JPH0551567B2 - - Google Patents
Info
- Publication number
- JPH0551567B2 JPH0551567B2 JP32151887A JP32151887A JPH0551567B2 JP H0551567 B2 JPH0551567 B2 JP H0551567B2 JP 32151887 A JP32151887 A JP 32151887A JP 32151887 A JP32151887 A JP 32151887A JP H0551567 B2 JPH0551567 B2 JP H0551567B2
- Authority
- JP
- Japan
- Prior art keywords
- hesperetin
- reverse transcriptase
- virus
- acid
- retroviruses
- 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 - Lifetime
Links
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims description 24
- AIONOLUJZLIMTK-AWEZNQCLSA-N hesperetin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-AWEZNQCLSA-N 0.000 claims description 24
- 229960001587 hesperetin Drugs 0.000 claims description 24
- AIONOLUJZLIMTK-UHFFFAOYSA-N hesperetin Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-UHFFFAOYSA-N 0.000 claims description 24
- 235000010209 hesperetin Nutrition 0.000 claims description 24
- FTODBIPDTXRIGS-UHFFFAOYSA-N homoeriodictyol Natural products C1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 FTODBIPDTXRIGS-UHFFFAOYSA-N 0.000 claims description 24
- 229940124522 antiretrovirals Drugs 0.000 claims description 6
- 239000003903 antiretrovirus agent Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 2
- 241001430294 unidentified retrovirus Species 0.000 description 10
- 102100034343 Integrase Human genes 0.000 description 9
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 9
- 241000700605 Viruses Species 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 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
- 239000000203 mixture Substances 0.000 description 6
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 229940105329 carboxymethylcellulose Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000798 anti-retroviral effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- -1 fluidity promoters Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 108091034057 RNA (poly(A)) Proteins 0.000 description 2
- 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 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 239000001341 hydroxy propyl starch Substances 0.000 description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 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
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 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
- 241000450599 DNA viruses Species 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 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
- 108010067390 Viral Proteins Proteins 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 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
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229960003511 macrogol Drugs 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
- 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
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
［産業上の利用分野］
本発明は、レトロウイルスに起因する各種ウイ
ルス性疾患の治療に有効な抗レトロウイルス剤に
関するものである。
［従来の技術および問題点］
ウイルスに関する研究が為されるにつれ、ウイ
ルス性疾患の治療法が徐々に確立されつつある。
特に最近問題となつている後天性免疫不全症候
群（AIDS）を引き起こす、HIV（Human
Immuno deficiency Virus）、HTLV−Ｉ（成人
Ｔ細胞白血病ウイルス）等はレトロウイルスとし
て知られている。
レトロウイルスはウイルス粒子内に、RNA依
存DNA合成酵素（以下、逆転写酵素と称する）
を含むウイルスであり、以下のようにして増殖し
ている。
宿主細胞に感染後、まずRNAが逆転写酵素
によりDNAに転写される。
このDNAが宿主細胞染色体に組み込まれ、
次いで宿主細胞のRNA合成酵素によつて
mRNAが合成される。
このmRNAにより各種のウイルス蛋白が生
成される。
このレトロウイルスに起因するヒトの疾病に画
期的な治療効果を有する薬剤の開発が望まれてい
た。
［問題を解決するための手段］
本発明者等は種々の生薬について、レトロウイ
ルス増殖阻害効果に関する研究を行つた結果、生
薬陳皮より抽出単離したヘスペレチンにレトロウ
イルス増殖阻害効果のあることを見い出した。
本発明はこの知見に基づくもので、ヘスペレチ
ンを有効成分とする抗レトロウイルス剤である。
ヘスペレチンは抗炎症作用、抗アレルギー作
用、降圧作用を有することが知られている。ま
た、このヘスペレチンがDNAウイルスの増殖を
抑制することも知られているが、逆転写酵素を有
し、この逆転写酵素により増殖するレトロウイル
スに対して、抗レトロウイルス効果を有すること
は従来全く知られていなかつたことである。
ヘスペレチンは下記の化学構造で示される化合
物であり、東京化成工業株式会社より市販されて
いる。
［発明の効果］
本発明の抗レトロウイルス剤が抗レトロウイル
ス効果を有することについて実験例を挙げて説明
する。
実験例 １
マウス白血病ウイルス（ラウシヤー株）感染細
胞を培養し、中島等の方法［CONPARATIVE
LEUKEMIA RESEARCH 1973，
LEUKEMOGENESIS，ED.Y.ITO.AND R.M.
