WO2002000164A2 - Chemosensitizer - Google Patents
Chemosensitizer Download PDFInfo
- Publication number
- WO2002000164A2 WO2002000164A2 PCT/IB2001/001133 IB0101133W WO0200164A2 WO 2002000164 A2 WO2002000164 A2 WO 2002000164A2 IB 0101133 W IB0101133 W IB 0101133W WO 0200164 A2 WO0200164 A2 WO 0200164A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- resistance
- chemotherapeutic agents
- chemosensitizer
- piperine
- drug
- Prior art date
Links
- 230000003034 chemosensitisation Effects 0.000 title claims abstract description 20
- 239000006114 chemosensitizer Substances 0.000 title claims abstract description 19
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 22
- 229940127089 cytotoxic agent Drugs 0.000 claims abstract description 21
- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical compound C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 claims abstract description 17
- 229940075559 piperine Drugs 0.000 claims abstract description 17
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000019100 piperine Nutrition 0.000 claims abstract description 17
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims abstract description 9
- 229960001225 rifampicin Drugs 0.000 claims abstract description 9
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 9
- 229960003677 chloroquine Drugs 0.000 claims description 9
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 9
- -1 Dounorubicin Chemical compound 0.000 claims description 3
- 150000005528 benzodioxoles Chemical class 0.000 claims description 3
- 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 4
- 230000000340 anti-metabolite Effects 0.000 claims 2
- 229940100197 antimetabolite Drugs 0.000 claims 2
- 239000002256 antimetabolite Substances 0.000 claims 2
- 108010006654 Bleomycin Proteins 0.000 claims 1
- 190000008236 Carboplatin Chemical compound 0.000 claims 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims 1
- 229930012538 Paclitaxel Natural products 0.000 claims 1
- 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 1
- 229940009456 adriamycin Drugs 0.000 claims 1
- 229960001561 bleomycin Drugs 0.000 claims 1
- 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 1
- 229960004562 carboplatin Drugs 0.000 claims 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims 1
- 229960004316 cisplatin Drugs 0.000 claims 1
- 229960004679 doxorubicin Drugs 0.000 claims 1
- 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 1
- 229960005420 etoposide Drugs 0.000 claims 1
- 229960002949 fluorouracil Drugs 0.000 claims 1
- 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 1
- 229960001156 mitoxantrone Drugs 0.000 claims 1
- 229960001592 paclitaxel Drugs 0.000 claims 1
- 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 1
- 229960000303 topotecan Drugs 0.000 claims 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 claims 1
- 229960003048 vinblastine Drugs 0.000 claims 1
- 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 1
- 229960004528 vincristine Drugs 0.000 claims 1
- 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 1
- 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 1
- 150000001875 compounds Chemical class 0.000 abstract description 15
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- 239000003814 drug Substances 0.000 abstract description 15
- 230000002441 reversible effect Effects 0.000 abstract description 3
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- 241000700605 Viruses Species 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
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- 230000003211 malignant effect Effects 0.000 abstract description 2
- 244000045947 parasite Species 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000037406 food intake Effects 0.000 abstract 1
- 230000007246 mechanism Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 241000223960 Plasmodium falciparum Species 0.000 description 6
- 229930182555 Penicillin Natural products 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
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- 150000003522 tetracyclines Chemical class 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
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- 238000009825 accumulation Methods 0.000 description 2
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- 230000003115 biocidal effect Effects 0.000 description 2
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- 150000003952 β-lactams Chemical class 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 108010036941 Cyclosporins Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
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- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
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- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 description 1
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- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the objective of the present invention is to provide a chemosensitizer for therapeutic use.
- the further objective of the present invention is to provide a chemosensitizer, the dose of which, as chemosensitizer is achievable.
- Chemotherapeutic agents are used to treat infections caused by bacteria, virus, protozoa, parasites, etc. They are also used in management of various malignant diseases (cancer). The major problem associated with use of chemotherapeutic agents is resistance to chemotherapeutic agents.
- Mechanisms underlying resistance to chemotherapeutic agents include inactivation/modification of antibiotic (beta-lactams, chloramphenicol), insensitive target site (beta-lactams, glycopeptides, macrolides, tetracyclines), decreased drug accumulation in the form of enhanced efflux (tetracyclines, chloroquine, macrolides, anticancer drugs), by-pass of antibiotic sensitive step (methicillin, sulphonamides) etc.
- the common mechanisms underlying drug resistance is to restrict concentration of drug at the site of action usually intracellular. This can be in the from of restricting the entry of the drug into the cell by various mechanisms including altered cell wall permeability. It can also be in the form of removing the drug from site of action e.g.
- intracellular so that therapeutic concentration are not achieved. This is largely done by throwing out intracellular drug at a rate faster than usual so that balance of drug concentration is disturbed resulting into lower intracellular concentration. This is done through the mechanism which is known as efflux pump.
- the other mechanism of decreasing therapeutic concentration of a drug include metabolism/alteration of drug to inactive compound e.g. secretion of enzymes like penicillinase or B-lactamase which destroys penicillins or B-lactam antibiotics.
- chemotherapeutic agents e.g. penicillin's resistant penicillin like Cloxacillin, dicloxacillin, methicillin, flucloxacillin etc. or beta-lactamase resistance antibiotics like temocillin in a group o penicillin or advanced cephalosporins, monobactams etc.
- chemotherapeutic agents e.g. beta-lactamase inhibitors like clavulanic acid, salbactam, tazobactam to be- used along with antibiotics like amipicillin, amoxycillin, ticarcillin etc.
- chemosensitizers For example, calcium channel blocker, verpamil has been used to reverse chloroquine resistance in Plasmodium falciparum.
- modified tetracyclines has been used as chemosensitizers to overcome efflux mediated drug resistance.
- chemotherapeutic agents for restoring sensitivity to chemotherapeutic agents are broadly known as chemosensitizers (Table 2).
- Many drugs used for various therapeutic effect are found to be good for this purpose e.g. Verapamil, Reserpine, Cyclosporin.
- chemotherapeutic agents like rifampicin can work as a chemotherapeutic agent as well as chemosensitizer. Table 1:
- Nikadio H Antibiotic resistance caused by gram negative multi-drug pump efflux pumps.
- Roberts MC Tetracycline resistance determinants: mechanisms of action, regulation of expression, genetic mobility and distribution.
- Tetracyclines antibiotic action, uptake and resistance mechanisms. Arch Microbiol 1996; 165(6): 359-69.
- Papadopoulou MV et al. NLCQ-1 a novel hypoxic cytotoxin: potentiation of melphalan, cisDDPO and cyclophosphamide in vivo.
- Schmitz FJ et al. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the invitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus.
- the present invention provides a chemosensitizer for therapeutic use, the dose of which as chemosensitizer is achievable.
- the chemosensitizer as per the present invention belongs to R-1-3 benzodiaxoles.
- Piperine is a compound belonging to R-1-3 benozodiaxoles. Strains of M. tuberculosis growing in presence of 40 mcg/ml of rifampicin are inhibited at various concentrations of piperine, the concentration of which is not more than 5 mcg/ml. Similarly in case of chloroquine-resistant P. falciparum strains, amount of piperine is dependent on level of resistance and amount of chloroquine.
- the amount of chemosensitizer required is dependent on the compound, chemotherapeutic agent and level of resistance.
- Rifampicin is a chemotherapeutic agent useful in the management of tuberculosis. Resistance to rifampicin is a major health problem.
- Piperine is a compound belonging to a class of compound which can be grouped as R-1-3 benzodiaxole, where in, R is
- Chloroquine is used in the management of malaria.
- Plasmodium falciparum has acquired resistance to chloroquine. This is the major cause of morbidity and mortality caused by malaria.
- the table below shows how piperine at different concentrations overcomes P. falciparum resistance to chloroquine.
- the figures in each cell shows % inhibition of P. falciparum. It clearly shows that % inhibition for a resistant strain of P.falciparum can be improved by addition of piperine. Inhibition can be increased by increasing the dose of either compound.
- the amount of piperine required is dependent on level of resistance and amount of chemotherapeutic agent.
- Piperine was evaluated for its bioavailability and toxicity in animals.
- R-1-3 benzodioxole compounds useful as chemosensitizers are provided. These compounds can be useful in therapy as it is possible to achieve therapeutic levels in plasma.
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Abstract
Chemotherapeutic agents are used to treat infections caused by bacteria, virus, protozoa, parasites, and various malignant diseases like cancer. The major problem associated with use of chemotherapeutic agents is resistance to chemoptherapeutic agents. The drugs restoring sensitivity of chemotherapeutic agents are broadly known as chemosensitizers. Compounds belonging to a group of R-1-3-benzodiaxole are found to be chemosensitizer as per the present invention. Piperine is one such compound belonging to R-1-2benzodiaxole group. It is found to reverse resistance to chemotherapeutic agents like rifampicin at a dose which is easily achievable after oral ingestion of the drug.
Description
THE PATENTS ACT, 1970 THE COMPLETE SPECIFICATION
1. CHEMOSENSITIZER.
2. Dr. Bakuiesh Mafatial Khamar, residing at 201 "Ashadha", Vasundhara Colony, Gulbai Tekra, Ellisbridge, Ahmedabad 380 006, Gujarat, India, Nationality: Indian
3. The following specification particularly describes the nature, of this invention and the manner in which it is to be performed.
FIELD OF INVENTION
The objective of the present invention is to provide a chemosensitizer for therapeutic use.
The further objective of the present invention is to provide a chemosensitizer, the dose of which, as chemosensitizer is achievable.
BACKGROUND OF THE INVENTION
Chemotherapeutic agents are used to treat infections caused by bacteria, virus, protozoa, parasites, etc. They are also used in management of various malignant diseases (cancer). The major problem associated with use of chemotherapeutic agents is resistance to chemotherapeutic agents.
Mechanisms underlying resistance to chemotherapeutic agents include inactivation/modification of antibiotic (beta-lactams, chloramphenicol), insensitive target site (beta-lactams, glycopeptides, macrolides, tetracyclines), decreased drug accumulation in the form of enhanced efflux (tetracyclines, chloroquine, macrolides, anticancer drugs), by-pass of antibiotic sensitive step (methicillin, sulphonamides) etc. The common mechanisms underlying drug resistance is to restrict concentration of drug at the site of action usually intracellular. This can be in the from of restricting the entry of the drug into the cell by various mechanisms including altered cell wall permeability. It can also be in the form of removing the drug from site of action e.g. intracellular so that therapeutic concentration are not achieved.
This is largely done by throwing out intracellular drug at a rate faster than usual so that balance of drug concentration is disturbed resulting into lower intracellular concentration. This is done through the mechanism which is known as efflux pump. The other mechanism of decreasing therapeutic concentration of a drug include metabolism/alteration of drug to inactive compound e.g. secretion of enzymes like penicillinase or B-lactamase which destroys penicillins or B-lactam antibiotics.
Attempts have been made and efforts are on to counteract this acquired drug resistance. One way is to improve chemotherapeutic agents e.g. penicillin's resistant penicillin like Cloxacillin, dicloxacillin, methicillin, flucloxacillin etc. or beta-lactamase resistance antibiotics like temocillin in a group o penicillin or advanced cephalosporins, monobactams etc.
The other way is to find out drugs to overcome resistance for use along with chemotherapeutic agents e.g. beta-lactamase inhibitors like clavulanic acid, salbactam, tazobactam to be- used along with antibiotics like amipicillin, amoxycillin, ticarcillin etc.
However, this approach has been successful in situations wherein beta- lactamase enzyme has been the problem.
The present situation is faced with new mechanism of resistance, like enhancement of efflux responsible for multi-drug resistance. This was initially seen with tetracycliηe antibiotics, but now is extended to many antibiotics like ciprofloxacin, norfloxacin, chloroquine and also has extended to many anticancer therapies (shown in the list below) which is now the major mechanism of resistance.
To overcome this efflux, attempts have been made by use of compounds called chemosensitizers. For example, calcium channel blocker, verpamil has been used to reverse chloroquine resistance in Plasmodium falciparum.
Likewise, modified tetracyclines has been used as chemosensitizers to overcome efflux mediated drug resistance.
In case of anticancer therapies, several compounds have been identified that enhanced drug's accumulation inside the cell like verapamil, amiodarone, steroids, cyclosporins, phenothiazines and other compounds as shown in the list below.
The drugs to be used along with chemotherapeutic agents (Table 1 ) for restoring sensitivity to chemotherapeutic agents are broadly known as chemosensitizers (Table 2). Many drugs used for various therapeutic effect are found to be good for this purpose e.g. Verapamil, Reserpine, Cyclosporin.
Some of the chemotherapeutic agents like rifampicin can work as a chemotherapeutic agent as well as chemosensitizer.
Table 1:
REFERENCES:
1. Chiba P et al. Substituted 4- acylpyrazoles and 4-acylpyrazolones: synthesis and multidrug resistance modulating activity.
J Med Chem 1998; 41 : 4001-4011.
2. Norman BH. Inhibitors of MRP__1 mediated multi-drug resistance. Drugs of the Future 1998; 23(9): 1001 -13.
3. Nikadio H. Antibiotic resistance caused by gram negative multi-drug pump efflux pumps.
Clin Infect Dis 1998; 27 Suppl 1 : S32-41.
4. Pechere JC et al. Antibiotic efflux, a mechanism of multiple resistance in Pseudomonas aeruginosa.
Bull Acad Natl Med 1998; 182(3): 599-612.
5. Roberts MC. Tetracycline resistance determinants: mechanisms of action, regulation of expression, genetic mobility and distribution.
FEMS Microbiol Rev 1996; 19(1): 1-24.
6. Schnappinger D and Hillen W.
Tetracyclines: antibiotic action, uptake and resistance mechanisms. Arch Microbiol 1996; 165(6): 359-69.
7. Sum PE et al. Recent developments in tetracycline antibiotics. Curr Pharm Des 1998; 4(2): 119-32.
8. Nikaido H. Multiple antibiotic resistance and efflux. Curr Opin Microbiol 1998; 1 (5): 516-23.
9. Piddock LJ et al. Accumulation of rifampicin my Mycobacterium aurum, Mycobacterium smegmatis and Mycobacterium tuberculosis.
J Antimicrob Chemother 2000; 45(2): 159-65.
10. Aeschlimann JR et al. The effects of NorA inhibition on the activities of levofloxacin, ciprofloxacin, and norfloxacin against two genetically related strains of Staphylococcus aureus in an in vitro infection model.
J Antimicrob Chemother 1999; 44(3): 343-9.
11. Choudhuri BS et al. Isoniazid accumulation in Mycobacterium smegmatis id mediated by proton motive force driven and ATP dependent extrusion systems.
Biochem Biophys Res Commun 1999; 256(3): 682-4.
12. De Flora S et al. Modulation of the potency of promutagens and direct acting mutagens in bacteria by inhibitors of the multidrug resistance mechanism.
Mutagenesis 1997; 12(6): 431-5.
13. Theis JG et al. Assessment of systemic toxicity in children receiving chemotherapy with cyclosporihe for sarcoma.
Med Paediatr Oncol 2000; 34(4): 242-9.
14. Hafkemeyer P et al. Chemoprotection of haematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multi-drug resistant cancers.
Hum Gene Ther 2000; 11 (4): 555-65.
15. Rafatro H et al. Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria.
Biochem Pharmacol 2000; 59(9): 1053-61.
16. Yanagisawa T et al. Biricodar (VX-710): an effective chemosensitizer in neuroblastoma.
Br J Cancer 1999; 80(8): 1190-6.
17. Papadopoulou MV et al. NLCQ-1 , a novel hypoxic cytotoxin: potentiation of melphalan, cisDDPO and cyclophosphamide in vivo.
Int J Radiat Oncol Biol Phys 1998; 42(4): 775-9.
18. Sharom FJ. The P-Glycoprotein efflux pump: How does it transports drugs?
J Memb Biol 1997; 160(3): 161-75. )
19. Schmitz FJ et al. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the invitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus.
J Antimicrob Chemother 1998; 42(6): 807-10.
20. Markham PN. Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob Ag Chemother 1999; 43(4): 988-9.
21. Nakanishi N et al. Mechanisms of clinical resistance to fluoroquinόlones in Staphylococcus aureus.
Antimicrob Ag Chemother 1991 ; 35(12): 2562-7.
22. Nelson ML. Inhibition of Tetracycline efflux antiport protein by 13-Thio- Substitute, 5-hydroxy-6-deoxytetracyclines.
J Med Chem 1993; 36: 37-7.
23. Courtois A et al. Inhibition of multi-drug resistance-associated protein (MRP) activity by rifampicin in human multi-drug resistant lung tumor cells. Cancer Lett 1999; 139(1 ): 97-104.
24. Piddock LJ et al. Accumulation of rifampicin my Mycobacterium aurum, Mycobacterium smegmatis and Mycobacterium tuberculosis. Antimicrob Ag Chemother 2000; 45(2): 159-65.
SUMMARY OF THE INVENTION
The present invention provides a chemosensitizer for therapeutic use, the dose of which as chemosensitizer is achievable. The chemosensitizer as per the present invention belongs to R-1-3 benzodiaxoles.
Piperine is a compound belonging to R-1-3 benozodiaxoles. Strains of M. tuberculosis growing in presence of 40 mcg/ml of rifampicin are inhibited at various concentrations of piperine, the concentration of which is not more than 5 mcg/ml.
Similarly in case of chloroquine-resistant P. falciparum strains, amount of piperine is dependent on level of resistance and amount of chloroquine.
DESCRIPTION OF THE INVENTION
According to the present invention it is observed that R-1-3 Benzodioxole compounds with structural formula
The amount of chemosensitizer required is dependent on the compound, chemotherapeutic agent and level of resistance.
The following examples provide proof of such compounds working as chemosensitizer.
EXAMPLE 1
Rifampicin is a chemotherapeutic agent useful in the management of tuberculosis. Resistance to rifampicin is a major health problem.
A strain of mycobacterium is considered resistant if it grows in presence of rifampicin 40 mcg/ml.
Piperine is a compound belonging to a class of compound which can be grouped as R-1-3 benzodiaxole, where in, R is
Piperine with structural formula
The table below gives results of such study against nine different such strains. It is clear that all strains growing in vitro in presence of 40 mcg/ml of rifampicin are inhibited at various concentration of piperine. The concentration of piperine required for this purpose is not more than 5 mcg/ml.
Chloroquine is used in the management of malaria. One of the organism, Plasmodium falciparum has acquired resistance to chloroquine. This is the major cause of morbidity and mortality caused by malaria.
The table below shows how piperine at different concentrations overcomes P. falciparum resistance to chloroquine. The figures in each cell shows % inhibition of P. falciparum. It clearly shows that % inhibition for a resistant strain of P.falciparum can be improved by addition of piperine. Inhibition can be increased by increasing the dose of either compound.
The amount of piperine required is dependent on level of resistance and amount of chemotherapeutic agent.
Piperine was evaluated for its bioavailability and toxicity in animals.
The results of the pharmacokinetic study in rat (Figure 1) shows that compound is absorbed from intestinal tract when given orally. It also indicates that compound has a long half-life.
The toxicological study also reveals that piperine is non toxic.
Pharmacokinetic study in humans (table below and Figure 2) also reveal that piperine is absorbed from gastrointestinal tract, and adequate therapeutic concentration can be achieved.
Thus, according to the present invention is provided R-1-3 benzodioxole compounds useful as chemosensitizers. These compounds can be useful in therapy as it is possible to achieve therapeutic levels in plasma.
Claims
1. R-1 -3 Benzodioxoles as a chemosensitizer with a structural formula
2. A chemosensitizer as c <la;imxed in claim 1 can be piperine wherein R is
y Piperine
3. A chemosensitizer as claimed in claim' 1 to 2 "is useful in overcoming resistance of chemotherapeutic agents.
4. Chemotherapeutic agent as claimed in claim 3 can be rifampicin.
5. Chemotherapeutic agents as claimed in claim 3 can be antimetabolites.
6. Antimetabolites as claimed in claim 5 can be selected from group comprising Doxorubicin, Dounorubicin, Vincristine, Vinblastine, Paclitaxel, Carboplatin, Etoposide, Taxotrene, Topotecan, Adriamycin, Cisplatin, 5-Fluorouracil, Mitoxantrone, Bleomycin and. the like.
7. Chemotherapeutic agent as claimed in claim 3 can be chloroquine.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EA200200288A EA005672B1 (en) | 2000-06-28 | 2001-06-26 | Chemosensitizer |
| EP01940915A EP1296682A4 (en) | 2000-06-28 | 2001-06-26 | Chemosensitizer |
| APAP/P/2002/002453A AP2002002453A0 (en) | 2000-06-28 | 2001-06-26 | Chemosensitizer |
| AU74403/01A AU7440301A (en) | 2000-06-26 | 2001-06-26 | Chemosensitizer |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN591/MUM/2000 | 2000-06-26 | ||
| IN591MU2000 | 2000-06-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2002000164A2 true WO2002000164A2 (en) | 2002-01-03 |
| WO2002000164A8 WO2002000164A8 (en) | 2002-05-16 |
| WO2002000164A3 WO2002000164A3 (en) | 2002-10-24 |
Family
ID=11097259
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2001/001133 WO2002000164A2 (en) | 2000-06-26 | 2001-06-26 | Chemosensitizer |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1296682A4 (en) |
| AP (1) | AP2002002453A0 (en) |
| AU (1) | AU7440301A (en) |
| EA (1) | EA005672B1 (en) |
| RU (1) | RU2002107449A (en) |
| WO (1) | WO2002000164A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006514972A (en) * | 2003-03-31 | 2006-05-18 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | Use of cumin extract and piperine to influence the biological effectiveness of anti-infectives |
| WO2006103527A1 (en) * | 2005-03-31 | 2006-10-05 | Council Of Scientific And Industrial Research | Aromatic substituted pentadienoic acid amide for combination with anti-infective drugs |
| EP2468868A1 (en) | 2006-06-26 | 2012-06-27 | The University Of British Columbia | Chemotherapeutic sensitizers |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5439891A (en) * | 1993-10-29 | 1995-08-08 | Kapil; Randhir S. | Process for preparation of pharmaceutical composition with enhanced activity for treatment of tuberculosis and leprosy |
| IN176897B (en) * | 1993-10-29 | 1996-09-28 | Cadila Lab Ltd | |
| US5744161A (en) * | 1995-02-24 | 1998-04-28 | Sabinsa Corporation | Use of piperine as a bioavailability enhancer |
| EP0935964A1 (en) * | 1998-02-12 | 1999-08-18 | Panacea Biotec Limited | Pharmaceutical compositions containing NSAIDs and piperine |
-
2001
- 2001-06-26 EP EP01940915A patent/EP1296682A4/en not_active Withdrawn
- 2001-06-26 WO PCT/IB2001/001133 patent/WO2002000164A2/en not_active Application Discontinuation
- 2001-06-26 EA EA200200288A patent/EA005672B1/en not_active IP Right Cessation
- 2001-06-26 AU AU74403/01A patent/AU7440301A/en not_active Abandoned
- 2001-06-26 AP APAP/P/2002/002453A patent/AP2002002453A0/en unknown
- 2001-06-26 RU RU2002107449/14A patent/RU2002107449A/en not_active Application Discontinuation
Non-Patent Citations (2)
| Title |
|---|
| DATABASE CAPLUS [Online] SHENOY ET AL.: 'Characterization of potentially mutagenic products from the nitrosation of perperin', XP002908374 Retrieved from STN Database accession no. 117:212755 & CANCER LETTERS vol. 64, no. 3, 1992, pages 235 - 239 * |
| See also references of EP1296682A2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006514972A (en) * | 2003-03-31 | 2006-05-18 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | Use of cumin extract and piperine to influence the biological effectiveness of anti-infectives |
| WO2006103527A1 (en) * | 2005-03-31 | 2006-10-05 | Council Of Scientific And Industrial Research | Aromatic substituted pentadienoic acid amide for combination with anti-infective drugs |
| EP2468868A1 (en) | 2006-06-26 | 2012-06-27 | The University Of British Columbia | Chemotherapeutic sensitizers |
| US8440625B2 (en) | 2006-06-26 | 2013-05-14 | University Of British Columbia | Secreted protein acidic and rich in cysteine (SPARC) as chemotherapeutic sensitizers |
Also Published As
| Publication number | Publication date |
|---|---|
| EA200200288A1 (en) | 2003-02-27 |
| AP2002002453A0 (en) | 2002-06-30 |
| EP1296682A4 (en) | 2004-11-10 |
| RU2002107449A (en) | 2003-11-20 |
| AU7440301A (en) | 2002-01-08 |
| WO2002000164A3 (en) | 2002-10-24 |
| EA005672B1 (en) | 2005-04-28 |
| EP1296682A2 (en) | 2003-04-02 |
| WO2002000164A8 (en) | 2002-05-16 |
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