fe+2] Chemical compound CN(C(CCC(O)=O)(C([O-])=O)C(O)=O)C([O-])=O.N.[Fe+2] RZTXLBSUYPIGSE-UHFFFAOYSA-L 0.000 claims description 3
- 102000002070 Transferrins Human genes 0.000 claims description 3
- 108010015865 Transferrins Proteins 0.000 claims description 3
- XNSQZBOCSSMHSZ-UHFFFAOYSA-K azane;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate;iron(3+) Chemical compound [NH4+].[Fe+3].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O XNSQZBOCSSMHSZ-UHFFFAOYSA-K 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 238000005286 illumination Methods 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- UUGUGLBRYMQUHN-UHFFFAOYSA-N 2-hydroxypropanoic acid;iron Chemical compound [Fe].CC(O)C(O)=O UUGUGLBRYMQUHN-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- NVVGMIRCFUVBOB-UHFFFAOYSA-N acetic acid;iron Chemical compound [Fe].CC(O)=O NVVGMIRCFUVBOB-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 37
- 239000002184 metal Substances 0.000 abstract description 37
- 238000011282 treatment Methods 0.000 abstract description 35
- 230000002265 prevention Effects 0.000 abstract description 32
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical class NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 abstract description 26
- -1 pentyl ester Chemical class 0.000 abstract description 18
- 239000004480 active ingredient Substances 0.000 abstract description 8
- 125000004494 ethyl ester group Chemical group 0.000 abstract description 7
- 150000004702 methyl esters Chemical class 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 3
- 229910019142 PO4 Inorganic materials 0.000 abstract description 3
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 3
- 239000010452 phosphate Substances 0.000 abstract description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 abstract description 3
- 241000024188 Andala Species 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract 1
- 238000000034 method Methods 0.000 description 34
- 239000003795 chemical substances by application Substances 0.000 description 28
- 230000000694 effects Effects 0.000 description 13
- 239000002158 endotoxin Substances 0.000 description 12
- 229920006008 lipopolysaccharide Polymers 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 108090000695 Cytokines Proteins 0.000 description 9
- 102000004127 Cytokines Human genes 0.000 description 9
- 230000035876 healing Effects 0.000 description 9
- 238000002428 photodynamic therapy Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 230000002757 inflammatory effect Effects 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 150000002681 magnesium compounds Chemical class 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 102000010445 Lactoferrin Human genes 0.000 description 5
- 108010063045 Lactoferrin Proteins 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 210000003038 endothelium Anatomy 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 description 5
- 229940078795 lactoferrin Drugs 0.000 description 5
- 235000021242 lactoferrin Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 150000003752 zinc compounds Chemical class 0.000 description 5
- YNVZDODIHZTHOZ-UHFFFAOYSA-K 2-hydroxypropanoate;iron(3+) Chemical compound [Fe+3].CC(O)C([O-])=O.CC(O)C([O-])=O.CC(O)C([O-])=O YNVZDODIHZTHOZ-UHFFFAOYSA-K 0.000 description 4
- XJECNSWAHCMYNZ-UHFFFAOYSA-N C=C.[Fe].[Na] Chemical group C=C.[Fe].[Na] XJECNSWAHCMYNZ-UHFFFAOYSA-N 0.000 description 4
- 239000005749 Copper compound Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000001845 chromium compounds Chemical class 0.000 description 4
- 150000001869 cobalt compounds Chemical class 0.000 description 4
- 150000001880 copper compounds Chemical class 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 4
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 4
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 description 4
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000005078 molybdenum compound Substances 0.000 description 4
- 150000002752 molybdenum compounds Chemical class 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 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 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000001835 viscera Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- ZLHFONARZHCSET-UHFFFAOYSA-N 5-aminolevulinic acid hydrochloride Chemical compound Cl.NCC(=O)CCC(O)=O ZLHFONARZHCSET-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 235000019737 Animal fat Nutrition 0.000 description 2
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WTBIAPVQQBCLFP-UHFFFAOYSA-N N.N.N.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O Chemical compound N.N.N.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O WTBIAPVQQBCLFP-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UMEAURNTRYCPNR-UHFFFAOYSA-N azane;iron(2+) Chemical compound N.[Fe+2] UMEAURNTRYCPNR-UHFFFAOYSA-N 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 229960003644 aztreonam Drugs 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 150000002816 nickel compounds Chemical class 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 229950003776 protoporphyrin Drugs 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 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
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- ROYPGAQNKYWYDI-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;magnesium Chemical compound [Mg].OC(=O)CC(O)(C(O)=O)CC(O)=O ROYPGAQNKYWYDI-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 102000018727 5-Aminolevulinate Synthetase Human genes 0.000 description 1
- 108010052384 5-Aminolevulinate Synthetase Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- JZVJHZVSZQSQLL-UHFFFAOYSA-N C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(CN)N.[Na].[Na].[Mg] Chemical compound C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.C(CN)N.[Na].[Na].[Mg] JZVJHZVSZQSQLL-UHFFFAOYSA-N 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
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- HNBPGMZUKDCQEE-UWTATZPHSA-N D-alanyl phosphate Chemical compound C[C@@H](N)C(=O)OP(O)(O)=O HNBPGMZUKDCQEE-UWTATZPHSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000272496 Galliformes Species 0.000 description 1
- 206010065713 Gastric Fistula Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 206010021929 Infertility male Diseases 0.000 description 1
- 208000008081 Intestinal Fistula Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000007466 Male Infertility Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NSEQHAPSDIEVCD-UHFFFAOYSA-N N.[Zn+2] Chemical compound N.[Zn+2] NSEQHAPSDIEVCD-UHFFFAOYSA-N 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
- 206010029803 Nosocomial infection Diseases 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- GLMQHZPGHAPYIO-UHFFFAOYSA-L azanium;2-hydroxypropane-1,2,3-tricarboxylate;iron(2+) Chemical compound [NH4+].[Fe+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O GLMQHZPGHAPYIO-UHFFFAOYSA-L 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- UBLOJEHIINPTTG-UHFFFAOYSA-J disodium;zinc;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Zn+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UBLOJEHIINPTTG-UHFFFAOYSA-J 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000001497 healthy food Nutrition 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003553 hypophosphatemic effect Effects 0.000 description 1
- 229940124644 immune regulator Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 208000013469 light sensitivity Diseases 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- PJJZFXPJNUVBMR-UHFFFAOYSA-L magnesium benzoate Chemical compound [Mg+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 PJJZFXPJNUVBMR-UHFFFAOYSA-L 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- JWSMTBMIGYJJJM-UHFFFAOYSA-N magnesium;azane Chemical compound N.[Mg+2] JWSMTBMIGYJJJM-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- VNOYUJKHFWYWIR-ITIYDSSPSA-N succinyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 VNOYUJKHFWYWIR-ITIYDSSPSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61K31/28—Compounds containing heavy metals
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial 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)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供对败血症的预防和治疗有用的败血症治疗药。制备含有5‑氨基乙酰丙酸(5‑ALA)或其衍生物或其药理学上可接受的盐作为有效成分的败血症的预防剂和/或治疗剂。优选使这些ALA类中含有柠檬酸亚铁钠等含金属化合物。作为上述ALA类,可适宜地例示ALA和该ALA的甲酯、乙酯、丙酯、丁酯、戊酯等各种酯类、以及它们的盐酸盐、磷酸盐、硫酸盐等。
Description
技术领域
本发明涉及败血症的预防剂和/或治疗剂,更详细而言,涉及含有5-氨基乙酰丙酸(5-ALA)或其衍生物或其药理学上可接受的盐作为有效成分的败血症的预防剂和/或治疗剂。
背景技术
败血症被确定为由创伤·产褥·疾病等的细菌感染所引起的重症度高的全身性炎性反应综合征(systemic inflammatory response syndrome:SIRS)。SIRS的实质是高细胞因子血症,由于作为炎症性物质的细胞因子和感染细菌所释放的毒素的作用,血管扩张而引起血压降低。该血压降低若显著发展,则会因身体各部位的血流量不足而增大各内脏器官发生功能障碍的风险。若为防止多器官功能衰竭而使心脏的血流量增大,则虽然心率加快,但由于过度负荷而使心功能降低,对重要内脏器官的血液供给慢性地不足而成为败血症性休克状态,并发展成“多器官功能衰竭”。尽管利用抗生素的治疗已经确立,但据报道在美国每年败血症患者为75万人以上、其中的21万人死亡,在日本每年的患者数也达到10万人。出于这样的背景,迫切希望开发有效的败血症的预防方法、治疗方法。
作为败血症的死亡率高的主要原因,可举出:迄今为止开发的所有败血症治疗药都只是进行针对由高细胞因子血症所引起的二次伤害进行的对症治疗,针对高细胞因子血症本身的败血症治疗药并不存在。虽然抗生素的进步使得可以控制感染症的病菌,但即便是死菌,也残留有细胞因子诱导能力,根据情况也会因活菌而存在细胞因子诱导能力高的情形。作为针对高细胞因子血症的治疗方法,虽考虑应用了血液透析疗法的血液净化疗法(吸附血中的细胞因子),但其效果并不恒定,对机体的侵入性也高。包括前述方法在内,迄今为止已对败血症时的高细胞因子血症尝试了许多治疗方法,但学术上并无对多数患者有效的药物和治疗方法。近年来普通病房中开始采取处置,并尝试着通过减少使用肺动脉导管来减少院内感染的几率,另外使抗生素给药早期化,通过上述措施使得败血症的死亡率有减小的倾向,但不言而喻其幅度很小。败血症治疗中,除了利用抗生素的治疗以外,有可能还未发现某种重要的治疗。
另外,以往作为与败血症相同地由细菌感染所引起的寻常性痤疮的治疗方法之一,已知有光动力学治疗(PDT治疗)。PDT治疗是组合光敏剂和光照射的治疗方法。5-ALA自身不具有光敏性,但在体内经代谢而成为光敏物质原卟啉IX(PPIX),因而被用于癌症的PDT治疗(参照例如专利文献1~3)。对于使用5-ALA的寻常性痤疮的PDT疗法已有临床病例的报道,效果显著(参照例如非专利文献1)。PDT治疗对皮肤上的细菌感染确实显示出了效果,但为了杀灭败血症那样的血中的细菌,必须对血中照射直接光源。然而,由于适于PPIX激发的吸收波长与血红蛋白的吸收光谱重叠,需要借助导管等将激发光源插入血管,有可能促进进一步的感染而使感染症恶化,因而针对败血症致病菌的PDT治疗不仅存在异议,还因为并不现实,因而研究并无进展。另外,PDT即使能够成为杀菌技术也对上述高细胞因子血症无效。
另一方面,5-ALA作为广泛存在于动物、植物和菌类中的四吡咯生物合成通路的中间体而为人所知,通常借助于5-氨基乙酰丙酸合成酶,由琥珀酰CoA和甘氨酸进行生物合成。还开发了使用5-ALA的光线力学疗法或光动力学治疗(以下也称为“ALA-PDT”),作为侵害性低且能保持QOL的治疗方法而受到关注,报道了使用5-ALA等的肿瘤诊断·治疗剂等。另外还已知,5-ALA可用作成人病、癌症、男性不育的预防改善剂或治疗剂(参照例如专利文献4~6)。
专利文献1:日本专利第2731032
专利文献2:日本特开2006-124372
专利文献3:日本特表2002-512205
专利文献4:WO2010/050179
专利文献5:日本特开2011-16753
专利文献6:WO2009/139156
非专利文献1:Arch Dermatol,Sep2000;136:1093-1095
发明内容
人们迫切期望开发出对败血症有效的预防剂和/或治疗剂。特别是迫切期望开发对高细胞因子血症真正有效且副作用少的败血症的预防剂和/或治疗剂。本发明的课题在于提供对败血症的预防和治疗有用的败血症的预防剂和/或治疗剂。
本发明人等对败血症患者的病况、重症度、进展、预后、临床检查值、各种治疗方法所获得的成绩等巨大的数据进行了详细调查,进而对以往的临床报道病例全面地进行了跟踪,获得了如下结论,即,在败血症患者的病况中最重要的是血中细胞因子的量,并着眼于抑制炎症性细胞因子的化合物的筛选,反复进行研究,结果完全出人意料地发现5-ALA具有炎症性细胞因子抑制效果。应予说明,5-ALA虽然如上述背景技术所述已知可通过光照射进行PDT杀菌,但本发明中并不需要光照射。
对于以往作为具有多种健康促进效果的健康食品已知的5-ALA,完全没有预料到其具有抑制作为高细胞因子血症致病物质的炎症性细胞因子这样的出人意料的效果。已经清楚这是与本发明人等已发现的5-ALA的抗氧化效果和免疫赋活反应明显不同的机理,并且如上所述,各种抗生素中并不存在克服高细胞因子血症的例子,因而本身无法仅用抗菌作用来说明。5-ALA是通过何种机理来抑制炎症性细胞因子需要留待今后进行研究。
进而,本发明人等针对给药方法、与药剂(针对高细胞因子血症所引起的二次伤害的药剂)的组合、或给药量等反复进行各种研究,确立了含有5-ALA和铁剂作为有效成分的败血症的治疗剂、预防剂,从而完成了本发明。
即,本发明涉及:
(1)败血症的预防剂和/或治疗剂,其含有下述式(I)所示的化合物或其盐,
式中,R1表示氢原子或酰基,R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基;
(2)如前述(1)所述的败血症的预防剂和/或治疗剂,其特征在于,R1和R2为氢原子;
(3)如前述(1)或(2)所述的败血症的预防剂和/或治疗剂,其特征在于,还含有一种或二种以上的含金属化合物;
(4)如前述(3)所述的败血症的预防剂和/或治疗剂,其特征在于,含金属化合物为铁化合物、镁化合物、锌化合物、镍化合物、钒化合物、铜化合物、铬化合物、钼化合物或钴化合物;
(5)如前述(4)所述的败血症的预防剂和/或治疗剂,其特征在于,含金属化合物为铁化合物;
(6)如前述(5)所述的败血症的预防剂和/或治疗剂,其特征在于,铁化合物为选自氯化铁、三氧化二铁、硫酸铁、焦磷酸亚铁、柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠、柠檬酸铁铵、焦磷酸铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺四乙酸铁铵、二羧基甲基谷氨酸铁钠、二羧基甲基谷氨酸铁铵、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、血红素铁、右旋糖酐铁、三亚乙基四胺铁、乳铁蛋白铁(lactoferrin iron)、转铁蛋白铁(transferrin iron)、叶绿素铁钠、铁蛋白铁(Ferritin iron)、含糖氧化铁和硫化甘氨酸铁中的1种或2种以上的铁化合物;
(7)如前述(6)所述的败血症的预防剂和/或治疗剂,其特征在于,铁化合物为柠檬酸亚铁钠;
(8)如前述(1)~(7)中任一项所述的败血症的预防剂和/或治疗剂,其用于对IL-6和/或IL-8的产生的抑制。
另外,本发明还涉及:
(9)预防和/或治疗败血症的方法,其特征在于,向对象给予上述式(I)所示的化合物或其盐;
(10)预防和/或治疗败血症的方法,其特征在于,向对象给予前述(1)~(8)中任一项所述的败血症的预防剂和/或治疗剂。
作为(9)的其它方式,可举出:
上述方法,其特征在于,R1和R2为氢原子;
上述方法,其特征在于,还含有一种或二种以上的含金属化合物;
上述方法,其特征在于,含金属化合物为铁化合物、镁化合物、锌化合物、镍化合物、钒化合物、铜化合物、铬化合物、钼化合物或钴化合物;
上述方法,其特征在于,含金属化合物为铁化合物;
上述方法,其特征在于,铁化合物为选自氯化铁、三氧化二铁、硫酸铁、焦磷酸亚铁、柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠、柠檬酸铁铵、焦磷酸铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺四乙酸铁铵、二羧基甲基谷氨酸铁钠、二羧基甲基谷氨酸铁铵、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、血红素铁、右旋糖酐铁、三亚乙基四胺铁、乳铁蛋白铁、转铁蛋白铁、叶绿素铁钠、铁蛋白铁、含糖氧化铁、和硫化甘氨酸铁中的1种或2种以上的铁化合物;
上述方法,其特征在于,铁化合物为柠檬酸亚铁钠。
另外,本发明还涉及:
(11)上述式(I)所示的化合物或其盐,其用于败血症的预防和/或治疗。
作为(11)的其它方式,可举出:
5-ALA或其盐,其用于败血症的预防和/或治疗;
上述式(I)所示的化合物或其盐和一种或二种以上的含金属化合物,其用于败血症的预防和/或治疗;
上述发明,其特征在于,含金属化合物为铁化合物、镁化合物、锌化合物、镍化合物、钒化合物、铜化合物、铬化合物、钼化合物或钴化合物;
上述发明,其特征在于,含金属化合物为铁化合物;上述发明,其特征在于,铁化合物为选自氯化铁、三氧化二铁、硫酸铁、焦磷酸亚铁、柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠、柠檬酸铁铵、焦磷酸铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺四乙酸铁铵、二羧基甲基谷氨酸铁钠、二羧基甲基谷氨酸铁铵、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、血红素铁、右旋糖酐铁、三亚乙基四胺铁、乳铁蛋白铁、转铁蛋白铁、叶绿素铁钠、铁蛋白铁、含糖氧化铁、和硫化甘氨酸铁中的1种或2种以上的铁化合物;
上述发明,其特征在于,铁化合物为柠檬酸亚铁钠。
另外,本发明还涉及:
(12)预防和/或治疗败血症用的试剂盒,其包含:a)上述式(I)所示的化合物或其盐;b)含金属化合物。
另外,本发明还涉及:
(13)预防和/或治疗败血症的方法,其特征在于,向对象同时或先后给予:a)上述式(I)所示的化合物或其盐;b)含金属化合物。
另外,本发明还涉及:
(14)预防药剂和/或治疗药剂的组合,其包含:a)前述(1)~(8)中任一项所述的败血症的预防剂和/或治疗剂,b)败血症的预防剂·治疗剂·并用剂;
(15)预防药剂和/或治疗药剂的组合,其包含:a)上述式(I)所示的化合物或其盐,b)含金属化合物,c)败血症的预防剂·治疗剂·并用剂。
进而,本发明还涉及:
(16)a)上述式(I)所示的化合物或其盐在制造败血症的预防剂和/或治疗剂中的用途。
作为本发明的其它方式,可举出:
IL-6和/或IL-8的产生的抑制剂,其含有ALA类、或含有ALA类和含金属化合物;
抑制IL-6和/或IL-8的产生的方法,其特征在于,向对象给予ALA类、或给予ALA类和含金属化合物;
ALA类、或ALA类和含金属化合物,其用于对IL-6和/或IL-8的产生的抑制;
用于抑制IL-6和/或IL-8的产生的试剂盒,其含有ALA类和含金属化合物;
抑制IL-6和/或IL-8的产生的方法,其特征在于,向对象同时或先后给予ALA类和含金属化合物;
预防药剂和/或治疗药剂的组合,其包含上述IL-6和/或IL-8的产生的抑制剂以及败血症的预防剂·治疗剂·并用剂;
预防药剂和/或治疗药剂的组合,其包含ALA类和含金属化合物以及败血症的预防剂·治疗剂·并用剂;
ALA类在制造IL-6和/或IL-8的产生的抑制剂中的用途。
本发明的以ALA类作为有效成分的败血症的预防剂和/或治疗剂具有优异的败血症的治疗效果和预防效果。进而,通过与现有的败血症治疗药并用,从而具有如下效果,即,提高针对过去无法触及的高细胞因子血症治疗的药效、或者降低副作用强的现有败血症治疗药的给药量。认为本发明的败血症的预防剂和/或治疗药与现有的败血症治疗药的机理完全不同。
附图说明
[图1]是示出在ALA的存在下、使用将人肺动脉血管内皮细胞与脂多糖(LPS)混合培养的败血症模型、以ELISA法测定上清中的IL-6而得的结果的图。
[图2]是示出在ALA的存在下、使用将人肺动脉血管内皮细胞与LPS混合培养的败血症模型、以ELISA法测定上清中的IL-8而得的结果的图。
具体实施方式
作为本发明的败血症的预防剂和/或治疗剂,只要是含有上述式(I)所示的化合物或其盐(ALA类)作为有效成分即可,没有特别限制,除了ALA类之外,还可以含有铁化合物等含金属化合物。进而,优选能够用于抑制IL-6和/或IL-8产生的物质。本发明的败血症的预防剂和/或治疗剂还可以用作药品、准药品、饮食品、饲料、饵料、宠物食品。另外,本发明的预防和/或治疗败血症的方法的特征在于,向人、以及家畜类·家禽类或宠物等对象给予上述本发明的败血症的预防剂和/或治疗剂。除了上述ALA类之外并不含有铁化合物等含金属化合物、而以ALA类作为单一有效成分的败血症的预防剂和/或治疗剂,对于另外摄取有铁化合物等的对象、或体内铁化合物等的浓度高的对象特别有效。
另外,作为本发明的预防和/或治疗败血症用的试剂盒,只要是各自含有ALA类和铁化合物等含金属化合物作为有效成分的试剂盒则没有特别限制,优选为能够用于抑制IL-6和/或IL-8产生的试剂盒。对于使用上述本发明的预防和/或治疗败血症用的试剂盒的本发明的预防和/或治疗败血症的方法,其特征在于,向人、以及家畜·家禽类或宠物等对象同时或先后给予ALA类和铁化合物等含金属化合物。
而且另外,作为本发明的预防药剂和/或治疗药剂的组合,只要是上述本发明的败血症的预防剂和/或治疗剂与败血症的预防剂·治疗剂·并用剂的组合、或者ALA类和铁化合物等含金属化合物与败血症的预防剂·治疗剂·并用剂的组合,则没有特别限制,通过给予这些预防药剂和/或治疗药剂的组合也可以预防和/或治疗败血症。这些组合的各制剂(成分)可以同时或分开给予。
进而,本发明还涉及用于败血症的预防和/或治疗的ALA类、或用于败血症的预防和/或治疗的ALA类和铁化合物等含金属化合物。另外,本发明还涉及ALA类在制造败血症的预防剂和/或治疗剂中的用途、或者ALA类和铁化合物等含金属化合物在制造败血症的预防剂和/或治疗剂中的用途。
上述ALA类之中,可适宜地例示式(I)的R1和R2均为氢原子时的5-ALA或其盐。5-ALA是也被称为δ-氨基乙酰丙酸的一种氨基酸。另外,作为5-ALA衍生物,还可举出:式(I)的R1为氢原子或酰基,式(I)的R2为氢原子、直链或支链烷基、环烷基、芳基或芳烷基的5-ALA以外的化合物。
作为式(I)中的烷基,可举出甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基等直链或支链的碳原子数1~8的烷基。
作为式(I)中的环烷基,可举出饱和或可存在一部分不饱和键的碳原子数3~8的环烷基,具体的可举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环十二烷基、1-环己烯基等。
作为式(I)中的芳烷基,其芳基部分与下述芳基含义相同,烷基部分与前述烷基含义相同,可举出例如碳原子数7~15的芳烷基,具体可举出苯基甲基、苯基乙基、苯基丙基、苯基丁基、二苯基甲基(benzhydryl)、三苯基甲基、萘基甲基、萘基乙基等。
作为式(I)中的芳基,可举出例如碳原子数6~14的芳基,具体可举出苯基、萘基、蒽基、菲基等。
另外,作为式(I)中的酰基,可举出直链或支链的碳原子数1~8的烷酰基,具体可举出甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、特戊酰基、己酰基、辛酰基、苄基羰基等,或者可举出碳原子数7~14的芳酰基,具体可举出苯甲酰基、1-萘甲酰基、2-萘甲酰基等。
作为本发明中所使用的ALA衍生物,可例示ALA的氨基被酰化、羧基被酯化而成的化合物。优选可举出酰基为甲酰基、乙酰基、丙酰基、丁酰基等的化合物,酯基为甲酯、乙酯、丙酯、丁酯、戊酯等的化合物,进一步可举出甲酰基和甲酯、乙酰基和甲酯、丙酰基和甲酯、丁酰基和甲酯、甲酰基和乙酯、乙酰基和乙酯、丙酰基和乙酯、丁酰基和乙酯的组合等。
作为ALA或ALA衍生物的药理学上可接受的盐,可举出药理学上可接受的酸加成盐、金属盐、铵盐、有机胺加成盐等。作为酸加成盐,可举出例如盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硝酸盐、硫酸盐等各种无机酸盐,甲酸盐、乙酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、富马酸盐、马来酸盐、苹果酸盐等各有机酸加成盐。作为金属盐,可举出锂盐、钠盐、钾盐等各种碱金属盐,镁、钙盐等各种碱土金属盐,铝、锌等各种金属盐。作为铵盐,可举出铵盐、四甲基铵盐等烷基铵盐等。作为有机胺盐,可举出三乙基胺盐、哌啶盐、吗啉盐、甲苯胺盐等各种盐。
ALA或ALA衍生物也可以通过化学合成、利用微生物的生产、利用酶的生产中的任意方法来制造。例如,ALA衍生物中相对于氨基的酰基、或相对于羧基的酯基等可以通过化学合成的常规方法,利用氨基的酰化、或羧基的酯化等来制造。
欲获得式(I)所示的ALA或ALA衍生物的盐的情况下,在式(I)所示的化合物以盐的形式获得时,直接进行纯化即可,另外在以游离的形式获得时,溶解或悬浮于适当的有机溶剂中并加入酸或碱而通过通常的方法成盐即可。
ALA类有时也以与水或各种溶剂的加成物的形式存在,这些加成物也可以用于本发明的败血症的预防剂和/或治疗剂等中。
作为可用于本发明的败血症的预防剂和/或治疗剂等中的ALA类,例如,可将ALA或ALA衍生物或它们的盐的任一者单独使用,或2种以上适宜组合使用。在ALA或ALA衍生物或它们的盐中,理想的是ALA和该ALA的甲酯、乙酯、丙酯、丁酯、戊酯等各种酯类、以及它们的盐酸盐、磷酸盐、硫酸盐等,作为最理想的化合物可以举出ALA的盐酸盐、ALA的磷酸盐。
另外,本发明的败血症的预防剂和/或治疗剂还可以与ALA类并用并含有含金属化合物。含金属化合物可在不造成过量症状的范围内使用,例如,相对于ALA类,可以以摩尔比1∶0.01~1∶10、优选1∶0.1~1∶5、更优选1∶0.2~1∶2来使用含金属化合物。
作为上述含金属化合物,可举出铁化合物、镁化合物、锌化合物、镍化合物、钒化合物、钴化合物、铜化合物、铬化合物、钼化合物等。它们之中,优选铁化合物、镁化合物、锌化合物,特别优选铁化合物。这些含金属化合物是指在分子内具有该金属的化合物。只要不损害本发明的效果则没有特别限制。例如,作为在分子内具有铁的铁化合物,可举出柠檬酸亚铁、柠檬酸铁钠、柠檬酸铁铵、焦磷酸铁、血红素铁、右旋糖酐铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、亚乙基二胺五乙酸铁铵、三亚乙基四胺铁、二羧基甲基谷氨酸铁钠、二羧基甲基谷氨酸铵铁铵、乳铁蛋白铁、转铁蛋白铁、氯化铁、三氧化二铁、叶绿素铁钠、铁蛋白铁、富马酸亚铁、焦磷酸亚铁、含糖氧化铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、硫酸铁、硫化甘氨酸铁等,其中,优选柠檬酸亚铁和柠檬酸铁钠。
作为在分子内具有镁的镁化合物,优选柠檬酸镁、苯甲酸镁、乙酸镁、氧化镁、氯化镁、氢氧化镁、碳酸镁、硫酸镁、硅酸镁、硝酸镁、二亚乙基三胺五乙酸二铵镁、乙二胺四乙酸二钠镁、镁原卟啉。
作为在分子内具有锌的锌化合物,优选氯化锌、氧化锌、硝酸锌、碳酸锌、硫酸锌、二亚乙基三胺五乙酸二铵锌、乙二胺四乙酸二钠锌、锌原卟啉、含锌酵母。
这些含金属化合物可以各自单独使用,也可以2种以上混合使用,可以与ALA类同时或分开给予。剂型和给药方法可以与ALA类相同,另外也可以分开使用。
本发明的并用ALA类和铁化合物等含金属化合物的预防和/或治疗败血症的方法中,可以以含有ALA类和含金属化合物的组合物的形式给药、或者以各自单独的形式同时或先后给药。各自单独地给药时优选为同时给药,但各自单独地先后给药时,ALA类和铁化合物等含金属化合物的给药则优选以能够实现加合效果、优选协同效果的方式来给药。
本发明的败血症的预防剂和/或治疗剂、或本发明的预防和/或治疗败血症用的试剂盒中,可以将现有的败血症的预防剂·治疗剂·并用剂(与预防剂·治疗剂并用的药剂),即,预防剂和/或治疗剂和/或并用剂组合使用。作为上述败血症的预防剂·治疗剂·并用剂,可举出例如,青霉素系、β-内酰胺系、头孢烯系(cefems)、碳青霉烯系、青霉烯系、林可霉素系、单菌霉素(monobactam)系、四环素系、氯霉素系、磷霉素、新喹诺酮(NewQuinolone)系、氟喹诺酮系、氨基糖苷系、糖肽系、利奈唑胺等抗菌剂,以及有可能在败血症治疗中给予的任何药剂,例如,输液、重碳酸、血管收缩药、血栓防止溶解剂、强心剂、溃疡预防药、类固醇、活化蛋白C、血液制剂或精氨酸、藻酸、ω-3等免疫调节物质等。认为这些败血症的预防剂·治疗剂·并用剂与5-ALA对败血症的治疗效果相关的机理各自完全不同,因此,并用的意义重大,可期待加合效果,根据情况还可期待协同效果。这些败血症的预防剂·治疗剂·并用剂可以各自单独使用,也可以2种以上混合使用。这些败血症的预防剂·治疗剂·并用剂可以与本发明的败血症的预防剂和/或治疗剂同时或分开给药。剂型和投与方法可以与本发明的败血症的预防剂和/或治疗剂相同,另外也可以分开使用。
ALA类也可以直接单独给药,根据需要可以加入其它药效成分、营养剂等其它成分,通常理想的是制为各种医药制剂,该医药制剂可以将活性成分与药理学上可接受的一种或二种以上的载体混合、通过制剂学的常规方法来制造。作为可配合于ALA类中的载体,可使用适于摄取的有机或无机的固体或液体的、通常为惰性的制药学上可接受的载体材料。具体例示有结晶性纤维素、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物性或动物性脂肪和油、胶质(gum)、聚亚烷基二醇等载体。
作为本发明的败血症的预防剂和/或治疗剂、本发明的预防和/或治疗败血症用的试剂盒的各成分、或本发明的预防药剂和/或治疗药剂的组合的各成分的给药途径,可举出包括舌下给药的经口给药,或包括滴鼻给药、吸入给药、包括滴注的静脉内给药,利用巴布剂等的经皮给药,通过栓剂、或使用经鼻胃管、经鼻肠管、胃瘘管或肠瘘管的强制性经肠营养法进行的给药等非经口给药等。应予说明,本发明的预防药剂和/或治疗药剂的组合中的现有的败血症的预防剂·治疗剂·并用剂的给药途径优选采用各药剂已得到认可的给药途径。
作为本发明的败血症的预防剂和/或治疗剂、本发明的预防和/或治疗败血症用的试剂盒的各成分、或本发明的预防药剂和/或治疗药剂的组合的各成分的剂型,可对应于上述给药途径适宜确定,可举出注射剂、滴鼻剂、滴注剂、片剂、胶囊剂、颗粒剂、散剂、溶液剂、溶解于糖浆等中的水剂、巴布剂、栓剂等。对于本发明的败血症的预防剂和/或治疗剂、本发明的预防和/或治疗败血症用的试剂盒的各成分,除了医药用途之外,还可制为片剂或胶囊剂的补充剂的形态。另外,特别是对吞咽困难的老年人和婴幼儿等,优选为在口中显示快速崩解性的崩解片的形态、或适于经鼻胃管给药的溶液剂的形态。这些制剂可适宜使用溶剂、分散剂、增量剂、赋形剂等,根据常规方法制造。
为了制备本发明的败血症的预防剂和/或治疗剂、或本发明的预防和/或治疗败血症用的试剂盒,可根据需要添加药理学上可接受的载体、赋形剂、稀释剂、添加剂、崩解剂、粘合剂、包衣剂、润滑剂、增滑剂、滑润剂、风味剂、甜味剂、增溶剂、溶剂、凝胶化剂、营养剂等,具体可例示:水、生理盐水、动物性脂肪和油、植物油、乳糖、淀粉、明胶、结晶性纤维素、胶质、滑石、硬脂酸镁、羟丙基纤维素、聚亚烷基二醇、聚乙烯醇、甘油。例如,注射剂可以添加水、生理盐水、植物油、增溶剂、保存剂等,并按照常规方法来制造,片剂可以混合例如乳糖、淀粉、硬脂酸镁、羟丙基纤维素、聚乙烯醇、表面活性剂、甘油等各种添加剂,并按照常规方法来制造,吸入剂可以添加例如乳糖等并按照常规方法来制造。应予说明,将这些制剂制备为水溶液时,为了防止化合物(I)的分解,需要留意不使水溶液成为碱性。成为碱性时,可通过除去氧来防止有效成分的分解。
本发明的败血症的预防剂和/或治疗剂、本发明的预防和/或治疗败血症用的试剂盒,除了人之外还可在家畜·家禽类和宠物等兽医领域中使用。作为上述预防剂和/或治疗剂的给药的量·频率·期间,在对象为人时,根据败血症患者的年龄、体重、症状等而有所不同,对于制剂中所含的ALA类的给药量,以摩尔数换算,ALA类的总计以ALA·盐酸盐换算通常成人每人可以为1mg~3000mg,理想为3mg~1000mg,更理想为10mg~700mg,给药可以为早上或晚上,并不特别选择给药时期,一天一次或在给药量多时优选以多次给药。摄取的天数根据症状而有所不同,理想的是在症状缓和后继续摄取3~4天。
以下,通过实施例更具体地说明本发明,但本发明的技术范围并不受这些例示所限定。
实施例1
使用将人肺动脉血管内皮细胞与具有促进炎症性细胞因子分泌的作用的脂多糖(LPS)混合培养的败血症模型,进行了用ELISA法测定上清中的IL-6(图1)、IL-8(图2)的以下实验。败血症中受损频率最高的内脏器官是肺,因而本实验中使用了人肺动脉血管内皮细胞。
使用人肺动脉血管内皮细胞(5×105个细胞/孔,n=3孔),按照LPS和5-ALA添加的有无分为以下4组。
(1)无刺激下的对照(图中:对照)
(2)添加5-ALA(100μM)混合培养3小时(图中:+ALA)
(3)添加LPS(1μg/mL)混合培养3小时(图中:+LPS)
(4)添加5-ALA(100μM)和LPS(1μg/mL)混合培养3小时(图中:+ALA,LPS)
在添加了5-ALA的组中,按照以摩尔比计5-ALA∶柠檬酸亚铁钠=1∶0.5的比例添加了柠檬酸亚铁钠。
结果确认,在以LPS刺激人肺动脉血管内皮细胞、促进炎症性细胞因子分泌、模拟败血症的模型中,通过添加5-ALA和柠檬酸亚铁钠进行混合培养,确认到炎症性细胞因子IL-6、IL-8产生被抑制。(n=3,图1、2:+ALA,LPS)
产业上的可利用性
本发明的败血症的预防剂和/或治疗剂可在医疗领域有利地利用。
Claims (7)
1.下述式(I)所示的化合物或其盐、和铁化合物在制造IL-6和/或IL-8的产生的抑制剂中的用途,
式中,R1表示氢原子,R2表示氢原子、或者直链或支链烷基。
2.如权利要求1所述的用途,其特征在于,R1和R2为氢原子。
3.如权利要求1或2所述的用途,其特征在于,铁化合物为选自氯化铁、三氧化二铁、硫酸铁、焦磷酸亚铁、柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠、柠檬酸铁铵、焦磷酸铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺四乙酸铁铵、二羧基甲基谷氨酸铁钠、二羧基甲基谷氨酸铁铵、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、血红素铁、右旋糖酐铁、三亚乙基四胺铁、乳铁蛋白铁、转铁蛋白铁、叶绿素铁钠、铁蛋白铁、含糖氧化铁和硫化甘氨酸铁中的1种或2种以上的铁化合物。
4.如权利要求3所述的用途,其特征在于,铁化合物为柠檬酸亚铁钠。
5.如权利要求1或2所述的用途,其特征在于,对IL-6和/或IL-8的产生的抑制不需要光照射。
6.如权利要求3所述的用途,其特征在于,对IL-6和/或IL-8的产生的抑制不需要光照射。
7.如权利要求4所述的用途,其特征在于,对IL-6和/或IL-8的产生的抑制不需要光照射。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-177203 | 2011-08-12 | ||
JP2011177203 | 2011-08-12 | ||
PCT/JP2012/005125 WO2013024589A1 (ja) | 2011-08-12 | 2012-08-10 | 敗血症の予防剤及び/又は治療剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103747784A CN103747784A (zh) | 2014-04-23 |
CN103747784B true CN103747784B (zh) | 2018-01-30 |
Family
ID=47714926
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280037274.7A Expired - Fee Related CN103747784B (zh) | 2011-08-12 | 2012-08-10 | 败血症的预防剂和/或治疗剂 |
Country Status (5)
Country | Link |
---|---|
US (1) | US9474770B2 (zh) |
EP (1) | EP2745838B1 (zh) |
JP (1) | JP6052736B2 (zh) |
CN (1) | CN103747784B (zh) |
WO (1) | WO2013024589A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI571455B (zh) | 2011-12-07 | 2017-02-21 | Sbi Pharmaceuticals Co Ltd | To prevent alcohol from causing discomfort to the human body of the hangover preventive agent and / or therapeutic agent |
US9962350B2 (en) * | 2014-07-11 | 2018-05-08 | Sbi Pharmaceuticals Co., Ltd. | Agent for improving normal development rate of fertilized eggs |
JP7113434B2 (ja) * | 2017-05-31 | 2022-08-05 | Sbiファーマ株式会社 | 過活動膀胱の予防剤または治療剤 |
CN109608249A (zh) * | 2019-02-02 | 2019-04-12 | 浙江科罗尼生物科技有限公司 | 二价铁供给液体及其应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101010076A (zh) * | 2004-09-02 | 2007-08-01 | 克斯莫石油株式会社 | 健康功能改善剂 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5079262A (en) | 1989-07-28 | 1992-01-07 | Queen's University At Kingston | Method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid |
FR2777782B1 (fr) | 1998-04-22 | 2001-05-18 | Alexandre Marti | Solution pour la preparation d'une substance pharmaceutique pour le diagnostic et/ou le traitement de lesions tissulaires |
JP5034032B2 (ja) | 2004-09-29 | 2012-09-26 | Sbiファーマ株式会社 | 腫瘍診断剤 |
EP2305237B1 (en) | 2008-05-14 | 2014-04-30 | SBI Pharmaceuticals Co., Ltd. | Therapeutic agent for male sterility |
WO2010050179A1 (ja) * | 2008-10-27 | 2010-05-06 | Sbiアラプロモ株式会社 | 5-アミノレブリン酸若しくはその誘導体、又はそれらの塩を有効成分とする成人病の予防・改善剤 |
JP5611548B2 (ja) | 2009-07-08 | 2014-10-22 | Sbiファーマ株式会社 | 5−アミノレブリン酸若しくはその誘導体、又はそれらの塩を有効成分とするがんの予防・改善剤 |
-
2012
- 2012-08-10 CN CN201280037274.7A patent/CN103747784B/zh not_active Expired - Fee Related
- 2012-08-10 EP EP12824258.3A patent/EP2745838B1/en active Active
- 2012-08-10 WO PCT/JP2012/005125 patent/WO2013024589A1/ja active Application Filing
- 2012-08-10 US US14/237,407 patent/US9474770B2/en active Active
- 2012-08-10 JP JP2013528918A patent/JP6052736B2/ja not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101010076A (zh) * | 2004-09-02 | 2007-08-01 | 克斯莫石油株式会社 | 健康功能改善剂 |
Non-Patent Citations (1)
Title |
---|
Endotoxemia in Transgenic Mice Overexpressing Human Glutathione Peroxidases;Oleg Mirochnitchenko等;《Circulation Research》;20000818;289-295 * |
Also Published As
Publication number | Publication date |
---|---|
JP6052736B2 (ja) | 2016-12-27 |
US9474770B2 (en) | 2016-10-25 |
EP2745838A1 (en) | 2014-06-25 |
EP2745838B1 (en) | 2017-07-26 |
WO2013024589A1 (ja) | 2013-02-21 |
EP2745838A4 (en) | 2015-03-18 |
JPWO2013024589A1 (ja) | 2015-03-05 |
CN103747784A (zh) | 2014-04-23 |
US20140186464A1 (en) | 2014-07-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104487067B (zh) | 流行性感冒病毒感染症的预防·治疗剂 | |
CN103747784B (zh) | 败血症的预防剂和/或治疗剂 | |
CN104487066A (zh) | 放射线损害的预防和/或治疗剂 | |
RU2418587C1 (ru) | Способ лечения злокачественных опухолей головного мозга | |
CN104105482B (zh) | 红细胞生成素产生促进剂 | |
EP2338495A1 (en) | Iron bis-glycinate chelate for use in the oral treatment of anemia in patients with celiac disease | |
JP4960872B2 (ja) | 消化管からの微量元素の吸収障害の予防及び治療に使用するための栄養製剤及び/又は医薬製剤 | |
TWI590823B (zh) | Cancerous anemia to improve, prevention agent | |
JP4395368B2 (ja) | 細胞殺傷活性を有するカルシウム塩 | |
JP2003510363A (ja) | 医薬組成物及びその使用法 | |
RU2516969C1 (ru) | Препарат для профилактики и лечения желудочно-кишечных болезней новорожденных телят, протекающих с признаками диареи | |
RU2417782C1 (ru) | Способ лечения ацидоза рубца | |
RU2338516C2 (ru) | Железосодержащее средство для профилактики и лечения анемии у животных | |
Andriiaka et al. | OPTIMIZATION OF DIAGNOSIS OF SECONDARY METABOLIC DISORDERS AND TREATMENT TACTICS IN PATIENTS WITH ANEMIA IN NEOPLASTIC DISEASE IN COLORECTAL CANCER | |
RU2461394C2 (ru) | Способ лечения гнойно-воспалительных осложнений у онкоурологических больных | |
RU2395278C1 (ru) | Способ получения комплексного препарата для профилактики и лечения патологий обмена веществ и нарушений функций иммунной системы животных | |
KR20070014114A (ko) | 괴사성 장염의 치료 | |
UA146823U (uk) | Застосування інфузійного комплексного препарату сорбілакт поліфункціональної дії для нормалізації гематологічних показників оперованих хворих на рак шлунка після гастректомії | |
CA3219872A1 (en) | Compounds inhibiting the synergistic carsinogenic effect of heavy metals in the presence of other carcinogens for use in the treatment of cancer | |
RU2247514C2 (ru) | Биологически активная добавка к пище | |
RU2239425C1 (ru) | Способ лечения колибактериоза и сальмонеллеза у поросят | |
JP2021525285A (ja) | 2,3,5−置換されたチオフェン化合物の放射線治療増進用途 | |
UA133151U (uk) | Застосування інфузійного комплексного препарату сорбілакт поліфункціональної дії для білокзберігаючої дії в оперованих хворих на рак середнього грудного відділу стравоходу в ранньому післяопераційному періоді | |
RU2229883C2 (ru) | Способ лечения и профилактики диспепсии телят, поросят | |
RU2200567C1 (ru) | Способ профилактики и лечения желудочно-кишечных болезней новорожденных телят |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1194993 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1194993 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180130 |