DUTCHER，UNIV.OF TOKYO PRESS
TOKYO／KARGER，BASEL，PP.603−605
（1975）］に準拠して、逆転写酵素を分離精製し
た。次に、以下の組成の反応混合液を調製した。
Γ 逆転写酵素 １単位／ml
Γテンプレート・プライマー複合体としてのポリ
アデニル酸・オリゴチミジル酸複合体［ポリア
デニル酸（フアルマシア製）：オリゴチミジル
酸（フアルマシア製）＝４：１］ 2μｇ／ml
Γ トリス塩酸（pH8.0） 50mM
Γ ジチオスレイトール 5mM
Γ 塩化カリウム 50mM
Γ 塩化マンガン 0.2mM
Γ ［3H］デオキシチミジン三リン酸 0.01mM
（以下、［3H］dTTPと略す）
（400cpm／pmol）
Γ グリセロール 15（ｖ／ｖ）％
Γ 精製水 適量
〓１単位とは、逆転写酵素が37℃、１時間で
dNTP（デオキシ核酸三リン酸）1nmolを消費す
る比活性単位である。この反応混合液20μに、
ヘスペレチンおよび精製水を加えて50μとし、
［3H］dTTPの酸不溶性画分への放射活性の取り
込みをベツクマン・シンチレーシヨンカウンター
で測定して、逆転写酵素活性とし、各濃度におけ
る阻害率を算出した。その結果を第１表に示す。
[Industrial Field of Application] The present invention relates to an antiretroviral agent effective in treating various viral diseases caused by retroviruses. [Prior Art and Problems] As research on viruses continues, treatments for viral diseases are gradually being established. HIV (Human
Immuno deficiency virus), HTLV-I (adult T-cell leukemia virus), and the like are known as retroviruses. Retroviruses contain RNA-dependent DNA synthase (hereinafter referred to as reverse transcriptase) within their virus particles.
It is a virus containing After infecting a host cell, RNA is first transcribed into DNA by reverse transcriptase. This DNA is integrated into the host cell chromosome,
then by host cell RNA synthase
mRNA is synthesized. Various viral proteins are produced from this mRNA. There has been a desire to develop a drug that has an epoch-making therapeutic effect on human diseases caused by this retrovirus. [Means for Solving the Problem] As a result of conducting research on the retrovirus growth inhibiting effect of various herbal medicines, the present inventors discovered that hesperetin extracted and isolated from the herbal medicine Chinpi has a retrovirus growth inhibiting effect. Ta. The present invention is based on this knowledge and is an antiretroviral agent containing hesperetin as an active ingredient. Hesperetin is known to have anti-inflammatory, anti-allergic, and antihypertensive effects. It is also known that hesperetin inhibits the proliferation of DNA viruses, but until now it has no antiretroviral effect against retroviruses that contain reverse transcriptase and propagate by this reverse transcriptase. This was something that was unknown. Hesperetin is a compound shown by the chemical structure shown below, and is commercially available from Tokyo Kasei Kogyo Co., Ltd. [Effects of the Invention] The fact that the antiretroviral agent of the present invention has an antiretroviral effect will be explained with reference to experimental examples. Experimental Example 1 Cells infected with murine leukemia virus (Raussier strain) were cultured, and the method of Nakajima et al. [CONPARATIVE
LEUKEMIA RESEARCH 1973,
LEUKEMOGENESIS，ED.Y.ITO.AND RM
DUTCHER, UNIV.OF TOKYO PRESS
TOKYO/KARGER, BASEL, PP.603−605
(1975)], reverse transcriptase was isolated and purified. Next, a reaction mixture having the following composition was prepared. Γ Reverse transcriptase 1 unit/ml Γ Polyadenylic acid/oligothymidylic acid complex as a template/primer complex [polyadenylic acid (manufactured by Pharmacia): oligothymidylic acid (manufactured by Pharmacia) = 4:1] 2 μg/ml Γ Tris-HCl (pH8.0) 50mM Γ Dithiothreitol 5mM Γ Potassium chloride 50mM Γ Manganese chloride 0.2mM Γ [ 3H ]deoxythymidine triphosphate 0.01mM (hereinafter abbreviated as [ 3H ]dTTP)
(400cpm/pmol) Γ Glycerol 15 (v/v)% Γ Purified water Appropriate amount 〓1 unit means that reverse transcriptase is
It is a unit of specific activity that consumes 1 nmol of dNTP (deoxynucleic acid triphosphate). Add 20μ of this reaction mixture to
Add hesperetin and purified water to make 50μ,
The incorporation of radioactivity into the acid-insoluble fraction of [ 3 H]dTTP was measured using a Beckman scintillation counter to determine reverse transcriptase activity, and the inhibition rate at each concentration was calculated. The results are shown in Table 1.
【表】
実験例 ２
MT−２細胞を濃度３×104個／mlに調製し、
10％FCS（ギブコ社製）を含むRPMI1640（ギブコ
社製）培地中において培養した。２日後、MT−
２細胞200個あたり１個のHIVを感染させた後、
ヘスペレチン5μｇ／ml添加群と非添加群（対照
群）に分けて薬剤の添加効果を観察した。１週
後、生細胞数を計測した結果、本発明の抗レトロ
ウイルス剤によつて、HIVによるMT−２細胞変
性は90％以上抑制されることが確認された。
この結果から優れた抗レトロウイルス効果が確
認された。
以上のように本発明の抗レトロウイルス剤は、
レトロウイルスの増殖において必要な逆転写酵素
活性を阻害することにより、その増殖を抑制する
作用を有するものであるからレトロウイルスであ
ればいかなるウイルスにも適用することができ
る。
レトロウイルスの具体例としては、白血病ウイ
ルス、肉腫ウイルス、乳癌ウイルス、ビスウイル
ス、マエデイウイルス、HIV、HTLV−Ｉ等が
挙げられる。
次に、ヘスペレチンの経口投与での急性毒性試
験をddY系雄性マウス及びウイスター（Wistar）
系雄性ラツトを用いて行つたところ、ヘスペレチ
ンは１ｇ／Kgの経口投与でも死亡例はなかつた。
このように、ヘスペレチンは、極めて毒性が低
く安全性の高いものである。
次に、ヘスペレチンの投与量および製剤化につ
いて説明する。
ヘスペレチンはそのまま、あるいは慣用の製剤
担体と共に動物および人に投与することができ
る。投与形態としては、特に限定がなく、必要に
応じ適宜選択して使用され、錠剤、カプセル剤、
顆粒剤、細粒剤、散剤等の経口剤、注射剤、坐剤
等の非経口剤が挙げられる。
経口剤として所期の効果を発揮するためには、
患者の年令、体重、疾患の程度により異なるが、
通常成人でヘスペレチンの重量として100〜6000
mgを、１日数回に分けての服用が適当と思われ
る。
本発明において錠剤、カプセル剤、顆粒剤等の
経口剤は、例えばデンプン、乳糖、白糖、マンニ
ツト、カルボキシメチルセルロース、コーンスタ
ーチ、無機塩類等を用いて常法に従つて製造され
る。
この種の製剤には、適宜前記賦形剤の他に、結
合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進
剤、矯味剤、着色剤、香料等を使用することがで
きる。それぞれの具体例は以下に示す如くであ
る。
［結合剤］
デンプン、デキストリン、アラビアゴム末、ゼ
ラチン、ヒドロキシプロピルスターチ、メチルセ
ルロース、カルボキシメチルセルロースナトリウ
ム、ヒドロキシプロピルセルロース、結晶セルロ
ース、エチルセルロース、ポリビニルピロリド
ン、マクロゴール。
［崩壊剤］
デンプン、ヒドロキシプロピルスターチ、カル
ボキシメチルセルロースナトリウム、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、低置換ヒドロキシプロピルセルロー
ス。
［界面活性剤］
ラウリル硫酸ナトリウム、大豆レシチン、シヨ
糖脂肪酸エステル、ポリソルベート80。
［滑沢剤］
タルク、ロウ類、水素添加植物油、シヨ糖脂肪
酸エステル、ステアリン酸マグネシウム、ステア
リン酸カルシウム、ステアリン酸アルミニウム、
ポリエチレングリコール。
［流動性促進剤］
軽質無水ケイ酸、乾燥水酸化アルミニウムゲ
ル、合成ケイ酸アルミニウム、ケイ酸マグネシウ
ム。
また、ヘスペレチンは、懸濁液、エマルジヨン
剤、シロツプ剤、エリキシル剤としても投与する
ことができ、これらの各種剤形には、矯味矯臭
剤、着色剤を含有してもよい。
非経口剤として所期の効果を発揮するために
は、患者の年令、体重、疾患の程度により異なる
が、通常成人でヘスペレチンの重量として１日１
〜100mgまでの静注、点滴静注、皮下注射、筋肉
注射が適当と思われる。
この非経口剤は常法に従つて製造され、希釈剤
として一般に注射用蒸留水、生理食塩水、ブドウ
糖水溶液、注射用植物油、ゴマ油、ラツカセイ
油、ダイズ油、トウモロコシ油、プロピレングリ
コール、ポリエチレングリコール等を用いること
ができる。さらに必要に応じて、殺菌剤、防腐
剤、安定剤を加えてもよい。また、この非経口剤
は安定性の点から、バイアル等に充填後冷凍し、
通常の凍結乾燥技術により水分を除去し、使用直
前に凍結乾燥物から液剤を再調製することもでき
る。更に、必要に応じて適宜、等張化剤、安定
剤、防腐剤、無痛化剤等を加えても良い。
その他の非経口剤としては、外用液剤、軟膏等
の塗布剤、直腸内投与のための坐剤等が挙げら
れ、常法に従つて製造される。
実施例 １
結晶セルロース 84.5ｇ
ステアリン酸マグネシウム 0.5ｇ
カルボキシメチルセルロースカルシウム５ｇヘスペレチン 10ｇ
計 100ｇ
上記の処方に従つて，およびの一部を均
一に混合し、圧縮成型した後、粉砕し、および
の残量を加えて混合し、打錠機にて圧縮成型し
て一錠200mgの錠剤を得た。
この錠剤一錠には、ヘスペレチン20mgが含有さ
れており、成人１日５〜７錠を数回にわけて服用
する。
実施例 ２
コーンスターチ 84ｇ
ステアリン酸マグネシウム 0.5ｇ
カルボキシメチルセルロースカルシウム５ｇ
軽質無水ケイ酸 0.5ｇヘスペレチン 10ｇ
計 100ｇ
上記の処方に従つて〜を均一に混合し、圧
縮成型機にて圧縮成型後、破砕機により粉砕し、
篩別して顆粒剤を得た。
この顆粒剤１ｇには、ヘスペレチン100mgが含
有されており、成人１日１〜2.5ｇを数回にわけ
て服用する。
実施例 ３
コーンスターチ 89.5ｇ
軽質無水ケイ酸 0.5ｇヘスペレチン 10ｇ
計 100ｇ
上記の処方に従つて〜を均一に混合し、
200mgを２号カプセルに充填した。
このカプセル剤１カプセルには、ヘスペレチン
20mgが含有されており、成人１日５〜７カプセル
を数回にわけて服用する。
実施例 ４
注射用蒸留水 適量
ブドウ糖 200mgヘスペレチン 10mg
全量 15ml
注射用蒸留水におよびを溶解させた後、５
mlのアンプルに注入し、121℃で15分間加圧滅菌
を行つて注射剤を得た。[Table] Experimental example 2 MT-2 cells were prepared at a concentration of 3 x 10 cells/ml,
It was cultured in RPMI1640 (manufactured by Gibco) medium containing 10% FCS (manufactured by Gibco). 2 days later, MT-
2 After infecting 1 HIV per 200 cells,
The effects of drug addition were observed by dividing into a group to which hesperetin was added at 5 μg/ml and a group to which no hesperetin was added (control group). One week later, the number of viable cells was counted, and it was confirmed that the antiretroviral agent of the present invention suppressed MT-2 cell degeneration caused by HIV by 90% or more. This result confirmed an excellent antiretroviral effect. As described above, the antiretroviral agent of the present invention
Since it has the effect of suppressing the proliferation of retroviruses by inhibiting the reverse transcriptase activity necessary for their proliferation, it can be applied to any retrovirus. Specific examples of retroviruses include leukemia virus, sarcoma virus, breast cancer virus, bisvirus, maedi virus, HIV, HTLV-I, and the like. Next, we conducted an acute toxicity test of oral administration of hesperetin in ddY male mice and Wistar.
When this study was carried out using a strain of male rats, there were no cases of death even when hesperetin was orally administered at a dose of 1 g/Kg. Thus, hesperetin has extremely low toxicity and high safety. Next, the dosage and formulation of hesperetin will be explained. Hesperetin can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, including tablets, capsules,
Examples include oral preparations such as granules, fine granules, and powders, and parenteral preparations such as injections and suppositories. In order to exert the desired effect as an oral agent,
Although it varies depending on the patient's age, weight, and severity of the disease,
Usually 100 to 6000 as the weight of hesperetin in adults
It seems appropriate to take mg in divided doses several times a day. In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, inorganic salts, and the like. In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below. [Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol. [Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose. [Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80. [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate,
Polyethylene glycol. [Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate. Hesperetin can also be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain flavoring agents and coloring agents. In order to exert the desired effect as a parenteral agent, it depends on the age, weight, and severity of the disease of the patient, but in general, adults should take 1 dose of hesperetin per day.
Intravenous injections, intravenous drips, subcutaneous injections, and intramuscular injections of up to ~100 mg are considered appropriate. This parenteral preparation is manufactured according to a conventional method, and diluents generally include distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, mustard oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. can be used. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the standpoint of stability, this parenteral preparation is frozen after being filled into vials, etc.
The liquid formulation can also be reconstituted from the lyophilizate immediately prior to use by removing moisture by conventional lyophilization techniques. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate. Other parenteral preparations include liquid preparations for external use, liniments such as ointments, and suppositories for intrarectal administration, which are manufactured according to conventional methods. Example 1 Crystalline cellulose 84.5g Magnesium stearate 0.5g Carboxymethyl cellulose calcium 5g Hesperetin 10g Total 100g According to the above recipe, a part of and was mixed uniformly, compressed and molded, and then crushed, and the remaining amount of and was The mixture was added, mixed, and compressed using a tablet machine to obtain tablets each weighing 200 mg. One tablet of this tablet contains 20 mg of hesperetin, and adults should take 5 to 7 tablets a day in several doses. Example 2 Corn starch 84g Magnesium stearate 0.5g Calcium carboxymethyl cellulose 5g Light anhydrous silicic acid 0.5g Hesperetin 10g Total 100g Mix ~ uniformly according to the above recipe, compress and mold with a compression molding machine, and then crush with a crusher death,
Granules were obtained by sieving. 1 g of this granule contains 100 mg of hesperetin, and adults should take 1 to 2.5 g per day in several doses. Example 3 Cornstarch 89.5g Light anhydrous silicic acid 0.5g Hesperetin 10g Total 100g Mix ~ uniformly according to the above recipe,
200 mg was filled into No. 2 capsules. Each capsule contains hesperetin.
It contains 20 mg, and adults should take 5 to 7 capsules a day in several doses. Example 4 Distilled water for injection Appropriate amount Glucose 200mg Hesperetin 10mg Total amount 15ml After dissolving and in distilled water for injection, 5
The mixture was injected into a ml ampoule and autoclaved at 121°C for 15 minutes to obtain an injection.
Claims (1)
ルス剤。1.An antiretroviral agent containing hesperetin as an active ingredient.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62321518A JPH01163122A (en) | 1987-12-21 | 1987-12-21 | Anti-retrovirus agent |
| PCT/JP1988/000919 WO1989005141A1 (en) | 1987-12-10 | 1988-09-12 | Anti-retroviral drug |
| DE8888907791T DE3879688T2 (en) | 1987-12-10 | 1988-09-12 | ANTI-RETROVIRAL MEDICINAL PRODUCT. |
| KR1019890701470A KR920003577B1 (en) | 1987-12-10 | 1988-09-12 | Anti-retroviral drug |
| AT88907791T ATE87204T1 (en) | 1987-12-10 | 1988-09-12 | ANTI-RETROVIRAL DRUG. |
| EP88907791A EP0348509B1 (en) | 1987-12-10 | 1988-09-12 | Anti-retroviral drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62321518A JPH01163122A (en) | 1987-12-21 | 1987-12-21 | Anti-retrovirus agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01163122A JPH01163122A (en) | 1989-06-27 |
| JPH0551567B2 true JPH0551567B2 (en) | 1993-08-03 |
Family
ID=18133462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62321518A Granted JPH01163122A (en) | 1987-12-10 | 1987-12-21 | Anti-retrovirus agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01163122A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH037224A (en) * | 1989-03-08 | 1991-01-14 | Tsumura & Co | Anti-retrovirus agent |
-
1987
- 1987-12-21 JP JP62321518A patent/JPH01163122A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01163122A (en) | 1989-06-27 |
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