JP4802470B2 - Liver fibrosis inhibitor - Google Patents
Liver fibrosis inhibitor Download PDFInfo
- Publication number
- JP4802470B2 JP4802470B2 JP2004279950A JP2004279950A JP4802470B2 JP 4802470 B2 JP4802470 B2 JP 4802470B2 JP 2004279950 A JP2004279950 A JP 2004279950A JP 2004279950 A JP2004279950 A JP 2004279950A JP 4802470 B2 JP4802470 B2 JP 4802470B2
- Authority
- JP
- Japan
- Prior art keywords
- liver
- chronic hepatitis
- liver fibrosis
- administration
- polaprezinc
- 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
- 208000019425 cirrhosis of liver Diseases 0.000 title claims description 20
- 239000003112 inhibitor Substances 0.000 title claims description 8
- 208000006454 hepatitis Diseases 0.000 claims description 21
- 206010008909 Chronic Hepatitis Diseases 0.000 claims description 18
- 108700035912 polaprezinc Proteins 0.000 claims description 13
- 229950004693 polaprezinc Drugs 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 3
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 claims 1
- IUWLTSZHVYHOHY-FJXQXJEOSA-L zinc;(2s)-2-(3-azanidylpropanoylazanidyl)-3-(1h-imidazol-5-yl)propanoate Chemical compound [Zn+2].[NH-]CCC(=O)[N-][C@H](C([O-])=O)CC1=CN=CN1 IUWLTSZHVYHOHY-FJXQXJEOSA-L 0.000 description 12
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 11
- 206010016654 Fibrosis Diseases 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 206010019668 Hepatic fibrosis Diseases 0.000 description 5
- 206010067125 Liver injury Diseases 0.000 description 5
- 230000007882 cirrhosis Effects 0.000 description 5
- 210000003494 hepatocyte Anatomy 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 4
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 4
- -1 L-carnosine zinc salt Chemical class 0.000 description 4
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 4
- 230000004761 fibrosis Effects 0.000 description 4
- 231100000234 hepatic damage Toxicity 0.000 description 4
- 229920002674 hyaluronan Polymers 0.000 description 4
- 229960003160 hyaluronic acid Drugs 0.000 description 4
- 229960002591 hydroxyproline Drugs 0.000 description 4
- 230000008818 liver damage Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000013424 sirius red staining Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- MORUQNQGRSLTCD-FJXQXJEOSA-N (2s)-2-(3-aminopropanoylamino)-3-(1h-imidazol-5-yl)propanoic acid;zinc Chemical class [Zn].NCCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 MORUQNQGRSLTCD-FJXQXJEOSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 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 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000354 acute hepatitis Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、慢性肝炎の進行に伴って生じる肝線維化を抑制する医薬に関する。 The present invention relates to a medicament for suppressing liver fibrosis that occurs with the progression of chronic hepatitis.
慢性肝炎は、主に肝炎ウイルスによる慢性的な肝障害であり、急性ウイルス肝炎や一定期間経過しても治癒しないものや、同じような症状のものをいう。ウイルス性の慢性肝炎にはＢ型慢性肝炎、Ｃ型慢性肝炎等がある。ウイルス以外の原因としてはアルコール、薬物、中毒、脂肪肝、ウイルソン病、自己免疫性肝炎などがある。 Chronic hepatitis is a chronic liver disorder mainly caused by the hepatitis virus, and refers to acute viral hepatitis, those that do not cure even after a certain period of time, and those with similar symptoms. Examples of viral chronic hepatitis include chronic hepatitis B and chronic hepatitis C. Causes other than viruses include alcohol, drugs, poisoning, fatty liver, Wilson's disease, autoimmune hepatitis and the like.
