CN102083441B - 硝呋替莫用于治疗贾第虫病的应用 - Google Patents
硝呋替莫用于治疗贾第虫病的应用 Download PDFInfo
- Publication number
- CN102083441B CN102083441B CN2009801255081A CN200980125508A CN102083441B CN 102083441 B CN102083441 B CN 102083441B CN 2009801255081 A CN2009801255081 A CN 2009801255081A CN 200980125508 A CN200980125508 A CN 200980125508A CN 102083441 B CN102083441 B CN 102083441B
- Authority
- CN
- China
- Prior art keywords
- nifurtimox
- treatment
- cyst
- active substance
- phenol
- 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
- ARFHIAQFJWUCFH-IZZDOVSWSA-N Nifurtimox Chemical compound CC1CS(=O)(=O)CCN1\N=C\C1=CC=C([N+]([O-])=O)O1 ARFHIAQFJWUCFH-IZZDOVSWSA-N 0.000 title claims abstract description 31
- 229960002644 nifurtimox Drugs 0.000 title claims abstract description 31
- 201000006592 giardiasis Diseases 0.000 title abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 33
- 241000224467 Giardia intestinalis Species 0.000 claims description 26
- 229940085435 giardia lamblia Drugs 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 241000282472 Canis lupus familiaris Species 0.000 abstract description 17
- 241000282326 Felis catus Species 0.000 abstract description 7
- 206010011732 Cyst Diseases 0.000 description 29
- 208000031513 cyst Diseases 0.000 description 29
- 239000013543 active substance Substances 0.000 description 26
- -1 nitro free radical Chemical class 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 19
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 17
- 230000003115 biocidal effect Effects 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 230000029142 excretion Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 108010002156 Depsipeptides Proteins 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000000507 anthelmentic effect Effects 0.000 description 8
- 239000003651 drinking water Substances 0.000 description 8
- 235000020188 drinking water Nutrition 0.000 description 8
- 210000003608 fece Anatomy 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000001717 pathogenic effect Effects 0.000 description 7
- 239000000645 desinfectant Substances 0.000 description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000012207 quantitative assay Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 241000224466 Giardia Species 0.000 description 5
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 229960005473 fenbendazole Drugs 0.000 description 5
- IRHZVMHXVHSMKB-UHFFFAOYSA-N fenbendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1SC1=CC=CC=C1 IRHZVMHXVHSMKB-UHFFFAOYSA-N 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 5
- 244000045947 parasite Species 0.000 description 5
- 239000002423 protozoacide Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 210000003812 trophozoite Anatomy 0.000 description 5
- HKHXLHGVIHQKMK-UHFFFAOYSA-N 2-chloro-m-cresol Chemical compound CC1=CC=CC(O)=C1Cl HKHXLHGVIHQKMK-UHFFFAOYSA-N 0.000 description 4
- YJNUXGPXJFAUQJ-LYWANRAQSA-N PF1022A Chemical compound C([C@@H]1C(=O)N(C)[C@H](C(O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](CC=2C=CC=CC=2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O1)=O)CC(C)C)C1=CC=CC=C1 YJNUXGPXJFAUQJ-LYWANRAQSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 210000001198 duodenum Anatomy 0.000 description 4
- 210000003495 flagella Anatomy 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 244000052769 pathogen Species 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OSDLLIBGSJNGJE-UHFFFAOYSA-N 4-chloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 208000000291 Nematode infections Diseases 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- 241000282898 Sus scrofa Species 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 239000003139 biocide Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 235000013681 dietary sucrose Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- ZMQMTKVVAMWKNY-YSXLEBCMSA-N emodepside Chemical compound C([C@@H]1C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@H](C(O[C@H](CC=2C=CC(=CC=2)N2CCOCC2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O1)=O)CC(C)C)C(C=C1)=CC=C1N1CCOCC1 ZMQMTKVVAMWKNY-YSXLEBCMSA-N 0.000 description 3
- 108010056417 emodepside Proteins 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000008389 polyethoxylated castor oil Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- IYOLBFFHPZOQGW-UHFFFAOYSA-N 2,4-dichloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=C(Cl)C(C)=C1Cl IYOLBFFHPZOQGW-UHFFFAOYSA-N 0.000 description 2
- NKTOLZVEWDHZMU-UHFFFAOYSA-N 2,5-xylenol Chemical compound CC1=CC=C(C)C(O)=C1 NKTOLZVEWDHZMU-UHFFFAOYSA-N 0.000 description 2
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 description 2
- NCKMMSIFQUPKCK-UHFFFAOYSA-N 2-benzyl-4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1CC1=CC=CC=C1 NCKMMSIFQUPKCK-UHFFFAOYSA-N 0.000 description 2
- 229940061334 2-phenylphenol Drugs 0.000 description 2
- YCOXTKKNXUZSKD-UHFFFAOYSA-N 3,4-xylenol Chemical compound CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 2
- HXDOZKJGKXYMEW-UHFFFAOYSA-N 4-ethylphenol Chemical compound CCC1=CC=C(O)C=C1 HXDOZKJGKXYMEW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 241000224460 Diplomonadida Species 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000222712 Kinetoplastida Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- 206010048685 Oral infection Diseases 0.000 description 2
- 108010004210 PF 1022A Proteins 0.000 description 2
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 2
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 210000000588 acetabulum Anatomy 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229960002669 albendazole Drugs 0.000 description 2
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 230000001165 anti-coccidial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960001575 emodepside Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000003410 keratolytic agent Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000005645 nematicide Substances 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- 235000010292 orthophenyl phenol Nutrition 0.000 description 2
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 2
- 229960001914 paromomycin Drugs 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 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 2
- 244000062645 predators Species 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 1
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- MOOFYEJFXBSZGE-QJUDHZBZSA-N 1,2-bis[(z)-(4-chlorophenyl)methylideneamino]guanidine Chemical compound C=1C=C(Cl)C=CC=1\C=N/N=C(/N)N\N=C/C1=CC=C(Cl)C=C1 MOOFYEJFXBSZGE-QJUDHZBZSA-N 0.000 description 1
- QPVRKFOKCKORDP-UHFFFAOYSA-N 1,3-dimethylcyclohexa-2,4-dien-1-ol Chemical compound CC1=CC(C)(O)CC=C1 QPVRKFOKCKORDP-UHFFFAOYSA-N 0.000 description 1
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-UHFFFAOYSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 1
- IYXUFNCIWJHFBR-UHFFFAOYSA-N 2-benzyl-4-chloro-3-methylphenol Chemical compound CC1=C(Cl)C=CC(O)=C1CC1=CC=CC=C1 IYXUFNCIWJHFBR-UHFFFAOYSA-N 0.000 description 1
- CDMGNVWZXRKJNS-UHFFFAOYSA-N 2-benzylphenol Chemical compound OC1=CC=CC=C1CC1=CC=CC=C1 CDMGNVWZXRKJNS-UHFFFAOYSA-N 0.000 description 1
- ZXPLGLMEXWSLCX-UHFFFAOYSA-N 2-chloro-3,5-dimethylphenol Chemical compound CC1=CC(C)=C(Cl)C(O)=C1 ZXPLGLMEXWSLCX-UHFFFAOYSA-N 0.000 description 1
- UNRRZPJVYQDQPL-UHFFFAOYSA-N 2-chloro-3-ethylphenol Chemical compound CCC1=CC=CC(O)=C1Cl UNRRZPJVYQDQPL-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-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
- KPFPEXKMIDAQNO-UHFFFAOYSA-N 3-chloro-2-phenylphenol Chemical compound OC1=CC=CC(Cl)=C1C1=CC=CC=C1 KPFPEXKMIDAQNO-UHFFFAOYSA-N 0.000 description 1
- KLSLBUSXWBJMEC-UHFFFAOYSA-N 4-Propylphenol Chemical compound CCCC1=CC=C(O)C=C1 KLSLBUSXWBJMEC-UHFFFAOYSA-N 0.000 description 1
- XRUHXAQEOJDPEG-UHFFFAOYSA-N 4-chloro-2-cyclohexylphenol Chemical compound OC1=CC=C(Cl)C=C1C1CCCCC1 XRUHXAQEOJDPEG-UHFFFAOYSA-N 0.000 description 1
- UUBASQRIVIRMIQ-UHFFFAOYSA-N 4-chloro-2-hexylphenol Chemical compound CCCCCCC1=CC(Cl)=CC=C1O UUBASQRIVIRMIQ-UHFFFAOYSA-N 0.000 description 1
- FJTSMZVGLUHJJK-UHFFFAOYSA-N 4-chloro-2-pentylphenol Chemical compound CCCCCC1=CC(Cl)=CC=C1O FJTSMZVGLUHJJK-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- CYYZDBDROVLTJU-UHFFFAOYSA-N 4-n-Butylphenol Chemical compound CCCCC1=CC=C(O)C=C1 CYYZDBDROVLTJU-UHFFFAOYSA-N 0.000 description 1
- SZWBRVPZWJYIHI-UHFFFAOYSA-N 4-n-Hexylphenol Chemical compound CCCCCCC1=CC=C(O)C=C1 SZWBRVPZWJYIHI-UHFFFAOYSA-N 0.000 description 1
- ZNPSUQQXTRRSBM-UHFFFAOYSA-N 4-n-Pentylphenol Chemical compound CCCCCC1=CC=C(O)C=C1 ZNPSUQQXTRRSBM-UHFFFAOYSA-N 0.000 description 1
- NMARPFMJVCXSAV-UHFFFAOYSA-N 5-[(3,5-diethoxy-4-pyrrol-1-ylphenyl)methyl]pyrimidine-2,4-diamine Chemical compound C=1C(OCC)=C(N2C=CC=C2)C(OCC)=CC=1CC1=CN=C(N)N=C1N NMARPFMJVCXSAV-UHFFFAOYSA-N 0.000 description 1
- 150000004958 5-nitroimidazoles Chemical class 0.000 description 1
- 208000000230 African Trypanosomiasis Diseases 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241001465677 Ancylostomatoidea Species 0.000 description 1
- 241000238421 Arthropoda Species 0.000 description 1
- RMXMVSZBZSDZJT-UHFFFAOYSA-N C(C)(C)C=1C=CC=C(C1)O.C1=C(C)C=CC(C(C)C)=C1O Chemical compound C(C)(C)C=1C=CC=C(C1)O.C1=C(C)C=CC(C(C)C)=C1O RMXMVSZBZSDZJT-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 0 CCC(**)NN*#CC*=C(C)N=O Chemical compound CCC(**)NN*#CC*=C(C)N=O 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000499489 Castor canadensis Species 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010012741 Diarrhoea haemorrhagic Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- NTAFJUSDNOSFFY-UHFFFAOYSA-N Ipronidazole Chemical group CC(C)C1=NC=C([N+]([O-])=O)N1C NTAFJUSDNOSFFY-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 235000011779 Menyanthes trifoliata Nutrition 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010037075 Protozoal infections Diseases 0.000 description 1
- 241000217239 Schizotrypanum Species 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001572 anti-trichomonad Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 244000144987 brood Species 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 229960005443 chloroxylenol Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960002227 clindamycin Drugs 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
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 206010013864 duodenitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950011561 epiroprim Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- LRMHFDNWKCSEQU-UHFFFAOYSA-N ethoxyethane;phenol Chemical compound CCOCC.OC1=CC=CC=C1 LRMHFDNWKCSEQU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940063190 flagyl Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- 229960001625 furazolidone Drugs 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 210000004837 gut-associated lymphoid tissue Anatomy 0.000 description 1
- 208000035861 hematochezia Diseases 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229950000107 ipronidazole Drugs 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000901 mepacrine Drugs 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- JUUCSAKZQUXQQB-UHFFFAOYSA-N n'-(4-aminophenyl)-n,n-dimethylethanimidamide Chemical compound CN(C)C(C)=NC1=CC=C(N)C=C1 JUUCSAKZQUXQQB-UHFFFAOYSA-N 0.000 description 1
- 229960002480 nitazoxanide Drugs 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229960002957 praziquantel Drugs 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229960004591 robenidine Drugs 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
- 238000004062 sedimentation Methods 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 229960000973 sulfadimethoxine Drugs 0.000 description 1
- 229960002135 sulfadimidine Drugs 0.000 description 1
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 208000009920 trichuriasis Diseases 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 150000003739 xylenols Chemical class 0.000 description 1
- 206010048282 zoonosis Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/15—Depsipeptides; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fodder In General (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Catching Or Destruction (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本发明涉及硝呋替莫用于治疗贾第虫病的应用，特别是在狗和猫中。
Description
技术领域
本发明涉及硝呋替莫用于治疗贾第虫病（Giardiose）的应用，特别是在狗和猫中。
背景技术
已知硝基杂环化合物对于原生动物疾病的效力(1)。
原生动物包括基础结构是真核细胞的单核有机体。但是，更具体的分类学显示了各系、纲、属和种的产地、形态学和生物化学新陈代谢方面的巨大差异。这就是根据它们的目标和有效成分，为什么化学物质一般不能同等良好地作用于所有原生动物，而只能作用于特定的几组原生动物(2，3，4)。
迄今为止，仅描述了硝呋替莫具有抗锥虫属的原生动物种，例如布氏锥虫和克氏锥虫的效力(5)。锥虫具有起源于基体(“毛基体”)的鞭毛，与基体相连，产生波形膜。在原生动物系统学中，具有该基本形态学类型的寄生虫属于动基体目。锥虫主要在血浆中生长，通过吸血节肢动物传播。这些病原体导致人的查加斯病(“锥虫病”)。硝呋替莫是现在几乎唯一的对这些病原体具有活性的化合物。该活性可能是基于对酶Trypanothione还原酶(一种特殊的锥虫酶)的抑制。这种酶在其他原生动物病原体中是不存在的。
硝呋替莫抗毛滴虫的活性在平行的专利申请文档中进行了描述。
贾第虫病是一种由贾第虫属的有鞭毛的单细胞寄生虫导致的感染性疾病。该属属于双滴虫目。最重要的代表是兰伯贾第虫(Giardia lamblia)(例如，肠贾第虫、十二指肠贾第虫)。阳性狗和猫样本的百分比，在全世界范围最高达50%，在中欧为2-7%。感染导致持续腹泻，并在一些情况下会由于十二指肠和空肠的炎症而导致粪便带血，特别是在最大半岁的非常幼小的动物中更是如此。慢性疾病可以导致当下生长延缓(6)。
已经描述了贾第虫-分离物中超过7种遗传型(A-G)。遗传型A + B是感染人的，也可以发生在猫、狗、河狸、羊、小牛、马、猪和猴子中。这就是为什么这种疾病被认为是“动物传染病”：人会通过被污染的饮用水而被狗和猫的胞囊感染。贾第虫感染是世界范围内导致人类中由所谓的“饮水感染的疾病爆发”(waterborn outbreaks)最常见的致病因子(7)。
一般是通过口腔途径，通过被污染的饮用水或感染的粪便通过胞囊的形式感染的。在消化道中，所谓滋养体是从胞囊中孵化出来的。滋养体的测定是11-17 x 7-11 µm，包含2个细胞核和8个鞭毛(鞭毛)。与其他类型的有鞭毛寄生虫不同，贾第虫滋养体不会在细胞内渗透到上皮细胞中。滋养体具有基节臼，借助这些基节臼它们可以把自己固定在人、猴、猪、狗和猫的消化道腔的外侧，在那里它们分裂繁殖。大量的攻击会阻断并改变消化道的吸收表面，在一些情况下会导致带血性腹泻。在盲肠中会再生成胞囊，并在首次感染后潜伏5-16天，通过粪便再次排泄出来。胞囊可以排泄4-5周的时间，并在数周时间保持感染(8，9)。
动基体目的重大形态学和生物化学差异在于：双滴虫目具有8个鞭毛和两个细胞核，但没有线粒体，也没有高尔基复合体，并且已知在生命周期中没有细胞内阶段。与锥虫相反，贾第虫的表面蛋白没有GPI锚(10)。
在狗和猫中，当前推荐的是用剂量为12.5-22 mg/kg体重的甲硝唑(Clont®，Flagyl®，Elyzol®)每天给药2次治疗5日(11)。甲硝唑和其他5-硝基咪唑是由丙酮酸-铁氧化还原蛋白-氧化还原酶活化的，形成了游离的硝基自由基，然后作用于寄生虫DNA的新陈代谢。这就是为什么异丙硝唑(Ipropan®，126 mg/l饮用水，经7日)和替硝唑(Fasigyn® ，44 mg/kg体重，经3日)也适合狗的贾第虫病的治疗的原因(12，13)。
苯并咪唑类中推荐的物质是甲苯达唑、阿苯达唑或芬苯达唑(口服3日)。苯并咪唑类通过与ß-微管素的亚单元结合而干扰微管蛋白的聚合。微管蛋白是寄生虫重要的细胞骨架成分，以特殊的方式稳定滋养体的基节臼。
用于人区段的物质包括抗生素(例如巴龙霉素，25-35 mg/kg/日，每日3次给药，7-10日)、米帕林和呋喃唑酮(100 mg t.i.d.，7日长)或硝唑尼特(500 mg b.i.d.，达3日) (14)。
很长时间以来，很多这些类型的活性物质都已经用于治疗贾第虫病，而对于大多数都可以检测出发生耐药性，并被证明会导致治疗中的失败。因此，研发新的活性物质和治疗概念是一种必需的(15)。
发明内容
令人惊奇地，我们现在已经发现，硝呋替莫具有抗贾第虫类的活性。该活性是迄今尚未有人描述过的。该活性直接作用于消化道致病阶段并预防胞囊形成。
因此，本发明涉及：
硝呋替莫在制备用于治疗由贾第虫类导致的疾病的药物中的应用。
硝呋替莫是式(I)的化合物：
任选，使用以常用的药学可接受盐的形式也是适当的。还任选使用该活性物质的水合物或其他溶剂化物，或者任选，使用它们的盐的水合物或其他溶剂化物也是同样适当的。
该应用可以是预防性和治疗性的。该活性直接作用于病原体的不同阶段；特别地，硝呋替莫作用于消化道的致病阶段并预防胞囊形成。
特别重要的贾第虫类是兰伯贾第虫(syn.肠贾第虫(Giardia intestinalis)、十二指肠贾第虫(Giardia duodenalis))、牛贾第虫(Giardia bovis)和山羊贾第虫(Giardia caprae)。这里所列的种类常互相同义使用，它们几乎不显示宿主特异性。
根据本发明所治疗的是动物(肉食动物和野生动物)，优选哺乳动物，诸如例如马、猪、兔，特别是狗或猫。
根据一个实施方案，优选治疗的哺乳动物是治疗野生动物，特别是肉食动物(狗、猫)。
人也适合治疗，因为人会通过被污染的饮用水而感染动物病原性的贾第虫类。
贾第虫病主要发现于幼小动物中，优选是3-10周龄的动物中，并导致严重的腹泻和减少的体重增加。
活性物质直接使用或以适当制剂的形式经肠内、胃肠外、经皮途径使用。
肠内施用活性物质是指，例如以粉末剂、栓剂、片剂、胶囊剂、锭剂、饮料、颗粒剂、灌服剂、大丸剂、含药饲料或饮用水的形式口服发挥作用。经皮施用是指，例如以浸没(浸-浸)、喷雾(喷雾)、沐浴、洗涤、涂覆(倾倒于上面和点于上面)以及拂扫的形式发挥作用。胃肠外施用是指例如以注射剂(肌内、皮下、静脉内、腹膜内)或通过植入剂的形式发挥作用。
适当的制剂是：
溶液，例如注射用溶液、口服溶液、稀释后口服给药的浓缩液、用于皮肤上或体腔内的溶液、浸液制剂、凝胶剂；
口服或经皮施用以及注射用乳剂和混悬剂；半固体制剂；
其中活性物质掺入软膏基质或水包油或油包水乳剂基质中的制剂；
固体制剂，例如粉末、预混合剂或浓缩剂、颗粒剂、丸剂、片剂、大丸剂、胶囊剂；气雾剂和吸入剂，包含活性物质的一定形状的物品。
注射用溶液是例如静脉内、肌内和皮下施用的。
口服溶液是直接施用的。浓缩剂在预先已经稀释至使用浓度后口服的。
用于皮肤的溶液是滴、涂、擦、溅、喷或通过浸没(浸-浸)、沐浴或洗涤用于皮肤上的。
凝胶剂应用于或涂于皮肤上或引入到体腔内。
涂覆制剂是倾倒或点到皮肤的限定区域上，其中活性物质渗透过皮肤，并系统性作用或分配于身体表面。
乳剂是油包水型或水包油型，可以口服、经皮或作为注射剂使用。
混悬剂可以口服、经皮或作为注射剂使用。
半固体制剂可以口服或经皮施用。它们与上述混悬剂和乳剂的不同仅在于它们更高的粘度。
为制备固体制剂，将活性物质与适当的载体混合，任选加入佐剂，并以所需要的形式。
根据本发明特别优选的是口服施用，片剂是常用口服使用形式中特别优选的。
所有上述的药物剂型、所使用的添加剂和佐剂以及这些药物剂型的制备基本上是技术人员已知的。
该活性物质可以与协同增效剂或与其他活性物质组合存在。所述的其他活性物质是：
抗球虫药例如罗贝胍或安普洛铵，在一些情况下与叶酸拮抗剂(例如乙胺嘧啶、依匹普林、甲氧苄啶)组合；抗生素诸如例如克林霉素、巴龙霉素或螺旋霉素；磺胺类药物诸如例如磺胺地索辛、磺胺二甲嘧啶、磺胺嘧啶；驱虫药诸如例如环缩酚肽(例如Emodepsid、PF1022A)、脒衍生物(三苯双脒、阿米泰尔、Bay d 9216)、吡喹酮或苯甲酸苄酯。
为得到长期的治疗效果，推荐有规律地消毒来作为动物保养程序的一部分。
驱虫药，特别是环辛缩酚肽例如PF1022A或Emodepsid适合控制人和动物的线虫感染 (16)。这样，胃肠道(也包括狗)中所有经济上重要的线虫都被破坏。同时，已知在非治疗动物的情况下，免疫应答(GALT = 肠相关淋巴样组织)用于抗蠕虫(17)。这称作免疫系统的Th2应答。在非感染的情况下，免疫应答通常是平衡的，即，用于抗原生动物、病毒和细菌的Th2应答的拮抗方式——称作Th1应答，与Th2应答一样高。
如果所述动物例如狗中存在线虫感染例如十二指肠虫、蛔虫或鞭虫感染，那么该平衡就会受到不利的影响，结果是在消化道中有例如由贾第虫类导致的显著的原生动物感染。如果现在通过适当的驱虫药克服线虫感染，那么通过Th1应答作用于这些原生动物就能间接增强对贾第虫类的防御。在硝呋替莫和驱虫药的组合中，现在硝呋替莫能显示对贾第感染的更好控制，因为后者部分包含在Th1应答的结果中，其中作为线虫控制的结果，间接增强了所述Th1应答，即消化道中寄生虫的数目已经减少了。
根据优选的实施方案，硝呋替莫与驱虫药联合使用。
优选使用的驱虫药是24-元环缩酚肽(Cyclodepsipeptide)(环辛缩酚肽类(Cyclooctadepsipeptide))。作为这些可以提及如下：
式(IIa)的化合物
其中
Z 代表氢、N-吗啉基、NH2、单-或二甲基氨基。
此外，可以提及下式(IIb)的化合物：
其中
R1，R2，R3，R4彼此独立地代表氢、C1-C10-烷基或芳基，特别是苯基，它们任选被羟基、C1-C10-烷氧基或卤素取代。
通式(IIb)的化合物是已知的，并可以通过EP-A-382 173，DE-A 4 317 432，DE-A 4 317 457，DE-A 4 317 458，EP-A-634 408，EP-A-718 293，EP-A-872 481，EP-A-685 469，EP-A-626 375，EP-A-664 297，EP-A-669 343，EP-A-787 141，EP-A-865 498，EP-A-903 347中所述的方法获得。
具有24个环原子的环缩酚肽也包括通式(IIc)的化合物，
其中
R1a，R2a，R11a和R12a彼此独立地代表C1-8-烷基、C1-8-卤代烷基、C3-6-环烷基、芳烷基、芳基，
R3a，R5a，R7a，R9a彼此独立地代表氢或者直链或支链C1-8-烷基，各基团任选可以被羟基、C1-4-烷氧基、羧基、
、羧酰胺、、咪唑基、吲哚基、胍基、-SH或C1-4-烷硫基取代，此外还代表芳基或芳烷基，它们分别可以被卤素、羟基、C1-4-烷基，C1-4-烷氧基取代，
R4a，R6a，R8a，R10a彼此独立地代表氢、直链C1-5-烷基、C2-6-链烯基、C3-7-环烷基，它们各自可以任选被羟基、C1-4-烷氧基、羧基、羧酰胺、咪唑基、吲哚基、胍基、SH或C1-4-烷硫基取代，此外还代表芳基或芳烷基，它们分别可以被卤素、羟基、C1-4-烷基，C1-4-烷氧基取代，以及它们的旋光异构体和外消旋体。
优选的式(IIc)化合物是那些化合物，其中
R1a，R2a，R11a和R12a彼此独立地代表甲基、乙基、丙基、异丙基、正-、仲-、叔-丁基或苯基，它们各自任选被卤素、C1-4-烷基、OH、C1-4-烷氧基取代，此外还代表苄基或苯基乙基，它们各自可以任选被所述适用于苯基的残基取代；
R3a-R10a
具有如上所述的含义。
特别优选的式(IIc)化合物是那些化合物，其中
R1a，R2a，R11a和R12a彼此独立地代表甲基、乙基、丙基、异丙基或正-、仲-、叔-丁基，
R3a，R5a，R7a，R9a代表氢、直链或支链C1-8-烷基，特别是甲基、乙基、丙基、异丙基、正-、仲-、叔-丁基，它们各自可以任选被C1-4-烷氧基特别是甲氧基、乙氧基，咪唑基、吲哚基或C1-4-烷硫基特别是甲硫基、乙硫基取代，此外还代表苯基、苄基或苯乙基，它们各自可以任选被卤素，特别是氯取代。
R4a，R6a，R8a，R10a彼此独立地代表氢、甲基、乙基、正丙基、正丁基、乙烯基、环己基，它们各自可以任选被甲氧基、乙氧基、咪唑基、吲哚基、甲硫基、乙硫基取代，此外还代表异丙基、仲丁基，此外还代表任选被卤素取代的苯基、苄基或苯基乙基。
式(IIc)的化合物也可以通过EP-A-382 173，DE-A 4 317 432，DE-A 4 317 457，DE-A 4 317 458，EP-A-634 408，EP-A-718 293，EP-A-872 481，EP-A-685 469，EP-A-626 375，EP-A-664 297，EP-A-669 343，EP-A-787 141，EP-A-865 498，EP-A-903 347中所述的方法获得。
所述非常特别优选的缩酚肽是由EP-OS 382 173已知的化合物PF 1022；它是其中两个取代基Z都代表氢的式(IIa)的化合物。因此PF 1022具有下式(IId)：
其他优选的缩酚肽是由PCT申请WO 93/19053中已知的化合物，它们是式(IIa)的化合物，
其中
Z代表N-吗啉基、NH2、单-或二甲基氨基。
这些化合物中非常特别优选的是缩酚肽Emodepside (PF 1022-221)。这是其中两个残基Z都代表吗啉基残基的式(IIa)的化合物。INN Emodepside代表具有下列系统名称的化合物：环[(R)-乳酰基-N-甲基-L-亮氨酰基-(R)-3-(对吗啉代苯基)乳酰基-N-甲基-L-亮氨酰基-(R)-乳酰基-N-甲基-L-亮氨酰基-(R)-3-(对吗啉代苯基)乳酰基-N-甲基-L-亮氨酰基。在WO 93/19053中描述了Emodepside，并且其具有下式：
根据它们的结构，上述适合组合的活性物质可以以立体异构体形式或作为立体异构体混合物存在，例如作为对映体或外消旋体。根据本发明可以使用立体异构体混合物和纯立体异构体。
此外，任选使用下列物质：活性物质与药学可接受的酸或碱的盐，特别是活性物质或它们的盐的溶剂化物，特别是水合物。
当硝呋替莫和第二活性物质特别是环缩酚肽组合使用时，可以分别或交错使用。在该情况下，硝呋替莫和第二活性物质各自配制成分开的药物。
同时使用也是可行的。根据适合该情况的使用形式，该组合物的活性物质配制在一个药剂中。
随时可用的制剂通常包含浓度为10 ppm-20%重量，优选0.1-10%重量的各个所述活性物质。
使用前稀释的制剂包含浓度为0.5-90%重量，优选5-50%重量的各个所述活性物质。在用于按计量加入到饮用水中的浓缩溶液中，各个所述活性物质以例如0.5-20%重量，优选1-15%重量，特别优选2-10%重量的浓度存在。
一般而言，为达到有效的结果，每天每kg体重施用量为约0.05-约400 mg，优选0.1-200 mg的活性物质被证明是有利的。
在与其他抗球虫药、抗生素或驱虫药的混合物中，本发明的活性物质可以1比0.01-50至最高1比1-50的比例存在。
该活性物质也可以与动物的饲料或饮用水一起施用。
饲料和食物包含0.005-1000 ppm，优选0.05-500 ppm的活性物质，并与适当的可食用物质合用。
这样的饲料和食物可以用于治疗和预防目的。
消毒剂可以用于补充用硝呋替莫的治疗。消毒剂用于给治疗期间动物(或人)所在的场所消毒。消毒剂优选通过破坏排泄出的胞囊形式来消除寄生虫的耐受阶段，因此防止了治疗结束后的再感染。因此，消毒剂可以在用硝呋替莫治疗前使用；但是，通常，最好是与硝呋替莫治疗的同时或者至少在硝呋替莫治疗完成之前使用。
消毒剂为例如基于杀生物性苯酚类和/或苯酚衍生物的那些。杀生物性苯酚类可以理解为是指具有游离OH基并具有杀生物活性的苯酚化合物。这些苯酚还可以具有环取代基诸如例如卤素(特别是氯)、C1-6-烷基、C3-6-环烷基、苯基、氯苯基、苄基和/或氯苄基。
非氯化杀生物性苯酚是例如：2-甲基苯酚、3-甲基苯酚、4-甲基苯酚、4-乙基苯酚、2,4-二甲基苯酚、2,5-二甲基苯酚、3,4-二甲基苯酚、2,6-二甲基苯酚、4-正丙基苯酚、4-正丁基苯酚、4-正戊基苯酚、4-正己基苯酚、麝香草酚(5-甲基-2-异丙基苯酚)、2-苯基苯酚、4-苯基苯酚、2-苄基苯酚。优选使用的非氯化杀生物性苯酚是2-苯基苯酚。
氯化杀生物性苯酚是例如：4-氯-3-甲基苯酚(PCMC，对氯-间甲酚)、4-氯-3-乙基苯酚、2-正戊基-4-氯苯酚、2-正己基-4-氯苯酚、2-环己基-4-氯苯酚、4-氯-3,5-二甲酚(PCMX，对氯-间二甲酚)、2,4-二氯-3,5-二甲酚(DCMX，二氯-对二甲酚)、4-氯-2-苯基苯酚、2-苄基-4-氯苯酚、苄基-4-氯-间甲酚，4-氯苄基二氯-间甲酚。优选的氯化杀生物性苯酚是2-苄基-4-氯苯酚、4-氯-3,5-二甲酚、2, 4-二氯-3,5-二甲酚，特别是4-氯-3-甲基苯酚。
在本发明的全文中，苯酚衍生物应当理解为其中OH基衍生化的苯酚衍生的化合物，因此它们不包含游离OH基。它们优选是苯酚醚，特别是具有1-6个碳原子的脂族醇的那些。作为优选的例子，可以提及的是苯氧基乙醇。
优选使用在WO 2007/009606中所述的消毒剂，包含杀生物剂和角质层分离剂。在WO 2007/009606中详述了适当的杀生物剂或杀生物剂的组合与适当的角质层分离剂，将该文献作为明确的参考。
具体实施方式
实施例
制剂例
实施例
1 (
液体制剂
)
：
在100 ml的混合比为1:10的甘油甲醛/甘油聚乙二醇蓖麻油酸酯(Cremophor® EL)/水中具有下列药物的混悬液：
● 500 mg 硝呋替莫
● 1000 mg 硝呋替莫
实施例
2 (
液体制剂
)
：
在100 ml的混合比为1 ：5的Cremophor® EL/水中具有下列药物的混悬液
● 500 mg 硝呋替莫
● 1000 mg 硝呋替莫
实施例
3 (
固体制剂
)
将下述用量的活性物质以粉末形式填充到明胶胶囊中：
● 250 mg 硝呋替莫
实施例
4 (
片剂
)
硝呋替莫片剂是已知的，可以作为药物例如以Lampit®的商品名从市场上购买。
生物学实验例
实施例
1
用50 000个十二指肠贾第虫胞囊口服感染10-11周龄的幼小小猎犬，所述猎犬在感染前11日已经搬入动物中心。用于感染的胞囊是在蔗糖梯度辅助下从排泄贾第虫胞囊的狗的粪便中得到的，在4℃下在Bacto-Casitone 培养基中贮存不超过2周。从感染后的第10日起，将幼犬保持于分开的笼子中以收集各个体的每日总粪便。在治疗前4日(第-3至0日)进行胞囊排泄的定量测定，将幼犬随机分为两组，用于考察胞囊排泄。在第0日，用口服剂量50 mg/kg的硝呋替莫 (Lampit®)治疗治疗组的7只幼犬1次，同时对照组的6只犬保持不治疗。在治疗后的第1至第8日继续进行胞囊排泄的定量测定。
结果：用下式计算活性：
单次给药硝呋替莫后所计算的活性是90.4% (见表1)。
方法：用Hewlett (18)的改进版来进行胞囊排泄的定量测定：将4 g的粪便溶于100 ml的水中，过筛并使其沉降。将沉积物施用于1 M蔗糖梯度(比重1.13)，离心后在蔗糖-水-分离层浓缩胞囊，用吸量管吸出胞囊。在离心后的洗涤步骤后，将沉淀中的胞囊计数。然后，在显微镜下计数沉淀的等份试样(Aliquot)，计算每g粪便的胞囊数。
表1：用硝呋替莫治疗前和后的贾第虫胞囊排泄
T-3至T-1：治疗前的各日
T0：治疗日
T1至T8：治疗后的各日
实施例
2
在研究开始前用50 000个十二指肠贾第虫胞囊口服感染11-15周龄的幼小小猎犬，所述猎犬在感染前已经搬入动物中心至少2周。用于感染的胞囊是在蔗糖梯度辅助下从排泄贾第虫胞囊的狗的粪便中得到的，并在4℃下在Bacto-Casitone 培养基中贮存不超过2周。在该研究中包括排泄贾第虫胞囊的18只幼犬，将它们保持于分开的笼子中以收集各个体的每日总粪便。如实验145.717进行胞囊排泄的定量测定，改进在于在Fuchs-Rosenthal血细胞计数器辅助下在显微镜下计数沉淀的等份试样。在治疗前4日(第-3至0日)进行胞囊排泄的定量测定，将幼犬随机分为三组，用于考察胞囊排泄。连续三日(第0，1和2日)，在早晨用口服剂量50 mg/kg的硝呋替莫 (Lampit®)治疗治疗组1的6只幼犬，同时在该三天的早晨用口服剂量50 mg/kg的芬苯达唑(芬苯达唑片剂)治疗治疗组2的6只犬。对照组的6只犬保持不治疗。在治疗后的第1至第8日继续进行胞囊排泄的定量测定。
结果：所计算的硝呋替莫的活性是98.6%，而芬苯达唑的活性是48.3% (见表2)。
表2：与芬苯达唑治疗相比，用硝呋替莫治疗前和后贾第虫胞囊的排泄
T-3至T-1：治疗前的各日
T0，T1，T2：治疗日
T3-T8：治疗后的各日
参考文献
Claims (2)
1.硝呋替莫在制备用于治疗由贾第虫类导致的疾病的药物中的应用。
2.根据权利要求1的应用，其用于治疗由兰伯贾第虫导致的疾病。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102008031284.3 | 2008-07-02 | ||
| DE102008031284A DE102008031284A1 (de) | 2008-07-02 | 2008-07-02 | Neue Bekämpfungsmöglichkeit der Giardiose |
| PCT/EP2009/004475 WO2010000399A1 (de) | 2008-07-02 | 2009-06-20 | Verwendung von nifurtimox zur behandlung der giardiose |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102083441A CN102083441A (zh) | 2011-06-01 |
| CN102083441B true CN102083441B (zh) | 2013-07-24 |
Family
ID=41077987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801255081A Expired - Fee Related CN102083441B (zh) | 2008-07-02 | 2009-06-20 | 硝呋替莫用于治疗贾第虫病的应用 |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US8440612B2 (zh) |
| EP (1) | EP2310018B1 (zh) |
| JP (1) | JP5627579B2 (zh) |
| KR (1) | KR101720805B1 (zh) |
| CN (1) | CN102083441B (zh) |
| AR (1) | AR072425A1 (zh) |
| AU (1) | AU2009266125B2 (zh) |
| BR (1) | BRPI0913889B1 (zh) |
| CA (1) | CA2729730C (zh) |
| CL (2) | CL2010001577A1 (zh) |
| CO (1) | CO6321270A2 (zh) |
| CR (1) | CR20110022A (zh) |
| DE (1) | DE102008031284A1 (zh) |
| DK (1) | DK2310018T3 (zh) |
| DO (1) | DOP2010000405A (zh) |
| EC (1) | ECSP10010720A (zh) |
| ES (1) | ES2444581T3 (zh) |
| HK (1) | HK1158113A1 (zh) |
| IL (1) | IL209698A (zh) |
| MX (1) | MX2010014446A (zh) |
| MY (1) | MY157007A (zh) |
| NI (1) | NI201100008A (zh) |
| NZ (1) | NZ590276A (zh) |
| PE (1) | PE20110283A1 (zh) |
| PL (1) | PL2310018T3 (zh) |
| RU (1) | RU2538713C9 (zh) |
| SV (1) | SV2011003785A (zh) |
| UA (1) | UA103328C2 (zh) |
| WO (1) | WO2010000399A1 (zh) |
| ZA (1) | ZA201009225B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9173898B2 (en) * | 2010-10-12 | 2015-11-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods of treating giardiasis |
| RS62130B1 (sr) | 2015-05-20 | 2021-08-31 | Boehringer Ingelheim Animal Health Usa Inc | Antihelmintička depsipeptidna jedinjenja |
| KR102427124B1 (ko) | 2015-12-28 | 2022-07-28 | 뵈링거 잉겔하임 애니멀 헬스 유에스에이 인코포레이티드 | 구충성 뎁시펩티드 화합물 |
| AU2017361099A1 (en) | 2016-11-16 | 2019-06-06 | Boehringer Ingelheim Animal Health USA Inc. | Anthelmintic depsipeptide compounds |
| EP3750527A1 (en) * | 2019-06-13 | 2020-12-16 | Bayer AG | Stable tablet formulation of nifurtimox and process for producing the same |
| CN114377018B (zh) * | 2020-10-21 | 2024-02-06 | 中国医学科学院药物研究所 | 硝呋莫司在制备抗流感病毒药物中的应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3262930A (en) * | 1962-11-23 | 1966-07-26 | Bayer Ag | Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same |
| CN1046940A (zh) * | 1989-02-07 | 1990-11-14 | 明治制菓株式会社 | Pf1022物质、其制备方法及含该物质的驱虫组合物 |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH081908B2 (ja) * | 1987-07-22 | 1996-01-10 | 三菱電機株式会社 | 超格子半導体素子 |
| WO1993019053A1 (fr) | 1992-03-17 | 1993-09-30 | Fujisawa Pharmaceutical Co., Ltd. | Derive de depsipeptide, production et utilisation |
| DE4317458A1 (de) | 1992-06-11 | 1993-12-16 | Bayer Ag | Verwendung von cyclischen Depsipeptiden mit 18 Ringatomen zur Bekämpfung von Endoparasiten, neue cyclische Depsipeptide mit 18 Ringatomen und Verfahren zu ihrer Herstellung |
| CN1073560C (zh) | 1993-02-19 | 2001-10-24 | 明治制果株式会社 | 环缩酚酸肽pf1022衍生物 |
| DE4317432A1 (de) | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptide mit endoparasitizider Wirkung |
| DE4317457A1 (de) | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptide mit endoparasitizider Wirkung |
| JP3263947B2 (ja) | 1993-09-06 | 2002-03-11 | 藤沢薬品工業株式会社 | 環状デプシペプチド化合物 |
| DE4401389A1 (de) | 1994-01-19 | 1995-07-20 | Bayer Ag | Verwendung von cyclischen Depsipeptiden mit 12 Ringatomen zur Bekämpfung von Endoparasiten, neue cyclische Depsipeptide mit 12 Ringatomen und Verfahren zu ihrer Herstellung |
| DE4406025A1 (de) | 1994-02-24 | 1995-08-31 | Bayer Ag | Milchsäure-haltige cyclische Depsipeptide mit 18 Ringatomen als endoparasitizide Mittel und Verfahren zu ihrer Herstellung |
| RU2074038C1 (ru) * | 1994-06-16 | 1997-02-27 | Товарищество с ограниченной ответственностью Предприятие "ТЕПАРК" | Способ изготовления полых металлических емкостей |
| DE4437198A1 (de) | 1994-10-18 | 1996-04-25 | Bayer Ag | Verfahren zur Sulfonylierung, Sulfenylierung und Phosphorylierung von cyclischen Depsipeptiden |
| ES2322678T3 (es) | 1995-06-30 | 2009-06-24 | Astellas Pharma Inc. | Derivado de depsipeptido, procedimiento para su produccion y nuevo intermedio del mismo. |
| PL186168B1 (pl) | 1995-09-22 | 2003-11-28 | Bayer Ag | Nowe pochodne cyklodepsipeptydowej substancji PF1022 i kompozycje przeciwrobacze je zawierające |
| DE19545639A1 (de) | 1995-12-07 | 1997-06-12 | Bayer Ag | Verfahren zur Herstellung von substituierten Arylmilchsäure-haltigen Cyclodepsipeptiden mit 24 Ringatomen |
| US6503881B2 (en) * | 1996-08-21 | 2003-01-07 | Micrologix Biotech Inc. | Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics |
| US5874630A (en) * | 1998-01-06 | 1999-02-23 | Occidental Chemical Corporation | Synthesis of mercaptans from alcohols |
| US6133228A (en) * | 1998-05-28 | 2000-10-17 | Firmenich Sa | Slow release of fragrant compounds in perfumery using 2-benzoyl benzoates, 2-alkanoyl benzoates or α-keto esters |
| DE19828047A1 (de) * | 1998-06-24 | 1999-12-30 | Bayer Ag | Substituierte Cyclooctadepsipeptide |
| MX2007005570A (es) * | 2004-11-12 | 2007-07-09 | Celgene Corp | Metodos y composiciones que usan compuestos inmunomoduladores para el tratamiento y manejo de padecimientos parasiticos. |
| DE102005033496A1 (de) | 2005-07-19 | 2007-01-25 | Bayer Healthcare Ag | Desinfektionsmittel |
-
2008
- 2008-07-02 DE DE102008031284A patent/DE102008031284A1/de not_active Withdrawn
-
2009
- 2009-06-20 CN CN2009801255081A patent/CN102083441B/zh not_active Expired - Fee Related
- 2009-06-20 RU RU2011103475/15A patent/RU2538713C9/ru not_active IP Right Cessation
- 2009-06-20 PE PE2010001201A patent/PE20110283A1/es not_active Application Discontinuation
- 2009-06-20 NZ NZ590276A patent/NZ590276A/xx not_active IP Right Cessation
- 2009-06-20 BR BRPI0913889A patent/BRPI0913889B1/pt not_active IP Right Cessation
- 2009-06-20 MX MX2010014446A patent/MX2010014446A/es active IP Right Grant
- 2009-06-20 JP JP2011515179A patent/JP5627579B2/ja not_active Expired - Fee Related
- 2009-06-20 US US13/000,715 patent/US8440612B2/en not_active Expired - Fee Related
- 2009-06-20 DK DK09772099.9T patent/DK2310018T3/da active
- 2009-06-20 ES ES09772099.9T patent/ES2444581T3/es active Active
- 2009-06-20 MY MYPI2010006319A patent/MY157007A/en unknown
- 2009-06-20 CA CA2729730A patent/CA2729730C/en not_active Expired - Fee Related
- 2009-06-20 PL PL09772099T patent/PL2310018T3/pl unknown
- 2009-06-20 AU AU2009266125A patent/AU2009266125B2/en not_active Ceased
- 2009-06-20 KR KR1020117002111A patent/KR101720805B1/ko not_active Expired - Fee Related
- 2009-06-20 EP EP09772099.9A patent/EP2310018B1/de not_active Not-in-force
- 2009-06-20 WO PCT/EP2009/004475 patent/WO2010000399A1/de active Application Filing
- 2009-06-20 UA UAA201101135A patent/UA103328C2/uk unknown
- 2009-06-30 AR ARP090102439A patent/AR072425A1/es not_active Application Discontinuation
-
2010
- 2010-12-01 IL IL209698A patent/IL209698A/en active IP Right Grant
- 2010-12-22 ZA ZA2010/09225A patent/ZA201009225B/en unknown
- 2010-12-27 DO DO2010000405A patent/DOP2010000405A/es unknown
- 2010-12-27 CO CO10162857A patent/CO6321270A2/es active IP Right Grant
- 2010-12-27 EC EC2010010720A patent/ECSP10010720A/es unknown
- 2010-12-27 CL CL2010001577A patent/CL2010001577A1/es unknown
-
2011
- 2011-01-03 SV SV2011003785A patent/SV2011003785A/es active IP Right Grant
- 2011-01-05 NI NI201100008A patent/NI201100008A/es unknown
- 2011-01-11 CR CR20110022A patent/CR20110022A/es unknown
- 2011-11-25 HK HK11112838.8A patent/HK1158113A1/xx not_active IP Right Cessation
-
2013
- 2013-03-15 CL CL2013000709A patent/CL2013000709A1/es unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3262930A (en) * | 1962-11-23 | 1966-07-26 | Bayer Ag | Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same |
| CN1046940A (zh) * | 1989-02-07 | 1990-11-14 | 明治制菓株式会社 | Pf1022物质、其制备方法及含该物质的驱虫组合物 |
Non-Patent Citations (5)
| Title |
|---|
| Angel A Escobedo et al..Giardiasis:a pharmacotherapy review.《Expert Opinion on Pharmacotherapy》.2007,第8卷(第12期), * |
| Harder A.et al..Mechanisms of action of emodepsite.《Parasitology Research》.2005,第97卷 * |
| McKellar Quintin A.et al..Veterinary anthelmintics: old and new.《TRENDS in Parasitology》.2004,第20卷(第10期), * |
| Nitroheterocyclic drugs with broad spectrum activity;Raether W.et al.;《Parasitology Research》;20030226;第90卷;S19–S39 * |
| Raether W.et al..Nitroheterocyclic drugs with broad spectrum activity.《Parasitology Research》.2003,第90卷 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102083441B (zh) | 硝呋替莫用于治疗贾第虫病的应用 | |
| Zhang et al. | Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1 | |
| ES2264806T3 (es) | Tratamiento del dolor. | |
| US20040063769A1 (en) | Combinations of drugs (e.g., a benzimidazole and pentamidine) for the treatment of neoplastic disorders | |
| WO2012146933A1 (en) | Cyprodinil for use in medicine | |
| RU2636234C2 (ru) | Прокаспазная комбинированная терапия при глиобластоме | |
| US20200123127A1 (en) | Removal of senescence-associated macrophages | |
| Armson et al. | A review of chemotherapeutic approaches to the treatment of cryptosporidiosis | |
| CN102083440B (zh) | 硝呋替莫用于制备治疗由组织滴虫引起的疾病的药物的用途 | |
| ES2475266T3 (es) | Combinación coccidicida para uso veterinario | |
| Bleyen et al. | Non-curative, but prophylactic effects of paromomycin in Histomonas meleagridis-infected turkeys and its effect on performance in non-infected turkeys | |
| US20150094294A1 (en) | Compounds and methods for treating malaria | |
| EP3326629A1 (en) | Veterinary compositions and the uses thereof for preventing and/or treating parasitic infections in non-human mammals | |
| US20190030113A1 (en) | Dipeptidyl aldehydes for the treatment and/or prevention of parasitic diseases | |
| Leibowitz et al. | Treatment development for systemic Tetrahymena sp. infection in guppies, Poecilia reticulata Peters | |
| CN116549455A (zh) | PLK4抑制剂Centrinone在制备治疗包虫病药物中的应用 | |
| Abaza | Spotlights on new publications | |
| RU2275200C2 (ru) | Препарат против нематодозов животных |
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: 1158113 Country of ref document: HK |
|
| ASS | Succession or assignment of patent right |
Owner name: BAYER INTELLECTUAL PROPERTY GMBH Free format text: FORMER OWNER: BAYER ANIMAL HEALTH GMBH Effective date: 20130123 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20130123 Address after: German Monheim Applicant after: Bayer Pharma Aktiengesellschaft Address before: Germany Leverkusen Applicant before: Bayer Animal Health GmbH |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1158113 Country of ref document: HK |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130724 Termination date: 20200620 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |