CN104968358B - 涉及粘液素的疾病治疗 - Google Patents
涉及粘液素的疾病治疗 Download PDFInfo
- Publication number
- CN104968358B CN104968358B CN201380070938.4A CN201380070938A CN104968358B CN 104968358 B CN104968358 B CN 104968358B CN 201380070938 A CN201380070938 A CN 201380070938A CN 104968358 B CN104968358 B CN 104968358B
- Authority
- CN
- China
- Prior art keywords
- cancer
- mucin
- pharmaceutically acceptable
- composition
- solvate
- 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
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 32
- 201000010099 disease Diseases 0.000 title abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000012453 solvate Substances 0.000 claims abstract description 23
- 239000003172 expectorant agent Substances 0.000 claims abstract description 21
- 229940066491 mucolytics Drugs 0.000 claims abstract description 21
- 108010004032 Bromelains Proteins 0.000 claims abstract description 15
- 239000004365 Protease Substances 0.000 claims abstract description 15
- 235000019835 bromelain Nutrition 0.000 claims abstract description 15
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 48
- 239000003814 drug Substances 0.000 claims description 41
- 201000011510 cancer Diseases 0.000 claims description 20
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 17
- 239000002246 antineoplastic agent Substances 0.000 claims description 15
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 14
- 229940127089 cytotoxic agent Drugs 0.000 claims description 13
- 229960002949 fluorouracil Drugs 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 8
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 7
- 229960004316 cisplatin Drugs 0.000 claims description 7
- 229960004679 doxorubicin Drugs 0.000 claims description 7
- 229960000485 methotrexate Drugs 0.000 claims description 7
- 229960005277 gemcitabine Drugs 0.000 claims description 6
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 5
- 229930012538 Paclitaxel Natural products 0.000 claims description 5
- 229960004308 acetylcysteine Drugs 0.000 claims description 5
- 229960004397 cyclophosphamide Drugs 0.000 claims description 5
- 229960003668 docetaxel Drugs 0.000 claims description 5
- 229960001592 paclitaxel Drugs 0.000 claims description 5
- 210000004303 peritoneum Anatomy 0.000 claims description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 229960000684 cytarabine Drugs 0.000 claims description 4
- 229960005420 etoposide Drugs 0.000 claims description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 4
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 3
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 3
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 3
- 108010006654 Bleomycin Proteins 0.000 claims description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 3
- 108010092160 Dactinomycin Proteins 0.000 claims description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 3
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 claims description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 3
- 229930183665 actinomycin Natural products 0.000 claims description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 3
- 229960002756 azacitidine Drugs 0.000 claims description 3
- 229960002170 azathioprine Drugs 0.000 claims description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 3
- 229960001561 bleomycin Drugs 0.000 claims description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 3
- 229960001467 bortezomib Drugs 0.000 claims description 3
- 229960004117 capecitabine Drugs 0.000 claims description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
- 229960004630 chlorambucil Drugs 0.000 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 3
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 3
- 229950005454 doxifluridine Drugs 0.000 claims description 3
- 229960001904 epirubicin Drugs 0.000 claims description 3
- 229930013356 epothilone Natural products 0.000 claims description 3
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 3
- 229960000908 idarubicin Drugs 0.000 claims description 3
- 229960002411 imatinib Drugs 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 3
- 229960001428 mercaptopurine Drugs 0.000 claims description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001156 mitoxantrone Drugs 0.000 claims description 3
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 claims description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 3
- 229960001756 oxaliplatin Drugs 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 229960005079 pemetrexed Drugs 0.000 claims description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229930002330 retinoic acid Natural products 0.000 claims description 3
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 claims description 3
- 239000011885 synergistic combination Substances 0.000 claims description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 3
- 229960001278 teniposide Drugs 0.000 claims description 3
- 229960003087 tioguanine Drugs 0.000 claims description 3
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000653 valrubicin Drugs 0.000 claims description 3
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 3