これらの慢性肝炎が進行すると肝硬変となる。肝硬変の病理学的所見は、肝細胞の持続的な崩壊が起こり、通常では肝細胞の再生によって修復されるのが、肝細胞の障害が強くそれに続いて起こる炎症反応が長時間持続、反復することで線維が多くなって硬くなり、残存した肝細胞の強い再生とあわさって肝臓内に結節を形成する。この結節が肝臓内部の静脈を中心とする血管系を圧迫して、肝臓の内外の血行を大きく障害する。これによって門脈圧の亢進、肝血流の減少などが起こり、これらのことが更に肝細胞の障害を増悪させるという悪循環が起こる。 As these chronic hepatitis progresses, cirrhosis occurs. The pathological findings of cirrhosis are persistent destruction of hepatocytes, usually repaired by regeneration of hepatocytes, but the damage of the hepatocytes is strong and the subsequent inflammatory reaction persists and repeats for a long time As a result, the fibers become harder and harder, and together with the strong regeneration of the remaining hepatocytes, nodules are formed in the liver. This nodule compresses the vascular system centered on the veins inside the liver, greatly impairing blood circulation inside and outside the liver. This causes an increase in portal pressure, a decrease in hepatic blood flow, and the like, and this causes a vicious cycle in which the damage to hepatocytes is further exacerbated.
このように慢性肝炎から肝硬変に至る際に、肝の線維化が生じ、これにより可逆的な状態である慢性肝炎から不可逆的な状態である肝硬変になる。従って、慢性肝炎の進行に伴なって生じる肝線維化を抑制する薬剤は、慢性肝炎の治療薬として極めて重要である。 In this way, when hepatitis leads to cirrhosis, fibrosis of the liver occurs, which changes from reversible chronic hepatitis to irreversible cirrhosis. Therefore, a drug that suppresses liver fibrosis caused by the progression of chronic hepatitis is extremely important as a therapeutic drug for chronic hepatitis.
従来の慢性肝炎治療薬としては、インターフェロン、ラミブジン及び肝庇護剤等が知られているが、インターフェロン及びラミブジンは抗ウイルス剤であり、肝庇護剤は主に肝細胞障害に対する効果が期待される薬剤であり、肝線維化抑制効果はない。 As conventional therapeutic agents for chronic hepatitis, interferon, lamivudine, liver protection agent, etc. are known. And there is no liver fibrosis inhibitory effect.
一方、ポラプレジンク（Ｌ−カルノシン亜鉛塩）は、消化性潰瘍治療薬（特許文献１）として有用であることが知られており、広く使用されている。またポラプレジンクは、急性肝炎モデルである四塩化炭素肝障害に有効であることが知られている（特許文献２）。しかし、ポラプレジンクが慢性肝炎に対してどのような作用をするかは全く知られていない。
本発明の目的は、慢性肝炎における肝線維化を抑制する医薬を提供することにある。 An object of the present invention is to provide a medicament for suppressing liver fibrosis in chronic hepatitis.
そこで本発明者は、慢性肝炎モデルであり、四塩化炭素肝障害とは全く異なる機序で肝障害が生じることが知られているチオアセタミドモデルを用いて肝線維化抑制薬を探索したところ、ポラプレジンクが優れた肝線維化抑制作用を有することを見出し本発明を完成するに至った。 Therefore, the present inventor searched for a hepatic fibrosis inhibitor using a thioacetamide model, which is a chronic hepatitis model and is known to cause liver damage by a mechanism completely different from carbon tetrachloride liver damage. However, the present inventors have found that polaprezinc has an excellent liver fibrosis-inhibiting action and have completed the present invention.
すなわち、本発明は、ポラプレジンクを有効成分とする肝線維化抑制剤を提供するものである。 That is, the present invention provides a liver fibrosis inhibitor containing polaprezinc as an active ingredient.
本発明によれば、慢性肝炎に伴なって生じる肝線維化を顕著に抑制することができ、慢性肝炎から肝硬変への進行を防止することができる。 According to the present invention, it is possible to remarkably suppress liver fibrosis caused by chronic hepatitis, and to prevent progression from chronic hepatitis to cirrhosis.
本発明医薬の有効成分であるポラプレジンク、すなわち、Ｌ−カルノシン亜鉛塩は、例えば前記特許文献１、２、特公平７−１１６１６０号公報、特公平３−５３６７号公報等に記載の製法により得ることができる。
後記実施例に示すように、ポラプレジンクは慢性肝炎モデルであるチオアセタミドモデルに対し、優れた治療効果、特に肝線維化マーカーである、組織中のヒドロキシプロリン量、ヒアルロン酸を顕著に低下させ、かつ組織学的にも肝線維化を顕著に抑制し、またＴＧＦ−β1量も顕著に低下させる作用を有する。ポラプレジンクのこのような効果が、チオアセタミドの前投与でなく、チオアセタミドを投与している途中の投与、すなわち慢性肝炎発症後の投与でも得られたことは極めて重要である。従って、ポラプレジンクは、肝線維化抑制剤、特に慢性肝炎における肝線維化抑制剤として有用である。
Polaprezinc, that is, L-carnosine zinc salt, which is an active ingredient of the medicament of the present invention, is obtained by the production method described in, for example, Patent Documents 1 and 2, Japanese Patent Publication No. 7-116160, Japanese Patent Publication No. 3-5367, etc. Can do.
As shown in the examples below, polaprezinc significantly reduced the amount of hydroxyproline and hyaluronic acid in the tissue, which is an excellent therapeutic effect, especially a fibrosis marker, compared to the thioacetamide model, which is a chronic hepatitis model. and also significantly inhibited hepatic fibrosis histologically, also has the effect of also significantly reduced TGF-beta 1 volume. It is extremely important that such an effect of polaprezinc was obtained not during the pre-administration of thioacetamide but also during the administration of thioacetamide, that is, after the onset of chronic hepatitis. Therefore, polaprezinc is useful as a liver fibrosis inhibitor, particularly a liver fibrosis inhibitor in chronic hepatitis.
本発明の医薬としては、経口投与用製剤が好ましく、特に錠剤、散剤、顆粒剤、シロップ剤、カプセル剤等が好ましい。 As the medicament of the present invention, a preparation for oral administration is preferable, and tablets, powders, granules, syrups, capsules and the like are particularly preferable.
これらの製剤を製造するには、適当な添加剤、例えば注射用蒸留水、精製水、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、乳糖、ソルビット、マンニット、白糖、トウモロコシデンプン、結晶セルロース、ラクチトール、セルロース誘導体、アラビアゴム、トラガントゴム、ゼラチン、ポリソルベート８０、タルク、ステアリン酸マグネシウム、水、エタノール、白色ワセリン、グリセリン、脂肪、脂肪油、グリコール類、ステアリルアルコールなどの高級アルコール類、プラスチベース、パラフィン、ミツロウ、ポリオキシエチレン硬化ヒマシ油、サッカリン、パインシロップ等を適宜選択、組合わせて使用することができる。
In order to produce these preparations, suitable additives such as distilled water for injection, purified water, carboxymethylcellulose calcium, sodium carboxymethylcellulose, lactose, sorbit, mannitol, sucrose, corn starch, crystalline cellulose, lactitol, cellulose derivatives Arabic gum, tragacanth gum, gelatin,
ポラプレジンクの投与量は年齢、体重、病態症状、治療効果、投与方法、投与時期、投与回数、投与期間により異なるが、好ましくは成人１回あたり０．０１〜１０ｇであり、これは１日１〜４回に分けて投与してもよい。 The dose of polaprezin varies depending on age, body weight, pathologic symptoms, therapeutic effect, administration method, administration timing, administration frequency, administration period, but is preferably 0.01 to 10 g per adult, It may be administered in four divided doses.
次に実施例を挙げて本発明を更に詳細に説明するが、本発明は何ら実施例に限定されるものではない。 EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to an Example at all.
実施例１
ラットを１群１５匹ずつに分けた。対照群には、チオアセタミド水溶液（３００mg／Ｌ）を飲料水として、１０週間又は２０週間にわたって連続的に投与した。また試験群には、チオアセタミド水溶液（３００mg／Ｌ）を飲料水として、２０週間にわたって連続的に投与し、かつ１０週後から２０週までポラプレジンク２００mg／day／kg又は５００mg／day／kgを経口投与した。
Example 1
Rats were divided into 15 animals per group. In the control group, a thioacetamide aqueous solution (300 mg / L) was continuously administered as drinking water for 10 weeks or 20 weeks. In the test group, thioacetamide aqueous solution (300 mg / L) was administered as drinking water continuously for 20 weeks, and
対照群及び試験群のラットは、所定の投与終了後に殺し、肝臓を摘出した。肝線維化の血清中マーカーであるヒアルロン酸はラテックス凝集免疫比濁法で測定、肝組織の線維化のマーカーであるヒドロキシプロリンは塩酸処理しクロラミンとエルリッヒ液を使用し吸光度で測定した。肝線維化促進に特異的に作用し、肝組織内で増加するＴＧＦ−β1はＥＬＩＳＡ法で測定し。肝組織を染色する目的でシリウスレッド染色を行い、線維化の主役となる活性化した星細胞をα−ＳＭＡ免疫染色で特異的に同定した。また、肝障害のマーカーである血清中トランスフェレース、アルカリカリフォスファターゼを生化学的手法にて測定した。
それらの結果を、図１、図２、図３、図４及び表１に示す。
The rats in the control group and the test group were killed after the prescribed administration and the liver was removed. Hyaluronic acid, a serum marker of liver fibrosis, was measured by latex agglutination immunoturbidimetry, and hydroxyproline, a marker of liver tissue fibrosis, was treated with hydrochloric acid and measured by absorbance using chloramine and Erlich's solution. TGF-β 1 that specifically acts on the promotion of liver fibrosis and increases in liver tissue is measured by ELISA. Sirius red staining was performed for the purpose of staining liver tissue, and activated stellate cells that play a major role in fibrosis were specifically identified by α-SMA immunostaining. In addition, serum transferase and alkaline caliphosphatase, which are markers of liver damage, were measured by biochemical techniques.
The results are shown in FIG. 1, FIG. 2, FIG. 3, FIG.
図１、図２、図３及び図４から明らかなように、ポラプレジンクは、チオアセタミド投与開始から１０週後から投与を開始したにもかかわらず、肝線維化マーカーであるヒドロキシプロリン量、ヒアルロン酸及びＴＧＦ−β1量を有意に低下させ、組織的にも肝線維化を明確に抑制しており、肝線維化抑制剤として有用であることがわかる。また表１より、肝障害のマーカーであるアルカリホスファターゼ値を有意に改善しており、慢性肝炎の症状も改善していることが明らかである。 As is apparent from FIGS. 1, 2, 3 and 4, polaprezinc was administered in 10 weeks after the start of thioacetamide administration, but the amount of hydroxyproline, a marker of hepatic fibrosis, hyaluronic acid and TGF-beta 1 weight significantly decreased, organized to also clearly inhibited hepatic fibrosis, prove useful as a hepatic fibrosis inhibitor. In addition, it is clear from Table 1 that the alkaline phosphatase level, which is a marker of liver damage, is significantly improved, and the symptoms of chronic hepatitis are also improved.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004279950A JP4802470B2 (en) | 2004-09-27 | 2004-09-27 | Liver fibrosis inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004279950A JP4802470B2 (en) | 2004-09-27 | 2004-09-27 | Liver fibrosis inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006089439A JP2006089439A (en) | 2006-04-06 |
| JP4802470B2 true JP4802470B2 (en) | 2011-10-26 |
Family
ID=36230753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004279950A Active JP4802470B2 (en) | 2004-09-27 | 2004-09-27 | Liver fibrosis inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4802470B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019106851A1 (en) | 2017-11-30 | 2019-06-06 | 株式会社メディコ・コンスル | Combination drug suitable for treatment and prevention of non-alcoholic fatty liver disease (naflad) and/or non-alcoholic steatohepatitis (nash), and/or hepatic steatosis |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5933270A (en) * | 1982-08-19 | 1984-02-23 | Hamari Yakuhin Kogyo Kk | Zinc salt of carnosine and preparation thereof |
| JPS6314728A (en) * | 1986-07-03 | 1988-01-21 | Zeria Shinyaku Kogyo Kk | Preventive and remedy for hepatic disorder |
| JPH07116160B2 (en) * | 1987-08-10 | 1995-12-13 | 浜理薬品工業株式会社 | Crystalline L-carnosine zinc complex and method for producing the same |
-
2004
- 2004-09-27 JP JP2004279950A patent/JP4802470B2/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019106851A1 (en) | 2017-11-30 | 2019-06-06 | 株式会社メディコ・コンスル | Combination drug suitable for treatment and prevention of non-alcoholic fatty liver disease (naflad) and/or non-alcoholic steatohepatitis (nash), and/or hepatic steatosis |
| EP3718552A4 (en) * | 2017-11-30 | 2022-01-05 | Medico Consl Co., Ltd. | Combination drug suitable for treatment and prevention of non-alcoholic fatty liver disease (naflad) and/or non-alcoholic steatohepatitis (nash), and/or hepatic steatosis |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2006089439A (en) | 2006-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2002534384A (en) | Treatment and prevention of reactive oxygen metabolite-mediated cell damage | |
| EA014772B1 (en) | Treatment of liver diseases in which iron plays a role in pathogenesis | |
| CN109862888B (en) | Methods and pharmaceutical compositions for treating non-alcoholic steatohepatitis | |
| US20090069424A1 (en) | TGF-alpha expression inhibitors | |
| PT1932522E (en) | Therapeutic agent for liver disease containing 2-amino-1,3-propanediol derivative as active ingredient | |
| UA122063C2 (en) | Pharmaceutical combination comprising a selective s1p1 receptor agonist | |
| Kaplan et al. | Effects of delayed administration of octreotide in acute experimental pancreatitis | |
| CN100349609C (en) | Cirrhosis treating medicine | |
| EP2184063B1 (en) | The use of leonurine for the treatment of heart failure | |
| TW201609081A (en) | Method of treating liver disorders | |
| JP4802470B2 (en) | Liver fibrosis inhibitor | |
| CN111032041A (en) | Compositions and methods for treating rheumatoid arthritis | |
| US10548870B2 (en) | Method for treating multiple sclerosis | |
| CN110099690B (en) | Compound preparation suitable for treating non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis and/or hepatic steatosis | |
| US20040166112A1 (en) | Remedies for interstitial pneumonia, method of preparing animal model of said disease, and screening method using the same | |
| US5153221A (en) | Method for the treatment of acquired immune deficiency syndrome | |
| JP4702054B2 (en) | Enhancer | |
| EP2146714B1 (en) | Use of 4-cyclopropylmethoxy-<i>n</i>-(3,5-dichloro-1-oxidopyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide for the treatment of motor disorders related to parkinson's disease | |
| WO2016139740A1 (en) | Hepatic fibrosis-ameliorating agent | |
| KR101706660B1 (en) | Composition for Preventing and Treating Nephropathy Comprising Small Heterodimer Partner | |
| WO2018192469A1 (en) | Inhibitors of fabp4 and methods of treating arthritis | |
| US11058718B2 (en) | Method for treating non-alcoholic steatohepatitis (NASH) with the combination of polaprezinc and sodium selenite | |
| JP2007326824A (en) | Synoviocyte-growth inhibitor, pharmaceutical composition and therapy using the same | |
| WO2020191503A1 (en) | Methods and uses of bromantane and derivatives thereof for treating lung disease, fatty liver disease, and kidney disorders | |
| BR102021023761A2 (en) | PHARMACEUTICAL COMPOSITION CONTAINING CURCUMIN ANALOG FOR TREATMENT OF INFLAMMATION AND PAIN, AND USE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20070709 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20101214 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110214 |
|
| 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: 20110712 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110725 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 4802470 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140819 Year of fee payment: 3 |
|
| 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 |
|
| 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 |