- 229960003048 vinblastine Drugs 0.000 claims description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- 229960004355 vindesine Drugs 0.000 claims description 3
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 3
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 3
- 229960002066 vinorelbine Drugs 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000021780 appendiceal neoplasm Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 229940121672 Glycosylation inhibitor Drugs 0.000 claims 2
- 230000004988 N-glycosylation Effects 0.000 claims 2
- 229940122394 Sialyl transferase inhibitor Drugs 0.000 claims 2
- 239000003242 anti bacterial agent Substances 0.000 claims 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 2
- 230000000975 bioactive effect Effects 0.000 claims 2
- 230000003115 biocidal effect Effects 0.000 claims 2
- 206010073360 Appendix cancer Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 21
- 239000000651 prodrug Substances 0.000 abstract description 21
- 208000007536 Thrombosis Diseases 0.000 abstract description 16
- 230000003248 secreting effect Effects 0.000 abstract description 7
- 108010063954 Mucins Proteins 0.000 description 70
- 102000015728 Mucins Human genes 0.000 description 70
- 239000003795 chemical substances by application Substances 0.000 description 27
- -1 N-acetylcysteln Chemical compound 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- 230000000694 effects Effects 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 19
- 230000037396 body weight Effects 0.000 description 19
- 238000000034 method Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 239000002671 adjuvant Substances 0.000 description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 239000002207 metabolite Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 10
- 102100034256 Mucin-1 Human genes 0.000 description 10
- 239000003085 diluting agent Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000000969 carrier Substances 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 229940051875 mucins Drugs 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 description 8
- 210000003097 mucus Anatomy 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 235000019483 Peanut oil Nutrition 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 239000006210 lotion Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000000312 peanut oil Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 235000013772 propylene glycol Nutrition 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000416162 Astragalus gummifer Species 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920001615 Tragacanth Polymers 0.000 description 4
- 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 4
- 210000000481 breast Anatomy 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 4
- 239000006196 drop Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 229940057995 liquid paraffin Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 201000003883 Cystic fibrosis Diseases 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000010378 Pulmonary Embolism Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000003899 bactericide agent Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940044683 chemotherapy drug Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 229960001031 glucose Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 201000002818 limb ischemia Diseases 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000013610 patient sample Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 244000099147 Ananas comosus Species 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102000009016 Cholera Toxin Human genes 0.000 description 2
- 108010049048 Cholera Toxin Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 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 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010009066 Gastric Mucins Proteins 0.000 description 2
- 102000009338 Gastric Mucins Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 description 2
- 102100034263 Mucin-2 Human genes 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 230000004989 O-glycosylation Effects 0.000 description 2
- 206010033078 Otitis media Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000019485 Safflower oil Nutrition 0.000 description 2
- 206010059685 Sputum retention Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940023476 agar Drugs 0.000 description 2
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000003240 coconut oil Substances 0.000 description 2
- 235000019864 coconut oil Nutrition 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- PCKPVGOLPKLUHR-UHFFFAOYSA-N indoxyl Chemical group C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- 229920001206 natural gum Polymers 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000009268 pathologic speech processing Effects 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 208000032207 progressive 1 supranuclear palsy Diseases 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 235000005713 safflower oil Nutrition 0.000 description 2
- 239000003813 safflower oil Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- ZJMMJMHTXLTBFW-REOHCLBHSA-N (2r)-2-(carboxyamino)-3-sulfanylpropanoic acid Chemical compound OC(=O)N[C@@H](CS)C(O)=O ZJMMJMHTXLTBFW-REOHCLBHSA-N 0.000 description 1
- YLCSLYZPLGQZJS-VDQHJUMDSA-N (2r)-2-acetamido-3-sulfanylpropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(=O)N[C@@H](CS)C(O)=O.NCCCC[C@H](N)C(O)=O YLCSLYZPLGQZJS-VDQHJUMDSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ROWKJAVDOGWPAT-UHFFFAOYSA-N Acetoin Chemical compound CC(O)C(C)=O ROWKJAVDOGWPAT-UHFFFAOYSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- OLCWFLWEHWLBTO-HSZRJFAPSA-N BMS-214662 Chemical compound C=1C=CSC=1S(=O)(=O)N([C@@H](C1)CC=2C=CC=CC=2)CC2=CC(C#N)=CC=C2N1CC1=CN=CN1 OLCWFLWEHWLBTO-HSZRJFAPSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 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
- 241000282326 Felis catus Species 0.000 description 1
- 102000004878 Gelsolin Human genes 0.000 description 1
- 108090001064 Gelsolin Proteins 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 244000148687 Glycosmis pentaphylla Species 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000623900 Homo sapiens Mucin-13 Proteins 0.000 description 1
- 101000972286 Homo sapiens Mucin-4 Proteins 0.000 description 1
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 description 1
- 101000972276 Homo sapiens Mucin-5B Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 102100023124 Mucin-13 Human genes 0.000 description 1
- 102100022693 Mucin-4 Human genes 0.000 description 1
- 102100022496 Mucin-5AC Human genes 0.000 description 1
- 102100022494 Mucin-5B Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Chemical class 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 101710097834 Thiol protease Proteins 0.000 description 1
- UGPMCIBIHRSCBV-XNBOLLIBSA-N Thymosin beta 4 Chemical compound N([C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(C)=O UGPMCIBIHRSCBV-XNBOLLIBSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229940024546 aluminum hydroxide gel 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
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000003501 anti-edematous effect Effects 0.000 description 1
- 230000001567 anti-fibrinolytic effect Effects 0.000 description 1
- 230000003091 anti-genotoxic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940079919 digestives enzyme preparation Drugs 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 229960003262 erdosteine Drugs 0.000 description 1
- QGFORSXNKQLDNO-UHFFFAOYSA-N erdosteine Chemical compound OC(=O)CSCC(=O)NC1CCSC1=O QGFORSXNKQLDNO-UHFFFAOYSA-N 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000021312 gluten 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
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 102000035122 glycosylated proteins Human genes 0.000 description 1
- 108091005608 glycosylated proteins Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000002085 hemarthrosis Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000010687 lubricating oil Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 230000004682 mucosal barrier function Effects 0.000 description 1
- 230000003843 mucus production Effects 0.000 description 1
- 125000001446 muramyl group Chemical group N[C@@H](C=O)[C@@H](O[C@@H](C(=O)*)C)[C@H](O)[C@H](O)CO 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response 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
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 1
- 238000003210 sulforhodamine B staining Methods 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 239000003734 thymidylate synthase inhibitor Substances 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- 125000001493 tyrosinyl group Chemical class [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 229910052725 zinc Chemical class 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/22—Cysteine endopeptidases (3.4.22)
- C12Y304/22032—Stem bromelain (3.4.22.32)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/22—Cysteine endopeptidases (3.4.22)
- C12Y304/22033—Fruit bromelain (3.4.22.33), i.e. juice bromelain
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Zoology (AREA)
- Marine Sciences & Fisheries (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Inorganic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
本发明涉及组合物,其包含菠萝蛋白酶中所含的一种或多种化合物或其盐、溶剂化物或前药,和一种或多种粘液溶解剂或其盐、溶剂化物或前药,所述组合物用于治疗涉及粘液素的疾病,尤其是粘液素分泌癌症,或治疗涉及血凝块(血栓)的疾病。
Description
发明领域
大体上,本发明涉及用于治疗涉及粘液素的疾病,特别是用于治疗粘液素分泌癌症的组合物。此外,本发明的组合物涉及用于治疗涉及血凝块(血栓)的疾病的组合物。
发明背景
粘液素为由包括胃肠道、肺、肾脏、卵巢、乳腺和胰腺的上皮组织所产生的高分子量、高度糖基化的蛋白家族。在正常生理条件下,粘液素对上皮组织发挥保护作用。然而,粘液素也可涉及到疾病状态 (如囊胞性纤维症)。无法咳出粘液可导致包括呼吸疾病和胰腺病理的疾病。
粘液素高水平的表达与诊断有癌症的患者的新陈代谢和不良临床结果有关。正常情况下,上皮细胞的表面上粘液素的合成受到高度调节,但是在肿瘤中存在粘液素的产量增加,部分原因是人粘液素 (MUC1)的表达增加。粘液的表达和组成在上皮来源的癌症中改变,并且已知粘液的产生为一种负性预后因子。组成粘液屏障的分泌和跨膜粘液素被认为促进肿瘤发展。
腹膜假粘液瘤(“PMP”)是以腹部被由在阑尾中最常出现的肿瘤所产生的粘液素逐渐填满为特征的综合症。这种腹部填满引起重大的不适,并且在严重的情况下可导致患者的死亡。通常,进行重复的减量手术。然而,这具有发病率增高并且甚至死亡的后果。
血凝块(血栓)的形成是一些严重疾病的基础,如心肌梗塞、冠状动脉疾病、中风、大块肺栓塞和急性肢体缺血。患上血栓形成的可能性也可能在装有支架的患者中增加。
抗凝血药物(如肝素和华法令)可以用来治疗血栓形成。然而,这种抗凝血剂仅抑制血栓的形成或抑制既有血栓的生长。
因此,有需要治疗涉及粘液素的疾病并且为患涉及粘液素疾病的患者提供更好的结果。此外,有需要治疗涉及血栓的病症并且为患涉及血栓病症的患者提供更好的结果。目前意外地发现,包含菠萝蛋白酶中的一种或多种化合物和至少一种粘液溶解剂的组合物在降低粘液素的产生和帮助从体内去除粘液素中是有效的,对肿瘤生长具有直接的抑制效果,并且可增加化疗药物的细胞毒性。
此外,意外地发现,包含菠萝蛋白酶中的一种或多种化合物和至少一种粘液溶解剂的组合物在血栓的溶解中是有效的。
发明概述
根据本发明的第一方面,提供了组合物,其包含:
菠萝蛋白酶中的一种或多种化合物,或其代谢物、药学上可接受的盐、溶剂化物或前药;和
至少一种粘液溶解剂,或其代谢物、药学上可接受的盐、溶剂化物或前药。
菠萝蛋白酶(“Br”)为菠萝植物(Ananas Comosus)的提取物,其据信包含多种硫醇蛋白酶并且已知具有体内和体外的蛋白水解活性,和抗水肿、抗炎、抗血栓形成和纤维蛋白溶解活性。Br中的活性因子在生物化学方面仅具有一部分的表征。由于口服给药后它的疗效、它的安全性和缺乏不良副作用,Br具有作为治疗药物在患者之中好的依从性。
Br中的一种或多种化合物也被理解为Br中包含的全部化合物。
粘液溶解剂为溶解粘液的物质并且通常用来帮助减轻呼吸困难。这样的粘液溶解剂的实例包括N-乙酰半胱氨酸(“NAC”)、nacystelyn, 巯基乙基磺酸、羧甲半胱氨酸、N-acystelyn、厄多司坦、阿法链道酶、凝溶胶蛋白、胸腺素β4、葡聚糖和肝素。
NAC也是抗氧化剂和抗遗传毒性剂,并且在人中,主要对呼吸疾病,很好地建立了长期高剂量的安全性。优选地,本发明的粘液溶解剂为NAC。
根据第一方面的组合物,其中组合为协同组合。
根据本发明的第二方面,提供了根据本发明的第一方面所述的组合物,还包含至少一种其他生物活性化合物,或其代谢物、药学上可接受的盐、溶剂化物或前药。
化疗剂为癌症的治疗中使用的药剂。这样的化疗剂的实例包括放线菌素、全反式维甲酸、阿扎胞苷、咪唑硫嘌呤、博来霉素、硼替佐米、顺羧酸铂、卡培他滨、顺铂、苯丁酸氮芥、环磷酰胺、阿糖胞苷、柔毛霉素、多西他赛、去氧氟尿苷、阿霉素、表阿霉素、埃博霉素、依托泊苷、氟尿嘧啶(5-FU)、吉西他滨、羟基脲、去甲氧基柔红霉素、伊马替尼、二氯甲基二乙胺、巯嘌呤、甲氨蝶呤、米托蒽醌、奥沙利铂、紫杉醇、培美曲塞、替尼泊苷、硫鸟嘌呤、戊柔比星、长春花碱、长春新碱、长春地辛、长春瑞滨和5FU。
优选地,本发明的化疗剂为顺铂。
根据第二方面所述的组合物,其中组合为协同组合。
根据本发明的第三方面,提供了菠萝蛋白酶中的一种或多种化合物,根据本发明的第一方面的至少一种粘液溶解剂,和任选的根据本发明的第二方面的至少一种生物活性化合物的组合制剂,用于在治疗中同时、分别或依次使用。
根据本发明的第四方面,提供作为药物使用的根据本发明的第一或第二方面所述的组合物。
根据本发明的第五方面,提供用于治疗一种或多种涉及粘液素的疾病或用于治疗一种或多种涉及血栓的疾病的根据本发明的第一或第二方面的组合物。
根据本发明的第六方面,提供本发明的第一或第二方面的组合物在制备用于治疗一种或多种涉及粘液素的疾病或用于治疗一种或多种涉及血栓的疾病的药物中的用途。
根据本发明的第七方面,提供了治疗一种或多种涉及粘液素的疾病或治疗一种或多种涉及血栓的疾病的方法,所述方法包括对有需要的患者施用治疗有效量的本发明的第一或第二方面所述的组合物。
本发明的组合物可以用来治疗任何涉及粘液素的疾病,如癌症、腹膜假粘液瘤、胶耳、囊胞性纤维症、痰滞留、胸腔感染和与胆/胰腺支架有关的粘液,并且可以用来治疗任何涉及血栓的疾病,如血友病、心肌梗塞、冠状动脉疾病、中风、大块肺栓塞和急性肢体缺血、支架相关的血栓形成或关节血肿。
本发明的组合物可以用来治疗任何粘液素分泌癌症,如肺癌、乳腺癌、结肠直肠癌、甲状腺癌、前列腺癌、胃癌、胰腺癌、阑尾的癌症和卵巢癌。
本发明的组合物可以用来治疗腺癌。特别地,腺癌可为印戒细胞癌。
根据本发明的第八方面,提供了使用根据本发明的第一或第二方面所述的组合物从有需要的患者中去除粘液素的方法。
粘液素家族包括含有串联重复序列结构的蛋白质,所述结构具有高比例的脯氨酸、苏氨酸和丝氨酸(其构成PTS结构域)。粘液素由 PTS结构域通过在苏氨酸和丝氨酸残基上的GalNAC O-连接以及其它连接的广泛糖基化来进一步界定。人粘液素(MUC)家族由命名MUC1-MUC2的成员组成,它们已经被亚分类为分泌型和跨膜型。
分泌型粘液素(例如,MUC2、MUC5AC、MUC5B和MUC6) 可形成物理屏障,其作为粘液胶质为衬于呼吸道和胃肠道以及形成如肝脏、乳腺、胰腺和肾脏的器官的导管表面的上皮细胞提供保护。
跨膜型粘液素(例如,MUC1、MUC4、MUC13和MUC16)具有单跨膜区,并且有助于保护的粘液胶质穿过它们O-糖基化的串联重复序列的胞外区域,形成杆状结构,从细胞表面延伸大于100nm 并且超出多糖蛋白质复合物~10nm。
MUC1在高比例的癌和某些血液学恶性肿瘤中异常表达,使 MUC1过表达成为人类癌症中多种常见改变之一。
已经发现具有不同粘液素分泌类型的HT29结肠癌的克隆对常见化疗药物5FU和甲氨蝶呤具有不同程度的抗性。在具有结肠直肠癌粘液性组织学的患者中,具有赋予对5FU的抗性的结肠免疫反应性的粘液素(大部分为MUC2)和具有赋予对甲氨蝶呤的抗性的胃部反应性的粘液素与对化疗和存活的不良应答率有关。已知粘液素阻碍5FU 针对人胰腺癌细胞生长的细胞毒性效应。因此,粘液素可作为限制化疗作用的细胞屏障。这通过以下事实被进一步证明:抑制粘液素O- 糖基化增强5FU针对胰腺癌细胞系的细胞毒性效应,但对粘液素缺陷细胞系没有这样的增强效果。
附图简述
图1显示NAC、Br以及NAC和Br的组合对PMP粘液素的作用。
图2显示用NAC和Br的组合处理后三个小时,剩余的粘液素的重量百分比。
图3显示NAC和Br的组合对软粘液素的作用。
图4-6显示在裸鼠中NAC和Br的组合的体内功效。
图7显示NAC和Br的组合对不同细胞系的体外生长的效果。
图8-10显示NAC和Br的组合对化疗的效果。
图11和12显示NAC和Br的组合对MUC1细胞系的细胞毒性化疗的效果。
定义
“卤素”表示氟、氯、溴或碘,优选氟或氯。
“烃基”表示脂肪族碳氢基团,其可以是直链的或分支的,并且在链中包含约1至约20个碳原子。优选的烃基基团在链中含有约1- 约12个碳原子。更优选的烃基基团在链中含有约1-约6个碳原子。分支表示一种或多种低级烃基基团(如甲基、乙基或丙基)附接于直链烃基链。“低级烃基”表示在链中含有约1-约6个碳原子的基团,其可以为直链的或分支的。
“芳基”,自身或作为另一取代基的一部分,表示芳香族环状碳氢基团。优选的芳基具有6-10个碳原子。术语“芳基”包括多环系以及单环系。在本发明中使用的优选的芳基包括苯基和萘基。术语“芳基”也包括部分为芳香族的稠合的环状碳氢环(即,稠合的环之一为芳香族的并且另一为非芳香族的)。部分为芳香族的示例性芳基为茚满基。
“杂芳基”,自身或作为另一取代基的一部分,表示含有5至12 个选自C、N、O和S的环原子的环状或多环基团,其中至少一种环杂原子为O、N或S,并且其中构成环的至少一个为芳香族。在本发明中使用的示例性杂芳基包括咔唑基、carbolinlyl、chromenyl、cinnolinyl、呋喃基、苯并呋喃基、苯并呋咱基、异苯并呋喃基、咪唑基、苯并咪唑基、苯并咪唑啉基、吲唑基、吲哚基、异吲哚基、吲哚啉基、indolazinyl、indynyl、恶二唑基、恶唑基、苯并恶唑基、异恶唑基、吡喃基、吡嗪基、吡唑基、苯并吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹啉基、异喹啉基、四唑基、噻唑基、异噻唑基、噻二唑基、噻吩基、苯并噻吩基、苯并噻唑基、喹喔啉基、三嗪基和三唑基、以及以上的氮氧化物。
杂芳基的一个亚组含有5个环原子。在该实施方案中的示例性杂芳基为吡唑基、吡啶基、噻唑基和咪唑基。
杂芳基的另一亚组含有6个环原子。在该实施方案中的示例性杂芳基为吡啶基和嘧啶基。
术语“杂芳基”也包括部分为芳香族的稠合的环状杂环(即,稠合环之一为芳香族并且另一为非芳香族)。部分为芳香族的示例性杂芳基为苯并二氧杂环戊烯(benzodioxol)。
当如本文所定义的杂芳基被取代时,取代基可键合到杂芳基的环碳原子上,或具有允许取代的化合价的环杂原子上(即,N、O或S)。优选地,取代基键合到环碳原子上。同样,当杂芳基被定义为本文的取代基时,连接位点可以为杂芳基的环碳原子,或在具有允许取代的化合价的环杂原子上(即,N、O或S)。优选地,连接在环碳原子上。
“烃基”或“芳基”可为未取代的或任选地被一种或多种取代基取代,取代基可以相同或不同,每个取代基独立地选自卤素、烃基、芳基、环烃基、氰基、羟基、烃氧基、硫代烃基、氨基、-NH(烃基)、 -NH(环烃基)、-N(烃基)2、羧基和-C(O)O-烃基。合适的烃基的非限制性实例包括甲基、乙基、正丙基、异丙基和叔丁基。
杂原子表示选自N、O、P和S的原子。如果需要的话,任何未指定的化合价独立地选自H、OH、羰基、正烃基、芳基或烃氧基。
“p”-“u”可以独立地选自0-20,优选0-10,更优选0-6,并且最优选0-4。
“烃氧基”表示烃基-O-基团,其中烃基如之前所描述的。合适的烃氧基基团的非限制性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基。母体部分上的键通过醚氧。
“取代的”,如在取代的烃基中,表示取代可发生在一个或多个位置,并且,除非另外说明,每个取代位点的取代基独立地选自指定的选项,表示多种取代基可同时地在不同的位点上存在。优选地,每个取代基具有如上所定义的一种或多种二级取代基。优选地,二次取代基不被进一步取代。
应被理解为本发明的组合物中所包含的每种化合物也可涉及其代谢物、药学上可接受的盐、溶剂化物或前药。
本发明的化合物的“代谢物”指新陈代谢的中间体和产物。
“药学上可接受的盐”指常规的酸加成盐或碱加成盐,其保留粘液溶解剂的生物学效果和特性,并且从合适的无毒的有机或无机酸或有机或无机碱形成。示例性的酸加成盐包括从无机酸(如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸)中得到的那些酸加成盐以及从有机酸(如对甲苯磺酸、水杨酸、甲磺酸、草酸、琥珀酸、柠檬酸、苹果酸、乳酸、富马酸等等)中得到的那些酸加成盐。示例性的碱加成盐包括从铵、钾、钠和季铵氢氧化物(例如,氢氧化四甲胺) 中得到的那些碱加成盐。药学化合物(即,药物)被化学修饰为盐对药剂化学师来说是公知的技术以获得化合物的改进的物理和化学稳定性、吸水性、流动能力和溶解性。参见,例如,H.Ansel et.al., Pharmaceutical Dosage Forms and DrugDelivery Systems(6th Ed.1995) at pp.196and 1456-1457,将其通过引用并入本文。
“药学上可接受的”,如药学上可接受的载体、赋形剂等等,指药理上可接受的并且对具体化合物所施用的个体基本上无毒的。
本文也考虑到了本发明的化合物“前药”和“溶剂化物”。前药的讨论由T.Higuchiand V.Stella,Pro-drugs as Novel Delivery Systems (1987)14of theA.C.S.Symposium Series,and in Bioreversible Carriers in Drug Design,(1987)Edward B.Roche,ed.,American Pharmaceutical Association and Pergamon Press提供。术语“前药”指经过体内转化而产生本发明的化合物的化合物(例如,药物前体)、或其代谢物、药学上可接受的盐或溶剂化物。转化可通过不同的机制发生(例如,通过代谢或化学过程)。前药用途的讨论由T.Higuchi and W.Stella, "Prodrugs as Novel DeliverySystems,"Vol.14of the A.C.S.Symposium Series,and in Bioreversible Carriers inDrug Design,ed.Edward B. Roche,American Pharmaceutical Association andPergamon Press,1987 提供。
式(I)或(Ia)的化合物可包含不对称的或手性中心,并且因此以不同的立体异构形式存在。意图使式(I)或(Ia)的化合物的全部立体异构形式以及其混合物,包括外消旋混合物,形成本发明的一部分。此外,本发明包含全部几何学和位置异构体。非对映混合物可根据它们物理化学差异、通过本领域技术人员公知的方法分成它们各自的非对映体,例如,通过色谱分析法和/或分步结晶。可通过以下方式分离对映体:通过与适当的光学活性化合物(例如,如手性醇或莫舍酸氯化物的手性助剂)反应使对映体的混合物转化为非对映的混合物,分开非对映体并且使各个非对映体转化(例如,水解)为相应的纯的对映体。对映体也可通过使用手性HPLC柱被分开。本发明的手性中心可具有由IUPAC 1974所定义的S或R构型。
术语“盐”、“溶剂化物”、“前药”等等的使用意图等同地适用于本发明化合物的对映体、立体异构体、旋转异构体、互变异构体、位置异构体、外消旋物或前药的盐、溶剂化物和前药。
本文所用术语“治疗有效量”在其含义内包括本发明中使用的药剂或组合物的无毒、但是能提供预期治疗效果的足够量。所需的确切剂量将在个体间变化,取决于如被治疗的物种、个体的年龄和一般状态、被治疗的疾病状态的严重性、被施用的具体药剂、给药的方式等等的因素。因此,不可能规定适用于全部实施方案的确切的“有效量”。然而,对于任意给定的情况,适当的“有效量”可通过本领域技术人员仅使用常规实验所确定。如本申请中所使用的,单数形式“a”、“an”、“the”包括复数形式,除非上下文另有明确的指示。
本文所用术语“包含(comprising)”指“包含(including)”。词语“包含(comprising)”的变化形式,如“包含(comprise)”和“包含(comprises)”具有相应的变化含义。因此,例如,“包含(comprising)”式(I)或(Ia)的化合物的药物组合物可仅由该化合物组成或可包括一种或多种其他成分(例如,药学上可接受的载体,赋形剂和/或稀释剂)。
本文所用术语“多个”指多于一个。在某些具体的方面或实施方案中,多个可指2、3、4、5、6、7、8、9、10、11、12、13、14、 15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、 45、46、47、48、49、50、51或更多,以及其中可衍生的任何整数和其中可衍生的任何范围。
组合物、药物和试剂盒
本发明提供了本发明的药物组合物、试剂盒和药物以及至少一种药学上可接受的载体。为了从该发明所描述的化合物制备药物组合物,惰性的、药学上可接受的载体可为固体的或液体的。固体形式的制剂包括粉末、片剂、可分散的颗粒、胶囊剂、锭剂和栓剂。粉末和片剂可包含约5-约95%的活性组分。合适的固体载体为本领域所知,例如,碳酸镁、硬脂酸镁、滑石、糖或乳糖。片剂、粉末、锭剂和胶囊剂可被用作适于口服给药的固体剂型。药学上可接受的载体和不同组合物制备方法的实例可在A.Gennaro(ed.),Remington′sPharmaceutical Sciences,18th Edition,(1990),Mack Publishing Co.,Easton,Pennsylvania中找到。
液体形式的制剂包括溶液、悬浮液和乳剂,例如,用于肠胃外注射或腹腔内给药或注射的水或水-丙二醇溶液,或加入甜味剂和乳白剂用于口服的溶液、悬浮液和乳剂。液体形式的制剂也可包括用于鼻腔给药的溶液。
适于吸入的气雾剂可包括溶液和粉末形式的固体,其可与药学上可接受的载体组合,如惰性的压缩气体,例如,氮气。还包括固体形式制剂,其意图在使用前不久被转化为用于口服或肠胃外给药的液体形式制剂。这种液体形式包括溶液、悬浮液和乳剂。
本发明的化合物也可经皮递送。经皮组合物可采取乳膏、洗液、气溶胶和/或乳剂的形式,并且可以包括在基质或贮库类型的经皮贴片中,这也是本领域中为了该目的的常规形式。
本发明的化合物也可皮下递送。
本发明的组合物和药物可包含药学上可接受的载体、佐剂、赋形剂和/或稀释剂。就与组合物或药物的其它成分相容而言,载体、稀释剂、赋形剂和佐剂必须是“可接受的”,并且对其受体一般无害。药学上可接受的载体或稀释剂的非限制性实例为去矿质的或蒸馏的水、盐溶液、基于植物的油,如花生油、红花油、橄榄油、棉花籽油、玉米油,芝麻油,如花生油、红花油、橄榄油、棉花籽油、玉米油、芝麻油、花生油或椰子油;硅油类,包括聚硅氧烷,如聚甲基硅氧烷、聚苯基硅氧烷和聚甲苯基硅氧烷;挥发性聚硅酮;矿物油如液体石蜡、软石蜡或角鲨烷;纤维素衍生物如甲基纤维素、乙基纤维素、羧甲基纤维素、羧甲基纤维素钠或羟丙基甲基纤维素;低级烷醇类,例如乙醇或异丙醇;低级芳烷醇;低级聚亚烃基二醇或低级亚烃基二醇类,例如聚乙二醇、聚丙二醇、乙二醇、丙二醇、1,3-丁二醇或甘油;脂肪酸酯如棕榈酸异丙酯、肉豆蔻酸异丙酯或油酸乙酯;聚乙烯吡咯烷酮;琼脂;黄芪胶或阿拉伯树胶和凡士林。通常,载体或载体类将组成组合物或药物重量的约10%-约99.9%。
本发明的组合物和药物可以适合于通过注射给药(例如,肠胃外的给药,包括腹膜内、皮下、肌肉或静脉注射)、通过口服给药(如胶囊剂、片剂、囊片和冶金药)、通过局部给药(例如,以药膏、乳膏或洗液的形式、或作为滴眼剂适于递送的形式)、或通过鼻腔吸入 (例如,以气溶胶的形式)的形式存在。
为了作为可注射的溶液或悬浮液进行给药,无毒的肠胃外可接受的稀释剂或载体可包括,林格式溶液、等渗盐水、磷酸盐缓冲盐水、乙醇和1,2-丙二醇。用于制备肠胃外给药的组合物和药物的方法对本领域技术人员来说是显而易见的,并且在,例如Remington′sPharmaceutical Science,15th ed.,Mack Publishing Company,Easton,Pa 中更详细地描述。
对于口服给药,合适的载体、稀释剂、赋形剂和佐剂的一些实例包括花生油、液体石蜡、羧甲基纤维素钠、甲基纤维素、藻酸钠、阿拉伯树胶、黄芪胶、右旋糖、蔗糖、山梨醇、甘露醇、明胶和卵磷脂。此外,这些口服制剂可以包含合适的增香剂和着色剂。当以胶囊剂的形式使用时,胶囊剂可以用如单硬脂酸甘油酯或甘油硬脂酸酯的化合物包被,其延迟分解。佐剂通常包括软化剂、乳化剂、增稠剂、防腐剂、杀虫剂和缓冲剂。
用于口服给药的固体形式可包含人类和兽医药学实践可接受的粘结剂、甜味剂、崩解剂、稀释剂、增香剂、包被剂、防腐剂、润滑剂和/或延时剂。合适的粘结剂包括阿拉伯树胶、明胶、玉米淀粉、黄芪胶、藻酸钠、羧甲基纤维素或聚乙二醇。合适的甜味剂包括蔗糖、乳糖、葡萄糖、天冬甜素或糖精。合适的崩解剂包括玉米淀粉、甲基纤维素、聚乙烯吡咯烷酮、瓜尔豆胶、黄原胶、皂土、藻酸或琼脂。合适的稀释剂包括乳糖、山梨醇、甘露醇、右旋糖、瓷土、纤维素、碳酸钙、硅酸钙或磷酸氢钙。合适的增香剂包括薄荷油、冬青油、樱桃、桔子或木莓香精。合适的包被剂包括丙烯酸的聚合物或共聚物和 /或甲基丙烯酸和/或它们的酯类、蜡类、脂肪醇类、玉米蛋白、虫胶或谷蛋白。合适的防腐剂包括苯甲酸钠、维生素E、α-生育酚、维生素C、苯甲酸甲酯防腐剂、对羟基苯甲酸丙酯或亚硫酸氢钠。合适的润滑油包括硬脂酸镁、硬脂酸、油酸钠、氯化钠或滑石。合适的延时剂包括单硬脂酸甘油酯或双硬脂酸甘油酯。
除以上的试剂外,用于口服给药的液体形式可包含液体载体。合适的液体载体包括水、如橄榄油、落花生油、芝麻油、葵花油、红花油、花生油、椰子油的油、液体石蜡、乙二醇、丙二醇、聚乙二醇、乙醇、丙醇、异丙醇、丙三醇、脂肪醇类、甘油三酯或其混合物。
用于口服给药的悬浮液可进一步包含分散剂和/或悬浮剂。合适的悬浮剂包括羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、藻酸钠或乙酰基乙醇。合适的分散剂包括卵磷脂、脂肪酸(如硬脂酸)的聚氧乙烯酯、聚乙二醇山梨醇的单油酸酯或双油酸酯、硬脂酸酯或月桂酸酯、聚乙二醇山梨醇的单油酸酯或双油酸酯、硬脂酸酯或月桂酸酯等等。
口服给药的制剂可包含一种或多种乳化剂。合适的乳化剂包括如上所例示的分散剂或天然树胶,如瓜尔豆胶、阿拉伯树胶或黄芪胶。
本发明的局部制剂可包含活性组分连同一种或多种可接受的载体,以及任选的任何其他治疗组分。适于局部给药的制剂包括适于通过皮肤渗透到需要治疗部位的液体或半液体药剂,如擦剂、洗剂、霜剂、药膏或糊剂,和适于眼、耳或鼻给药的滴剂。
根据本发明的滴剂可包括无菌的水性或油性溶液或悬浮液。它们可通过使活性组分溶解在杀细菌和/或杀真菌剂和/或任何其他合适的防腐剂的水溶液中制备,并且任选的包括表面活性剂。得到的溶液可通过过滤被澄清,转移到合适的容器中并灭菌。灭菌可通过高压灭菌法或维持在90℃-100℃半小时、或通过过滤实现,随后通过无菌技术转移到容器中。适于在滴剂中包含的杀细菌和杀真菌剂的实例为硝酸苯汞或醋酸苯汞(0.002%)、氯化苯甲烃铵(0.01%)和醋酸氯己定 (0.01%)。用于制备油性溶液的合适的溶剂包括丙三醇、稀释的乙醇和丙二醇。
根据本发明的洗液包括适于应用于皮肤或眼的洗液。眼部洗液可包含无菌的水溶液,其任选地含有杀菌剂并且可通过和上面所描述的那些关于制备滴剂相似的方法制备。应用于皮肤的洗液或擦剂也可包括加速干燥并且冷却皮肤的试剂,如乙醇或丙酮,和/或湿润剂,如丙三醇、或如蓖麻油或花生油的油。
根据本发明的乳霜、药膏或糊剂为用于外敷的半固体剂型的活性组分。它们可通过将活性组分以细分的或粉末的形式,单独地或在水的或非水流体中的溶液或悬浮液,与油脂的或非油脂的基料混合来制备。基料可包含烃类,如硬的、软的或液体石蜡、丙三醇、蜂蜡、金属皂;粘液;自然来源的油如杏仁、玉米、花生、蓖麻或橄榄油、羊毛脂或其衍生物,或脂肪酸如硬脂酸或油酸,连同如丙二醇或聚乙二醇的醇类。
本发明的组合物和药物可引入任何合适的表面活性剂,如阴离子、阳离子或非离子表面活性剂,如山梨酸酯或其聚乙二醇衍生物。也可包括悬浮剂,如天然树胶、纤维素衍生物或无机材料,如硅酸盐质二氧化硅以及其它组分,如羊毛脂。
本发明的组合物和药剂可以脂质体的方式施用。形成脂质体的合适的方法为本领域所知,并且关于此的具体文献可参考Prescott,(Ed), (1976),"Methods in CellBiology,Volume XIV,Academic Press,New York,N.Y.p.33et seq.,将其通过引用的方式并入本文。
补充的活性组分,如佐剂或生物应答改性剂,也可引入本发明的组合物和药物中。
任何合适的佐剂可包括在本发明的组合物和药物中。例如,可以使用基于铝的佐剂。合适的基于铝的佐剂包括,但不限于,氢氧化铝、磷酸铝和其组合。可使用基于铝的佐剂的其它具体实例在欧洲专利第 1216053号和美国专利第6372223号中所描述。其它合适的佐剂包括弗氏不完全佐剂和完全佐剂(Difco Laboratories,Detroit,Mich.);默克公司佐剂65(Merck and Company,Inc.,Rahway,N.J.)、AS-2 (SmithKline Beecham,Philadelphia,Pa.)、铝酸盐如氢氧化铝凝胶(明矾)或磷酸铝、钙、铁或锌的盐、酰化的酪氨酸的不溶悬浮液、酰化的糖、阳离子或阴离子衍生的多糖、聚磷腈、生物降解性微球、单磷酰酯A和quil A、水包油乳剂,包括欧洲专利第0399843号、美国专利第7,029,678号和PCT公布WO 2007/006939号中所描述的那些乳剂、和/或其他细胞因子,如GM-CSF或白细胞介素-2、7、或12、粒细胞-巨噬细胞克隆-刺激因子(GM-CSF)、单磷酰酯A(MPL)、霍乱毒素(CT)或它的组成亚基、热不稳定肠毒素(LT)或它的组成亚基, toll样受体配体佐剂,如脂多糖(LPS)和其衍生物(例如,单磷酰酯A和3-去酰基单磷酰酯A)、胞壁酰二肽(MDP)和呼吸道合胞体病毒(RSV)的F蛋白。
优选地,当治疗分泌粘液素的癌症时,本发明的组合物通过口服、静脉内或腹腔给药递送。
优选地,当治疗PSP时,本发明的组合物通过腹腔注射递送。
优选地,当治疗血栓时,本发明的组合物通过在血栓部位注射来递送。
本发明的另一方面为试剂盒,其包含治疗有效量的每个粘液溶解剂、菠萝蛋白酶中的一种或多种化合物、任选的一种或多种生物活性化合物、以及药学上可接受的载体、介质或稀释剂。
本发明的另一方面为试剂盒,其包含治疗有效量的每个粘液溶解剂、菠萝蛋白酶中的一种或多种化合物、任选的一种或多种生物活性化合物、以及至少一种化疗剂,其中两种或更多种组分的量导致希望的治疗效果。
本发明的试剂盒可包含组件以帮助实现本发明的方法,例如,给药装置、缓冲液和/或稀释剂。试剂盒可包括用于容纳各种组件的容器和用于使用本发明的方法的试剂盒组件的说明书。
在某些实施方案中,试剂盒可为组合式试剂盒。
在其他的实施方案中,试剂盒可为分立式试剂盒。
给药的剂量和途径
药剂、组合物和药物可通过标准的途径施用于接受体,包括,但不限于,肠胃外(例如,腹膜内、静脉内、脊柱内、皮下或肌肉内)、口服、局部或黏膜途径(例如,鼻内)。在一些实施方案中,它们可单独地或与其他另外的治疗剂联合施用于接受体。在这样的实施方案中,给药可同时或依次进行。
通常,药剂、组合物和药物可以与给药的途径和接受体的身体特性(包括健康状况)相容的方式施用,并且以这样的方式使得产生预期的效果(即,治疗上有效的,产生免疫性的和/或保护的)。例如,适当的剂量可取决于多种因素,包括,但不限于,个体的身体特性(例如,年龄、体重、性别)、药剂、组合物或药物是用作单剂还是佐剂治疗,被治疗的疾病或病患的发展(例如,病理状态),以及对本领域技术人员来说显而易见的其它因素。
当确定试剂、组合物和药物的适当剂量时的各种总体考虑描述于例如,Gennaroet al.(Eds),(1990),"Remington′s Pharmaceutical Sciences",Mack Publishing Co.,Easton,Pennsylvania,USA;和Gilman et al.,(Eds),(1990),"Goodman And Oilman′s:The Pharmacological Bases of Therapeutics",Pergamon Press。
通常,本发明的药剂、组合物或药物可施用于患者的量为约50μg- 约5mg的活性组分。特别优选的剂量为约50μg-约500μg。一般地,有效剂量预期在约0.0001mg-约1000mg活性组分/kg体重/24小时的范围内;通常,约0.001mg-约750mg/kg体重/24小时;约0.01mg-约500mg/kg体重/24小时;约0.1mg-约500mg/kg体重/24小时;约0.1mg- 约250mg/kg体重/24小时;或约1.0mg-约250mg/kg体重/24小时;更通常地,有效剂量范围预期在约1.0mg-约200mg/kg体重/24小时的范围内;约1.0mg-约100mg/kg体重/24小时;约1.0mg-约50mg/kg体重/24小时;约1.0mg-约25mg/kg体重/24小时;约5.0mg-约50mg/kg 体重/24小时;约5.0mg-约20mg/kg体重/24小时;或约5.0mg-约 15mg/kg体重/24小时。
通常,在治疗应用中,治疗可用于疾病状态或病患的持续时间。此外,对本领域技术人员来说显而易见的是各个剂量的最佳使用量和使用间隔可由被治疗疾病状态或病患的性质和程度、给药的形式、途径和部位、以及被治疗的具体个体的性质所确定。使用常规的技术可确定最佳的剂量。
在很多情况下(例如,预防性应用),本发明的药剂、组合物或药物的数次或多次给药是可取的,例如,其可施用1、2、3、4、5、 6、7、8、9、10或更多次。给药可为约1-12周的间隔,并且在某些实施方案中,约1-4周的间隔。也考虑到了周期性的重复给药。
对本领域技术人员也显而易见的是最佳的给药过程可使用常规的疗程测定试验确定。
当两种或更多种实体(例如,药剂或药物)“联合”施用于个体时,它们可以在单一组合物同时施用、或在分别的组合物同时施用、或在分别的组合物在分别的时间施用。
本发明的某些实施方案涉及多种分别剂量的药剂、组合物或药物的给药。因此,本文所描述的用于预防处理和治疗处理的方法包含对个体给予多个分别的剂量,例如,在规定的时期内。因此,在一些实施方案中,方法包括施用初始剂量,然后可以施用加强剂量。加强可用于重新接种的目的。在不同的实施方案中,药剂、组合物或药物施用至少一次、两次、三次或更多次。
药剂、组合物或药物一般地可施用有效量以实现预期目的。更具体地说,它们可施用治疗有效量,治疗有效量表示对预防目标疾病或病患的发展或减轻目标疾病或病患既有症状有效的量。有效量的确定在本领域技术人员的能力内。例如,药剂、组合物或药物的治疗有效剂量可初步地从细胞培养试验中估计。例如,剂量可在动物模型中制定以达到循环的浓度范围,其包括如在细胞培养中所确定的IC50。这样的信息可用来更精确地确定人类和其它哺乳动物个体中有用的剂量。
治疗有效剂量指预防症状的发展、改善症状和/或延长在治疗下个体的存活的药剂、组合物或药物的量。药剂、组合物和药物的毒性和治疗效能可通过细胞培养和/或实验动物的标准药学试验确定(例如,通过确定LD50(对群体中50%的致死剂量)和ED50(对群体中 50%治疗有效的剂量))。毒性和治疗效果的剂量比为治疗指数,其可用LD50和ED50的比值表示。优选呈现高治疗指数的药剂、组合物和药物。从这样的细胞培养试验和/或动物研究中获得的数据可以用来制定在动物或其他哺乳类中使用的剂量范围。这样的化合物的剂量优选地位于包括ED50而毒性很小或没有毒性的循环浓度的范围内。剂量可以在该范围内变化,取决于采用的剂型和使用的给药途径。根据个体的病患,各个医师能容易地选择确切的制剂、给药途径和剂量(参见,例如,Fingl et al.,(1975),in"The PharmacologicalBasis of Therapeutics",Ch.1p.1,将其通过引用的方式并入本文)。可以各自地调整剂量和间隔以提供足够实现和维持预期治疗效果和/或最低有效浓度(MEC)的活性药剂的血浆水平。实现MEC的需要的剂量将取决于给药的途径和其它各个特性。生物试验和/或HPLC试验可以用来确定血浆浓度。
剂量间隔也可使用MEC值确定。通常,药剂、组合物和药物可以按照方案施用,所述方案在约10%-90%的时间将血浆水平维持在MEC之上,优选30%-90%的时间并且更优选约50%-90%的时间。在使用局部给药或选择性摄取的实施方案中,药物的有效局部浓度可不与血浆浓度相关。
优选的剂量为约500-50,000mg/kg体重/每天的粘液溶解剂、或粘液溶解剂的代谢物、药学上可接受的盐、溶剂化物或前药。当施用入腹膜腔内或肿瘤自身时,优选的剂量为约2000mg/kg体重/每天,并且特别优选剂量为约2500mg/kg体重/每天的粘液溶解剂、或粘液溶解剂的代谢物、药学上可接受的盐、溶剂化物或前药。当口服施用时,优选的剂量为约10,000mg/kg体重/每天的粘液溶解剂、或粘液溶解剂的代谢物、药学上可接受的盐、溶剂化物或前药。
当施用入腹膜腔内或肿瘤本身时,优选的剂量为约10-50mg/kg 体重/天的菠萝蛋白酶中一种或多种化合物,或化合物的代谢物、药学上可接受的盐、溶剂化物或前药。当口服施用时,优选的剂量为约 500-1000mg/kg体重/天的菠萝蛋白酶中一种或多种化合物,或化合物的代谢物、药学上可接受的盐、溶剂化物或前药。
生物活性化合物或化合物的代谢物、药学上可接受的盐、溶剂化物或前药的优选剂量与MIMS中所示的(出版物"The Monthly Index of Medical Specialities")推荐剂量范围一致。
本发明的化合物还可以与以下联合使用(共同或依次施用):一种或多种抗癌治疗,如放射治疗,和/或一种或多种化疗剂,如细胞生长抑制剂、细胞毒素剂(例如,但不限于,DNA交互剂(如顺铂或阿霉素));紫杉烷类(例如,多西紫杉醇、紫杉醇);拓扑异构酶 II抑制剂(如依托泊苷);拓扑异构酶I抑制剂(如伊立替康(或CPT-11)、 camptostar、或拓扑替康);微管蛋白交互剂(如紫杉醇、多西紫杉醇或埃博毒素);激素药剂(如它莫西芬);胸苷酸合成酶抑制剂(如 5-氟尿嘧啶);抗代谢药物(如甲氨蝶呤);烷化剂(如替莫唑胺(TEMODAR(TM)来自Schering-Plough Corporation,Kenilworth,New Jersey)、环磷酰胺);法呢基蛋白转移酶抑制剂(如,SARASAR(TM)(4~ [2-[4-[(11R)-3,10-二溴-8-氯-6,11-二氢-5H-苯并[5,6]环庚酮[1,2-b]吡啶-11-基-]-1-哌啶基]-2-氧乙基]-1-哌啶甲酰胺)、或SCH 66336来自Schering-Plough Corporation,Kenilworth,New Jersey)、替吡法尼 (或R115777,来自Janssen Pharmaceuticals)、L778.123(法呢基蛋白转移酶抑制剂来源于Merck&Company,Whitehouse Station, New Jersey);BMS 214662(法呢基蛋白转移酶抑制剂来源于 Bristol-Myers Squibb Pharmaceuticals,Princeton,NewJersey);信号转导抑制剂(如,易瑞沙(来源于Astra Zeneca Pharmaceuticals,England)、特罗凯(EGFR激酶抑制剂)、EGFR抗体(例如,C225)、GLEEVEC(TM) (C-abl激酶抑制剂来源于Novartis Pharmaceuticals,East Hanover, New Jersey));干扰素,例如,内含子(来源于Schering-Plough Corporation)、Peg-内含子(来源于Schering-Plough Corporation);激素治疗组合;芳香酶组合;阿糖胞苷、阿霉素、环磷酰胺和吉西他滨。
个体
本发明的预防和治疗方法可以应用于任何合适的个体。在一些实施方案中,个体为哺乳动物个体。例如,个体可以为小鼠、大鼠、狗、猫、牛、羊、马或有社会、经济或研究重要性的其它哺乳动物。因此,个体可以为哺乳动物,例如,人类或非人类哺乳动物。
本领域技术人员应了解,在不脱离本发明广泛描述的精神和范围的情况下,可以根据在具体实施方案中所公开的本发明作出的多种变化和/或修饰。因此,所提供的实施方案在全部方面被认为是说明性的,而不是限制性的。
总结
令人意外地发现,菠萝蛋白酶中的一种或多种化合物和至少一种粘液溶解剂的组合可以用于治疗产粘液素肿瘤,在产粘液素肿瘤中,粘液素从细胞中分泌并且呈现在表面上,并且在其中呈现细胞内的粘液素小球或呈现跨膜粘液素(印戒细胞种类)。
本发明的组合可以用来治疗任何肿瘤类型的印戒细胞癌,如乳腺、结肠直肠、胃、胰腺、阑尾、卵巢和其它部位的肿瘤,从而直接地抑制肿瘤的生长或促进其它治疗,以及治疗分泌粘液肿瘤和具有MUC1、 MUC2或其它跨膜受体的肿瘤,从而直接地抑制肿瘤生长或促进其它治疗。
本发明的组合:
●显著增加产粘液素癌细胞中化疗剂的效果和细胞毒性,并且具有直接的抗肿瘤效果和对癌细胞活力和生长的抑制效果,
●明显影响粘液素的肿瘤产生,并且
●在液化肿瘤粘液素中非常有效。
对于患有PSP的患者,将本发明的组合物一起或连续地注射入腹腔中使粘液素液化,允许组织的吸出或去除,并且解决或改善患者的问题。
本发明的组合可用于溶解粘液的体内的其他情况包括胶耳、囊胞性纤维症、痰滞留、胸腔感染、胆/胰腺支架和粘液素不利地影响健康的其他情况。
此外,本发明的组合可以用于溶解血栓,并且因此用于治疗涉及血栓的疾病。优选地,本发明的组合通过注射在血栓部位来施用。通过使血栓溶解,可停止疾病进程或可降低疾病的并发症。例如,当血友病患者膝盖流血时,本发明可用来使血栓溶解。此外,本发明可用于溶解血栓的其他疾病包括心肌梗塞、冠状动脉疾病、中风、大块肺栓塞、急性肢体缺血和支架有关的血栓形成。
以下将参考具体实施例来描述本发明,实施例不应该被理解为任何方式的限定。
实施例
A.腹膜假粘液瘤
实验1(实验室)
表1显示了来自经腹膜切开的31个患者中的PMP肿瘤中的结果。表1显示了用Br和NAC单独处理是无效的。肿瘤/粘液素的样本取自腹部并且然后用300μg/ml Br、5%NAC或二者的混合物在实验室中37℃处理3个小时。测量治疗前和治疗后的粘液素肿瘤的重量。当使用Br+NAC的组合时,在16个患者样本中,存在肿瘤完全或>90%的消失,并且在每种情况下单独用Br或NAC不存在重量的降低(或非常小的降低)。
表1:用改进的酶制剂分解粘液素
实验2(实验室)
图1显示了在实验室中溶解人PMP粘液素的时间进程。又一次发现,NAC或Br的对照不具有效果,但是NAC和Br的组合在12 小时内具有最大的效果,清楚地证明了组合治疗的效果。
图2显示了用Br和NAC的组合处理3个小时剩余的粘液素的百分比和肿瘤/胶状物的物理外观之间的关系。能够看出的是,在具有软粘液素的全部17个患者样本中,粘液素溶解,然而在具有硬粘液素的6个患者样品中,只有50%观察到粘液素的减少。
实验3(实验室)
溶解所需的时间与药剂浓度的关系
图3显示了时间进程实验,其显示软粘液素被2%NAC和 300μg/mLBr的组合处理3小时完全溶解,并与2%NAC和100μg/mLBr 的组合处理6小时相比。
实验1(动物研究)
为了研究体内效果,将2g人PMP粘液素植入3只裸鼠中,并且用Br和NAC处理动物实现完全的或近乎完全的溶解(参见图4)以及用缓冲对照处理的不溶解。
实验2(动物研究)
通过以下实验进一步扩展这些发现,在另12只植入3g粘液素的大鼠中增加Br的剂量(参见图5),在处理动物中含有很少的(若有的话)残留粘液素,并且在对照中无降低(参见图6)。
在为期50天治疗中,大鼠中未观察到毒性或体重降低的证据。
B.粘液素分泌癌症
在PMP试验中印戒癌样本中的肿瘤重量的显著降低表明Br和 NAC明显地降低了含有内部粘液素(印戒)的癌的重量。也在癌症以及PMP中研究了酶组合的直接效果。
MKN 45为人胃粘液素分泌型癌细胞系。研究了NAC、Br和组合对体外生长(SRB试验,72小时培养)的效果。图7(a)显示这些结果,以对照的%表示。单独的NAC和Br不具有或有很小的效果,然而无效的NAC和Br的浓度的组合产生高达90%的生长抑制。
5F12(图7( b) )为HT29结肠直肠癌细胞系的变异系,其分泌胃型粘液素并且对5FU有抗性。又一次观察到Br和NAC之间明显的协同作用。
5M21(图7( c) )为HT29细胞系的变异系,其产生结肠类型的粘液素并且对甲氨蝶呤有抗性。再次观察到Br和NAC之间的协同作用。
这些发现表明在Br和NAC各自具有很小的效果的情况下,Br 和NAC的组合对三种癌症细胞系生长具有高度显著的抑制效果。
C.Br和NAC的组合对化疗的效果
粘液素分泌癌症的化疗抗性是常见的。图8的实验再次涉及 HT29的变异系(5M21)。Br和NAC的组合是有效的,而各自的药剂是无效的。Br和NAC和顺铂的组合产生多于Br和NAC功效的双倍,表明Br和NAC能够增加细胞毒性化疗的效果(参见图8( c) )。
MUC1(跨膜)
MUC1为具有重要调节功能的跨膜粘液素类型的糖蛋白。
研究了两种间皮瘤细胞系PET和YOU(其均具有MUC1)。这些细胞系与肿瘤细胞不同,其外部分泌粘液素或在细胞中具有粘液素 (印戒细胞)。发现单独的NAC没有作用,单独的Br产生一定生长抑制(参见图9)。NAC和Br的组合显示提高的结果,特别是在较高浓度的NAC(例如,50mM)(并且值得注意的是,单独50mM的NAC 是无效的),并且NAC和25μg/ml Br的组合以及NAC和40μg/ml Br 的组合产生80-90%的抑制(参见图10)。
这些发现表明含有MUC1(或其他跨膜糖蛋白)的癌症对Br和 NAC的联合治疗是敏感的。
Br和NAC对MUC1细胞的细胞毒性化疗的效果
研究了MUC1细胞系中Br和NAC与化疗药物的组合(参见图 11和12)。
低剂量的顺铂是无效的,Br和NAC的组合的加入使功效加倍,再次表明Br和NAC显著地增加了含有MUC1的癌细胞的细胞毒性化疗的效果。
Claims (11)
2.根据权利要求1所述的组合物,其中所述组合物为协同组合。
3.用于治疗产生粘液素的癌症或腹膜假粘液瘤的组合物,其特征在于在权利要求1所述的组合物的基础上还进一步含有至少一种其它生物活性化合物或其药学上可接受的盐或溶剂化物,其中所述生物活性化合物选自N-糖基化抑制剂、唾液酸转移酶抑制剂、多药物转运抑制剂、抗生素和抗炎剂中的任何一种。
4.根据前述权利要求中任一项所述的组合物,其中所述化疗剂选自阿霉素、氟尿嘧啶(5-FU)和吉西他滨。
5.菠萝蛋白酶,N-乙酰半胱氨酸或其药学上可接受的盐或溶剂化物,选自以下的化疗剂:放线菌素、全反式维甲酸、阿扎胞苷、咪唑硫嘌呤、博来霉素、硼替佐米、顺羧酸铂、卡培他滨、顺铂、苯丁酸氮芥、环磷酰胺、阿糖胞苷、柔毛霉素、多西他赛、去氧氟尿苷、阿霉素、表阿霉素、埃博霉素、依托泊苷、氟尿嘧啶(5-FU)、吉西他滨、羟基脲、去甲氧基柔红霉素、伊马替尼、二氯甲基二乙胺、巯嘌呤、甲氨蝶呤、米托蒽醌、奥沙利铂、紫杉醇、培美曲塞、替尼泊苷、硫鸟嘌呤、戊柔比星、长春花碱、长春新碱、长春地辛和长春瑞滨,以及任选的根据权利要求3所述的生物活性化合物中的任何一种的组合制剂,其用于在治疗产生粘液素的癌症或腹膜假粘液瘤中同时、分别或依次使用。
6.由菠萝蛋白酶和至少一种粘液溶解剂或其药学上可接受的盐或溶剂化物组成的组合物在制备用于治疗产生粘液素的癌症或腹膜假粘液瘤的药物中的用途,其中所述粘液溶解剂为N-乙酰半胱氨酸或其药学上可接受的盐或溶剂化物。
7.根据权利要求6所述的用途,其中所述癌症选自肺癌、乳腺癌、结肠直肠癌、甲状腺癌、前列腺癌、胃癌、胰腺癌、阑尾的癌症、卵巢癌和间皮瘤。
8.根据权利要求6所述的用途,其中所述癌症为印戒细胞癌。
9.由菠萝蛋白酶、至少一种粘液溶解剂或其药学上可接受的盐或溶剂化物和至少一种其它生物活性化合物或其药学上可接受的盐或溶剂化物组成的组合物在制备用于治疗产生粘液素的癌症或腹膜假粘液瘤的药物中的用途,其中所述粘液溶解剂为N-乙酰半胱氨酸或其药学上可接受的盐或溶剂化物,所述生物活性化合物选自化疗剂、N-糖基化抑制剂、唾液酸转移酶抑制剂、多药物转运抑制剂、抗生素和抗炎剂中的任何一种。
10.根据权利要求9所述的用途,其中所述生物活性化合物为化疗剂。
11.根据权利要求10所述的用途,其中所述化疗剂选自阿霉素、氟尿嘧啶(5-FU)和吉西他滨。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211366234.9A CN116077631A (zh) | 2012-12-17 | 2013-12-17 | 涉及粘液素的疾病治疗 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2012905519 | 2012-12-17 | ||
AU2012905519A AU2012905519A0 (en) | 2012-12-17 | Treatment of diseases involving mucin | |
PCT/AU2013/001474 WO2014094041A1 (en) | 2012-12-17 | 2013-12-17 | Treatment of diseases involving mucin |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211366234.9A Division CN116077631A (zh) | 2012-12-17 | 2013-12-17 | 涉及粘液素的疾病治疗 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104968358A CN104968358A (zh) | 2015-10-07 |
CN104968358B true CN104968358B (zh) | 2022-11-18 |
Family
ID=50977393
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380070938.4A Active CN104968358B (zh) | 2012-12-17 | 2013-12-17 | 涉及粘液素的疾病治疗 |
CN202211366234.9A Pending CN116077631A (zh) | 2012-12-17 | 2013-12-17 | 涉及粘液素的疾病治疗 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211366234.9A Pending CN116077631A (zh) | 2012-12-17 | 2013-12-17 | 涉及粘液素的疾病治疗 |
Country Status (14)
Country | Link |
---|---|
US (2) | US11369666B2 (zh) |
EP (1) | EP2931296B1 (zh) |
JP (1) | JP6502853B2 (zh) |
KR (1) | KR102255753B1 (zh) |
CN (2) | CN104968358B (zh) |
AU (3) | AU2013362878B2 (zh) |
CA (1) | CA2895149C (zh) |
DK (1) | DK2931296T3 (zh) |
ES (1) | ES2727686T3 (zh) |
HK (1) | HK1211213A1 (zh) |
NZ (1) | NZ631536A (zh) |
TR (1) | TR201907858T4 (zh) |
WO (1) | WO2014094041A1 (zh) |
ZA (1) | ZA201503979B (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017011670A1 (en) | 2015-07-16 | 2017-01-19 | Prospect CharterCare RWMC, LLC d/b/a Roger Williams Medical Center | Compositions and methods for treating peritoneal cancers |
EP3362085B1 (en) * | 2015-10-14 | 2023-06-07 | Newsouth Innovations Pty Limited | Compositions for the treatment of diseases involving mucin |
WO2017195792A1 (ja) * | 2016-05-13 | 2017-11-16 | 国立大学法人熊本大学 | 新規なpeg修飾酵素及びそれを用いた抗がん剤デリバリー |
CN108066413A (zh) * | 2016-11-15 | 2018-05-25 | 李雁 | 标准桃金娘油的癌性黏液溶解作用及抗肿瘤新用途 |
AU2019225453A1 (en) * | 2018-02-23 | 2020-10-08 | MUCPharm Pty Ltd | Formulations containing mucin-affecting proteases |
TW202100506A (zh) | 2019-03-07 | 2021-01-01 | 美商柯納特斯製藥公司 | 半胱天冬酶(caspase)抑制劑及其使用方法 |
AU2021262136A1 (en) * | 2020-05-01 | 2022-12-08 | MUCPharm Pty Ltd | Preventing and treating viral infections |
CA3236057A1 (en) * | 2021-10-27 | 2023-05-04 | David Morris | Methods for treating respiratory diseases |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6517832B1 (en) * | 2001-08-24 | 2003-02-11 | Jeffrey L. Marrongelle | Formulations and methods for treating chronic migraine |
US20080075710A1 (en) * | 2006-09-25 | 2008-03-27 | Liquid Potions Llc | Herbal composition for treating hangovers |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2017507C (en) | 1989-05-25 | 1996-11-12 | Gary Van Nest | Adjuvant formulation comprising a submicron oil droplet emulsion |
DE4302060A1 (de) * | 1993-01-26 | 1994-07-28 | Mucos Pharma Gmbh & Co | Verwendung von Bromelain zur Krebstherapie und/oder Metastasen-Prophylaxe |
GB9326253D0 (en) | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
JPH08337532A (ja) * | 1995-06-14 | 1996-12-24 | Takeda Chem Ind Ltd | 医薬組成物 |
AT408615B (de) | 1998-09-15 | 2002-01-25 | Immuno Ag | Neue influenzavirus-impfstoffzusammensetzung |
GB9923176D0 (en) | 1999-09-30 | 1999-12-01 | Smithkline Beecham Biolog | Novel composition |
CH695414A5 (de) * | 2001-05-30 | 2006-05-15 | Guenter Holzner | Kosmetische Präparate gegen die Alterung der menschlichen Haut in einer Mehrkammer-Mischpackung. |
ATE537709T1 (de) * | 2003-11-26 | 2012-01-15 | Hills Pet Nutrition Inc | Verfahren zur verringerung des exkrementgeruchs von heimtieren |
EP1797900A1 (en) * | 2004-10-07 | 2007-06-20 | Kabushiki Kaisha Sangi | Preparation for percutaneous/permucosal absorption |
AR054822A1 (es) | 2005-07-07 | 2007-07-18 | Sanofi Pasteur | Emulsion inmuno adyuvante |
US20100166726A1 (en) * | 2007-03-07 | 2010-07-01 | Northeastern University | Compositions for improving cellular uptake of a chemotherapeutic agent in a cell exhibiting mucin deregulation |
TWI461193B (zh) * | 2009-07-24 | 2014-11-21 | Taipei Veterans General Hospital | 水飛薊或水飛薊賓用於治療神經受損之用途 |
JP5614978B2 (ja) * | 2009-12-22 | 2014-10-29 | 独立行政法人農業・食品産業技術総合研究機構 | 穀物由来のプロアントシアニジン含有抽出物、及びその製造方法 |
CN103285383B (zh) * | 2013-06-03 | 2015-01-07 | 海南通用同盟药业有限公司 | 一种包含菠萝蛋白酶的药物组合物及菠萝蛋白酶肠溶片 |
-
2013
- 2013-12-17 ES ES13866447T patent/ES2727686T3/es active Active
- 2013-12-17 TR TR2019/07858T patent/TR201907858T4/tr unknown
- 2013-12-17 EP EP13866447.9A patent/EP2931296B1/en active Active
- 2013-12-17 CN CN201380070938.4A patent/CN104968358B/zh active Active
- 2013-12-17 CA CA2895149A patent/CA2895149C/en active Active
- 2013-12-17 NZ NZ631536A patent/NZ631536A/en unknown
- 2013-12-17 KR KR1020157018076A patent/KR102255753B1/ko active IP Right Grant
- 2013-12-17 WO PCT/AU2013/001474 patent/WO2014094041A1/en active Application Filing
- 2013-12-17 DK DK13866447.9T patent/DK2931296T3/da active
- 2013-12-17 CN CN202211366234.9A patent/CN116077631A/zh active Pending
- 2013-12-17 JP JP2015546778A patent/JP6502853B2/ja active Active
- 2013-12-17 US US14/649,518 patent/US11369666B2/en active Active
- 2013-12-17 AU AU2013362878A patent/AU2013362878B2/en active Active
-
2015
- 2015-06-03 ZA ZA2015/03979A patent/ZA201503979B/en unknown
- 2015-12-07 HK HK15112050.5A patent/HK1211213A1/zh unknown
-
2017
- 2017-06-29 AU AU2017204436A patent/AU2017204436B2/en active Active
-
2019
- 2019-05-12 AU AU2019203315A patent/AU2019203315A1/en not_active Abandoned
-
2022
- 2022-06-27 US US17/850,593 patent/US20220401529A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6517832B1 (en) * | 2001-08-24 | 2003-02-11 | Jeffrey L. Marrongelle | Formulations and methods for treating chronic migraine |
US20080075710A1 (en) * | 2006-09-25 | 2008-03-27 | Liquid Potions Llc | Herbal composition for treating hangovers |
Also Published As
Publication number | Publication date |
---|---|
HK1211213A1 (zh) | 2016-05-20 |
ES2727686T3 (es) | 2019-10-17 |
US20150343035A1 (en) | 2015-12-03 |
AU2013362878B2 (en) | 2017-03-30 |
KR102255753B1 (ko) | 2021-05-26 |
EP2931296B1 (en) | 2019-02-27 |
CA2895149C (en) | 2023-08-22 |
CN116077631A (zh) | 2023-05-09 |
AU2019203315A1 (en) | 2019-05-30 |
AU2017204436A1 (en) | 2017-07-20 |
AU2017204436B2 (en) | 2019-05-30 |
DK2931296T3 (da) | 2019-06-03 |
TR201907858T4 (tr) | 2019-06-21 |
JP2016502981A (ja) | 2016-02-01 |
EP2931296A4 (en) | 2016-08-10 |
EP2931296A1 (en) | 2015-10-21 |
US11369666B2 (en) | 2022-06-28 |
ZA201503979B (en) | 2017-11-29 |
CA2895149A1 (en) | 2014-06-26 |
KR20150096445A (ko) | 2015-08-24 |
JP6502853B2 (ja) | 2019-04-17 |
WO2014094041A1 (en) | 2014-06-26 |
US20220401529A1 (en) | 2022-12-22 |
CN104968358A (zh) | 2015-10-07 |
NZ631536A (en) | 2016-12-23 |
AU2013362878A1 (en) | 2015-06-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104968358B (zh) | 涉及粘液素的疾病治疗 | |
JP6075903B2 (ja) | Pfkfb2阻害剤および抗癌治療法としての使用方法 | |
JP6666494B2 (ja) | がんの処置のための医薬の組合せ | |
US6403563B1 (en) | Antitumor composition containing a synergistic combination of an anthracycline derivative with a camptothecin derivate | |
JP2007535525A (ja) | β−カルボリン誘導体を含有する医薬組成物および癌を処置するためのそれらの使用 | |
EP1323423A1 (en) | Combined preparations comprising anthracycline derivatives | |
JP5440985B2 (ja) | メラノーマの治療 | |
TW201609094A (zh) | 治療癌症之新穎方法 | |
WO2017142269A1 (ko) | 신규한 인돌 유도체 및 이를 포함하는 항암 조성물 | |
US11364286B2 (en) | Compositions and methods for the treatment of diseases involving mucin | |
CA3112275A1 (en) | Compound and use thereof | |
JP2010526073A (ja) | 癌または前癌性症状およびその他の症状の治療のためのジヒドロピリジン誘導体 | |
KR20210150470A (ko) | A-노르-5α안드로스테인 화합물계 약물 및 항암제의 병용 | |
CN113993515B (zh) | 使用藏红花酸治疗实体肿瘤的方法 | |
CN104619325A (zh) | 治疗肿瘤的组合药物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C41 | Transfer of patent application or patent right or utility model | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20170116 Address after: New South Wales Australia Applicant after: NEWSOUTH INNOVATIONS Pty Ltd. Address before: Western Australia, Australia Applicant before: PITNEY PHARMACEUTICALS PTY LTD. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |