GB2487351A - Combination of syrosingopine and a biguanide - Google Patents
Combination of syrosingopine and a biguanide Download PDFInfo
- Publication number
- GB2487351A GB2487351A GB1100404.1A GB201100404A GB2487351A GB 2487351 A GB2487351 A GB 2487351A GB 201100404 A GB201100404 A GB 201100404A GB 2487351 A GB2487351 A GB 2487351A
- Authority
- GB
- United Kingdom
- Prior art keywords
- syrosingopine
- metformin
- combination
- treatment
- cells
- 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.)
- Withdrawn
Links
- ZCDNRPPFBQDQHR-SSYATKPKSA-N Syrosingopine Chemical compound C1=C(OC)C(OC(=O)OCC)=C(OC)C=C1C(=O)O[C@H]1[C@H](OC)[C@@H](C(=O)OC)[C@H]2C[C@@H]3C(NC=4C5=CC=C(OC)C=4)=C5CCN3C[C@H]2C1 ZCDNRPPFBQDQHR-SSYATKPKSA-N 0.000 title claims abstract description 124
- 229950006534 syrosingopine Drugs 0.000 title claims abstract description 124
- 229940123208 Biguanide Drugs 0.000 title claims abstract description 65
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 title claims abstract description 11
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 126
- 229960003105 metformin Drugs 0.000 claims abstract description 124
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 52
- 238000011282 treatment Methods 0.000 claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960003243 phenformin Drugs 0.000 claims abstract description 20
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 12
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 10
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 10
- 208000032839 leukemia Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 210000000653 nervous system Anatomy 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 6
- 201000009030 Carcinoma Diseases 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 210000003491 skin Anatomy 0.000 claims description 3
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 210000002808 connective tissue Anatomy 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 150000004283 biguanides Chemical class 0.000 abstract description 54
- 206010062016 Immunosuppression Diseases 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 5
- 229960004111 buformin Drugs 0.000 abstract description 3
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 79
- 150000001875 compounds Chemical class 0.000 description 20
- 239000003814 drug Substances 0.000 description 17
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical class O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 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 11
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 11
- 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 11
- 239000002253 acid Substances 0.000 description 11
- 229960003147 reserpine Drugs 0.000 description 11
- 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 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 230000037396 body weight Effects 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- -1 halogen acids Chemical class 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 230000001640 apoptogenic effect Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 108090000672 Annexin A5 Proteins 0.000 description 7
- 102000004121 Annexin A5 Human genes 0.000 description 7
- 210000003630 histaminocyte Anatomy 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 238000011278 co-treatment Methods 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000005784 autoimmunity Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 4
- 230000006052 T cell proliferation Effects 0.000 description 4
- 239000003472 antidiabetic agent Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 208000026278 immune system disease Diseases 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 244000061121 Rauvolfia serpentina Species 0.000 description 3
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 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 3
- 230000006907 apoptotic process Effects 0.000 description 3
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000001516 cell proliferation assay Methods 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
- 238000000576 coating method Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 2
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 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
- 229920002307 Dextran Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 206010018338 Glioma Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 208000034179 Neoplasms, Glandular and Epithelial Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000018359 Systemic autoimmune disease Diseases 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 229940125708 antidiabetic agent Drugs 0.000 description 2
- 230000007503 antigenic stimulation Effects 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940126523 co-drug Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic 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
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 235000021186 dishes Nutrition 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 230000017066 negative regulation of growth Effects 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 2
- CZJDUZOWQVAEEV-XIEZEKGWSA-N (+)-19-epi-Ajmalicine Natural products O=C(OC)C=1[C@@H]2[C@@H]([C@@H](C)OC=1)C[N+]1[C@H](c3[nH]c4c(c3CC1)cccc4)C2 CZJDUZOWQVAEEV-XIEZEKGWSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 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 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical group COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 1
- JDQDSEVNMTYMOC-UHFFFAOYSA-N 3-methylbenzenesulfonic acid Chemical compound CC1=CC=CC(S(O)(=O)=O)=C1 JDQDSEVNMTYMOC-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 102100035656 BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 Human genes 0.000 description 1
- 208000005440 Basal Cell Neoplasms Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 102000051485 Bcl-2 family Human genes 0.000 description 1
- 108700038897 Bcl-2 family Proteins 0.000 description 1
- 101150086017 Bcl2l11 gene Proteins 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 208000006274 Brain Stem Neoplasms Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- BLGXFZZNTVWLAY-DKJBZYCGSA-N Corynanthine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-DKJBZYCGSA-N 0.000 description 1
- DDRUVFKWNXGBTK-UHFFFAOYSA-N Corynanthine Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)OC(=O)C)=C3NC2=C1 DDRUVFKWNXGBTK-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229930105110 Cyclosporin A Natural products 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
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 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 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- 208000007842 Fibroepithelial Neoplasms Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 208000007569 Giant Cell Tumors Diseases 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 201000005618 Glomus Tumor Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000803294 Homo sapiens BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 208000010423 Lymphatic Vessel Tumors Diseases 0.000 description 1
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000010153 Mesonephroma Diseases 0.000 description 1
- 208000000811 Mesothelial Neoplasms Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 208000031675 Neoplasms, Adnexal and Skin Appendage Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 108010047620 Phytohemagglutinins Proteins 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100035548 Protein Bop Human genes 0.000 description 1
- 108050008794 Protein Bop Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 208000002669 Sex Cord-Gonadal Stromal Tumors Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000006288 Vascular Tissue Neoplasms Diseases 0.000 description 1
- 102000009659 Vesicular Monoamine Transport Proteins Human genes 0.000 description 1
- 108010020033 Vesicular Monoamine Transport Proteins Proteins 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
- AADVZSXPNRLYLV-XKLXXKPTSA-N Yohimbinic acid Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H]([C@@H]([C@@H]4C[C@H]33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-XKLXXKPTSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- GRTOGORTSDXSFK-XJTZBENFSA-N ajmalicine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 GRTOGORTSDXSFK-XJTZBENFSA-N 0.000 description 1
- 229940007897 ajmalicine Drugs 0.000 description 1
- 238000003349 alamar blue assay Methods 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
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000008524 alveolar soft part sarcoma Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer 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
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 208000020719 chondrogenic neoplasm Diseases 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 208000012106 cystic neoplasm Diseases 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940127004 drugs for type 2 diabetes Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000459 effect on growth Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 description 1
- SIVVHUQWDOGLJN-UHFFFAOYSA-N ethylsulfamic acid Chemical group CCNS(O)(=O)=O SIVVHUQWDOGLJN-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 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
- 201000006604 granular cell tumor Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 102000052611 human IL6 Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000025095 immunoproliferative disease Diseases 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000003641 microbiacidal effect Effects 0.000 description 1
- 229940124561 microbicide Drugs 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000022669 mucinous neoplasm Diseases 0.000 description 1
- 201000009368 muscle benign neoplasm Diseases 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 208000017708 myomatous neoplasm Diseases 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 238000009099 neoadjuvant therapy Methods 0.000 description 1
- 208000023833 nerve sheath neoplasm Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000003204 osmotic effect Effects 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
- 208000007312 paraganglioma Diseases 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 201000005528 peripheral nervous system neoplasm Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000001885 phytohemagglutinin Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- HLIBNTOXKQCYMV-UHFFFAOYSA-N propylsulfamic acid Chemical compound CCCNS(O)(=O)=O HLIBNTOXKQCYMV-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- ZLQMRLSBXKQKMG-UHFFFAOYSA-N rauniticine Natural products COC(=O)C1=CC2CC3N(CCc4c3[nH]c5ccccc45)CC2C(C)O1 ZLQMRLSBXKQKMG-UHFFFAOYSA-N 0.000 description 1
- BLGXFZZNTVWLAY-DIRVCLHFSA-N rauwolscine Chemical compound C1=CC=C2C(CCN3C[C@H]4CC[C@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-DIRVCLHFSA-N 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 208000016596 serous neoplasm Diseases 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000028467 sex cord-stromal tumor Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 208000010556 transitional cell papilloma Diseases 0.000 description 1
- 201000004420 transitional papilloma Diseases 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000025443 tumor of adipose tissue Diseases 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 201000011531 vascular cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- AADVZSXPNRLYLV-GKMXPDSGSA-N yohimbic acid Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@@H]([C@@H]([C@H]4C[C@H]33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-GKMXPDSGSA-N 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Transplantation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A pharmaceutical composition comprises a combination of syrosingopine and a biguanide, in particular metformin wherein preferably the relative amount (w/w) of syrosingopine and metformin is between 1 to 10 and 1 to 1000. The biguanides are preferably selected from metformin, phenformin or buformin. Exemplified combinations include syrosingopine and metformin and syrosingopine and phenformin for use in the treatment of cancer and immunosuppression in the treatment of autoimmune diseases. The syrosingopine and biguanide may be administered in the same or in different compositions.
Description
Combination of metformin and syrosingopine for the treatment of cancer and immunosuppression
Field of the Invention
The invention relates to a combination of syrosingopine and metformin or related biguanides, and the use of the combination of metformin and syrosingopine for the treatment of cancer and for achieving clinical immunosuppression.
Background Art
Anti-cancer therapy utilizes a combination of therapeutic interventions such as surgery, radiation therapy and chemotherapy. Surgery and radiation therapy are generally confined locally to the main site of tumor growth, while chemotherapy is applied to prevent tumor re-growth or against distant tumor foci. Chemotherapeutic agents are also used to reduce tumor growth to manage disease progression when radiotherapy or surgery is not an option.
Immunosuppressive agents are clinically used to suppress a pathological immune reaction which targets the own body (autoimmunity) or overshooting immune reactions as seen in allergy. They are also used to treat transplant rejection caused by the immune system. Basic to immune responses is activation and proliferation of T cells following antigenic stimulation, which act in turn as helper cells for B cells, regulatory cells or effector cells. Immunosuppressive agents such as rapamycin or cyclosporine A act by inhibiting early T cell activation/proliferation. As both cancer and immune responses involve cell proliferation, some agents, for example rapamycin or its analogs, were initially used for immunosuppression but found later application as anticancer agents (Recher et al., Blood 2005, 105:2527-34).
Chemotherapeutic drugs are most effectively used in combination therapy. The rationale is to apply drugs that work via different mechanisms in order to decrease the probability of developing drug-resistant cancer cells. Combination therapy also allows, for certain drug combinations, an optimal combined dose to minimize side effects. This is crucial as standard chemotherapeutic agents target essential cellular process such as DNA replication, cell division or induce DNA damage and thus have a general cytotoxic effect.
Finally, combination treatment of two compounds may uncover unanticipated synergisms and trigger effects not induced by a single compound. In recent years, drugs are also used in a neoadjuvant setting, i.e. prior to surgery, to reduce the tumor mass or to improve long-term survival.
Metformin is a widely used biguanide drug for type 2 diabetes. It is related to buformin and phenformin, two biguanides not used anymore in diabetes due to toxicity. Metformin is safe and well-tolerated and has been used in long-term management of diabetes for over years and is the most-prescribed anti-diabetic drug worldwide. The main clinical benefit of metformin in the treatment of type 2 diabetes is the suppression of hepatic gluconeogenesis to reduce hyperglycemia and improved insulin sensitivity; these effects are believed to be exerted by metformin-dependent stimulation of AMP-activated protein kinase (AMPK) activity. Basic to this effect is the fact, that metformin and other biguanides inhibit complex 1 of the respiratory chain (electron transfer chain) of mitochondria (El-Mir et al., J Biol Chem 2000, 275:223-228)A meta-analysis of diabetic patients receiving metformin versus an unrelated anti-diabetic agent revealed that the metformin receiving cohort had lower incidence of cancer (Evans et al., BMJ 2005, 330:1304-5; Bowker et al., Diabetes Care 2006, 29:254-8). This has stimulated recent research into the use of metformin as an anti-cancer agent or prophylactic with numerous studies and trials in progress, see Gonzalez-Angulo et al., Clin Cancer Res 2010, 16:1695-700.
Syrosingopine is a synthetic derivative of reserpine, an anti-hypertensive and anti- psychotic agent (J Am Med Assoc. 1959;170(17):2090- 2092.doi:1 0.lOOlfjama.1959.0301 0170052011; Lucas et al., J.Am.Chem.Soc. 1959, 81:1928-32). Syrosingopine was introduced clinically in the late 1950s. The reserpines are rarely used today due to the development of better drugs with fewer side-effects.
Reserpine acts by inhibition of the vesicular monoamine transporter leading to catecholamine depletion and this mode of action is believed to be shared by all the reserpine derivatives with an anti-hypertensive effect. Although it has been clinically used, syrosingopine is relatively poorly studied compared to reserpine and has never been investigated as an anti-cancer agent.
Summary of the Invention
The invention relates to a combination of syrosingopine and metformin or other biguanides, and to pharmaceutical compositions comprising syrosingopine and metformin or other big uanides.
The invention also relates to the use of a combination of syrosingopine and metformin or other biguanides and of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides for the treatment of cancer, in particular for the treatment of carcinoma, leukemia, myeloma, and lymphoma, and for achieving immunosuppression in autoimmunity, transplantation medicine and in other cases where immunsuppresion is desirable, such as diseases of the skin, in particular psoriasis, nervous system, in particular multiple sclerosis, and of the haemopoietic system, in particular anemias; to the use of a combination of syrosingopine and metformin or other biguanides for the preparation of a pharmaceutical composition for the treatment of cancer and achieving immunosuppression, and to methods of treatment of cancer and of achieving immunosuppression using a combination of syrosingopine and metformin or other biguanides, or of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides.
Brief Description of the Figures
Figure 1: Metformin and syrosingopine synergise to kill tumour cells in vitro.
A to H: different cell lines. M = metformin, S = syrosingopine AlamarBlue conversion cell proliferation assay. Cells were seeded into 96-well microtiter plates and compounds added at the indicated concentration. Seeding cell density ranged from 5,000 to 15,000 cells per well and was determined empirically for each cell type.
Plates were incubated for 3 days and proliferation determined by AlamarBlue conversion.
Growth was normalized to the untreated controls and shown as percentages (V-axis).
Panels A-E show inhibition curves in a panel of sensitive cells, while panel F shows the growth curve in non-responding HTI 080 fibrosarcoma cells. Panels G-H show results from two non-cancerous normal human fibroblast lines (Fib3 and Fib4). For each cell line the left panel shows a titration of metformin with a dashed line indicating the concentration (5 mM) selected for co-treatment with syrosingopine. Right panel shows a similar growth curve with syrosingopine alone (solid line), and treatment with syrosingopine in the presence of 5 mM metformin (dashed line). All data points were performed in tripliclate.
Figure 2: Time-course for long term metformin and syrosingopine co-treatment.
A549 and OPM2 cells were seeded at an initial cell density of 10,000 cells/mI and 100,000 cells/mI, respectively, and compounds (M = metformin, S = syrosingopine) added at the indicated concentrations. For control, cells were incubated with solvent (0.1% DMSO).
The wells were sampled at the indicated time points for cell counting (d = days of treatment). Cell density was plotted on the Y-axis (x 1000 cells/mI).
Figure 3: Induction of apoptosis by metformin and syrosingopine co-treatment OPM2 and RPM18226 cells were seeded at a density of 100,000 cells/S ml medium with addition of compounds. OPM2: 5 pM syrosingopine (S), 2 mM metformin (M). RPM18226: 2 pM syrosingopine (S), 1 mM metformin (M). No compound = C (control), combination of syrosingopine and metformin = S-'-M. 500 p1 of culture was harvested after 3 days and the cells were washed and stained with propidium iodide/annexin V for FACS (fluorescent activated cell sorter) analysis. Annexin V is an apoptotic marker and was detected using a FITC-coupied antibody on the FL 1-channel. Propidium iodide (Pt) exclusion staining for vital cells was detected simultaneously on the FL3-channel. For each measurement, the Fl and annexin V negative cells represent the viable cell population (white bars). Early apoptotic cells are Fl-negative, annexin V-positive (hatched bars) and late apoptotic cells are P1-positive, annexin V-positive (black bars). Bars are plotted on the Y-axis as a percentage of the total cell population.
Figure 4: The structurally related compound reserpine does not synergise with metformin.
6.5 and OPM2 cells were co-treated with reserpine (R) and mefformin (M) over a similar concentration range in parallel with syrosingopine (5). Left panels show the effect on growth proliferation with reserpine alone. Right panels show the growth inhibition of syrosingopine (solid line) or reserpine (dashed line) in the presence of metformin (5 mM).
All data points were performed in triplicate. Growth was normalized to the respective untreated controls and expressed as percentages (1-axis).
Figure 5: In vivo effect of syrosingopine and metformin co-treatment in a mouse syngeneic tumor model.
6.5 cells were injected into the flanks of immunocompatible DBA mice. Drug treatment commenced when tumours reached 100 mm2 in size. Mice were separated into treatment groups and injected intra-peritoneally with PBS (bars), syrosingopine (5, filled diamonds, 2 mg/kg body weight), mefformin (M, filled triangles, 250 mg/kg body weight) and metformin plus syrosingopine (S+M, crossed squares) daily for 15 days. Mice were sacrificed when tumour size became excessive (day 15) and tumours were dissected for measurement. (A) Chart showing tumour area (in mm2) measured over the course of the treatment, d = days. (B) Mean body weight (g) of the mice at the time of sacrifice. Figures (n) above each bar indicate the number of mice per treatment group.
Figure 6: Metformin synergizes with the biguanide phenformin Left panel: 6.5 cells treated with the metformin analogue phenformin (F) for 3 days and growth determined by cell proliferation assay. Right panel: 6.5 cells co-treated with syrosingopine (S) with increasing concentrations of phenformin. Y-axis: % growth relative to untreated controls.
Figure 7: Co-treatment of metformin and syrosingopine inhibit phytohaemagglutinin (PHA)-stimulated T cell proilferation measured at day 3 Human peripheral blood leukocytes were cultured in presence or absence of phytohaemagglutinin. in the presence of phytoaemagglutinin (right panel) the combination of increasing amounts of syrosingopine with 4 mM metformin inhibits sharply T cell proliferation at low concentrations of syrosingopine (dashed line), but not in the absence of metformin (straight line). In the absence of PHA stimulation (left panel), cells survive (as seen microscopically) but do not proliferate at day 3. This survival is only minimally affected by combining syrosingopine with metformin (dashed line).
Detailed Description of the Invention
The invention relates to a combination of syrosingopine and metformin or other biguanides, and to pharmaceutical compositions comprising syrosingopine and metformin or other big uanides.
The invention relates furthermore to the use of a combination of syrosingopine and metformin or other biguanides and of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides for the treatment of cancer, in particular for the treatment of carcinoma, leukemia, myeloma, and lymphoma, and for the treatment of immunological disorders such as autoimmunity.
Mefformin is 3-(diam inomethylidene)-1,1 -dimethylguanidine hydrochloride of formula (I) NXNXNH2 1 (I) Other biguanides considered are, for example, phenformin or buformin, preferably phenformin.
Phenformin is I -(diaminomethylidene)-2-(2-phenylethyl)guanidine of formula (II) (NyNyeNH2 NH NH (II) Syrosingopine is a derivative of reserpine of formula (Ill),
OX
H HL I H" II 0,_.0 (Ill)
wherein the 4-methoxy group of the 3,4,5-trimethoxybenzoate part of reserpine is replaced by a 4-ethoxycarbonyloxy group, as shown in formula (IV).
H 0 0 (IV)
In view of the close relationship between basic compounds and their acid addition salts, metformin or phenformin means the free base or any acid addition salt thereof, and syrosingopine means the free base or any acid addition salt thereof. Salts are especially the pharmaceutically acceptable salts of syrosingopine.
Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantane carboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3-or 4-methyl-benzenesulfonic acid methylsulfunc acid ethylsulfunc acid dodecylsulfunc acid N-cyclohexylsulfamic acid, N-methyl-, N-ethyl-or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
Pharmaceutical compositions according to the invention are, for example, compositions for enteral administration, such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration. The compositions comprise syrosingopine and metformin or other biguanides alone or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the combination of syrosingopine and metformin or other biguanides depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
The pharmaceutical compositions comprise from approximately 1% to approximately 95% of the combination of syrosingopine and metformin or other biguanides, single-dose administration forms comprising in the preferred embodiment from approximately 20% to approximately 90% combination of syrosingopine and metformin or other biguanides and forms that are not of single-dose type comprising in the preferred embodiment from approximately 5% to approximately 20% combination of syrosingopine and metformin or other biguanides. Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules. Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, drops, sprays, and dispersions. Examples are capsules containing from about 0.05 g to about 1.0 g combination of syrosingopine and metformin or other biguanides.
The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
Preference is given to the use of solutions of the combination of syrosingopine and metformin or other biguanides, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the combination of syrosingopine and metformin or other biguanides alone or together with a carrier, for example mannitol, can be made up before use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinyl-pyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80® (polyoxyethylene(20)sorbitan mono-oleate).
Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. In respect of such, special mention may be made of liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di-or trivalent, alcohol, especially glycol and glycerol. As mixtures of fatty acid esters, vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful.
The manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
Suitable carriers for preferred solid oral dosage forms are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinyl-pyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl-methylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the combination of syrosingopine and metformin or other biguanides.
Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the combination of syrosingopine and metformin or other biguanides in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the combination of syrosingopine and metformin or other biguanides is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of syrosingopine and metformin or other biguanides and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
For parenteral administration, aqueous solutions of a combination of syrosingopine and metformin or other biguanides or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable. The combination of syrosingopine and metformin or other biguanides, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
On the basis of the studies described in more detail below, the combination of metformin of formula (I) or phenformin of formula (II), and syrosingopine of formula (IV), and pharmaceutical compositions comprising metformin or phenformin and syrosingopine according to the invention show therapeutic efficacy against different types of cancer including carcinomas, sarcomas, gliomas, leukemias, lymphomas, e.g. epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, naevi and melanomas, soft tissue tumors including sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial like neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumors, lymphatic vessel tumors, osseous and chondromatous neoplasms, giant cell tumors, miscellaneous bone tumors, gliomas, glioblastomas, oligodendrogliomas, neuroepitheliomatous neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative diseases, leukemias including acute and chronic leukemias, miscellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.
On the basis of the studies described in more detail below, the combination of metformin of formula (I) or phenformin of formula (II) and syrosingopine of formula (IV), and pharmaceutical compositions compnsing metformin or phenformin and syrosingopine
II
according to the invention show therapeutic efficacy against immunological diseases sensitive to blockade of I cell proliferation including connective tissue diseases such as lupus erythematodes, sclerodermia, polymyositis/dermatomyositis, mixed connective tissue disease, rheumatoid arthritis, Sjögren-syndrome, panarteriitis nodosa, Wegeners granulomatosis; systemic autoimmune diseases such as rheumatoid arthritis, Goodpasture's syndrome, Wegener's granulomatosis, polymyalgia rheumatica, Guillain-Barré syndrome, multiple sclerosis; localized autoimmune diseases such as type I diabetes mellitus, [-lashimoto's thyroiditis, Graves' disease, celiac disease, Crohn's disease, ulcerative colitis, Addison's disease, primary biliary cirrhosis, autoimmune hepatitis, and giant cell arteritis.
The combination of syrosingopine and metformin or other biguanides, and pharmaceutical compositions comprising syrosingopine and metformin or other biguanides according to the invention may be applied in the form of fixed combinations. Such fixed combination may contain syrosingopine and metformin or other biguanides in a relative amount (weight per weight) of between Ito 10 and Ito 1'OOO, preferably between Ito 100 and Ito 200, such as a combination of Ito 130, whereby the maximum recommended daily dose of metformin based on the experience with diabetes type 2 is 2'SSO mg. Alternatively, a covalent linkage between syrosingopine and metformin or other biguanides may be envisaged.
Alternatively, the combination of syrosingopine and metformin or other biguanides may be applied in two different, separate pharmaceutical compositions, optionally being provided together in a kit. The administration of metformin or of other biguanides and of syrosingopine may also be staggered, or the compounds may be given independently of one another within a reasonable time window.
Pharmaceutical compositions comprising syrosingopine and metformin or other biguanides may be further combined with other chemotherapeutic agents. Therapeutic agents for possible combination are especially one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several selected from the group comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan, or an inhibitor of polyamine biosynthesis, an inhibitor of the mTOR pathway, an inhibitor of mTOR-complex I or mTOR complex 2, an inhibitor of protein kinase, especially of serine/threonine protein kinase, such as protein kinase C, or of tyrosine protein kinase, such as epidermal growth factor receptor tyrosine kinase, a cytokine, a negative growth regulator, such as TGF-R or IFN-a, an aromatase inhibitor, a classical cytostatic, an inhibitor of the interaction of an SH2 domain with a phosphorylated protein, an inhibitor of Bcl-2 and modulators of the Bcl-2 family members such as Bax, Bid, Bad, Bim, Nip3 and BH3-only proteins.
The combination of syrosingopine and metformin or other biguanides, and pharmaceutical compositions comprising syrosingopine and metformin or other biguanides may be administered especially for cancer therapy in combination with radiotherapy, immuno-therapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies or neo-adjuvant therapy in combination with surgery. Other possible treatments are therapy to maintain the patient's status after tumor regression, or chemopreventive therapy, for example in patients at risk.
The present invention relates furthermore to a method for the treatment of cancer and of immunological disorders suach as autoimmunity, which comprises administering a combination of syrosingopine and metformin or other biguanides, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment. The combination of syrosingopine and metformin or other biguanides can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment. In the case of an individual having a bodyweight of about 70 kg the daily dose administered is from approximately 0.05 g to approximately 3 g, preferably from approximately 0.25 g to approximately 1.5 g, of a combination of the present invention.
The invention relates to the use of a combination of syrosingopine and metformin or other biguanides and of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides for the treatment of cancer, in particular for the treatment of the particular cancers mentioned above. More specifically, the invention relates to the use of a combination of syrosingopine and metformin or other biguanides and of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides for the treatment of carcinomas, sarcomas, leukemias, myelomas, lymphomas, and cancers of the nervous system. Furthermore, the invention relates to the use of a combination of syrosingopine and metformin or other biguanides and of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides for achieving immuno-suppression in autoimmunity, transplantation medicine and in other cases where immunosuppression is desirable, in particular in immunological diseases sensitive to blockade of I cell proliferation, systemic autoimmune diseases, and localized autoimmune diseases, as explained above. More specifically, the invention relates to the use of a combination of syrosingopine and mefformin or other biguanides and of pharmaceutical compositions comprising syrosingopine and metformin or other biguanides for the treatment of autoimmune diseases, such as autoimmune diseases of the skin, nervous system, connective tissue, muscle, nervous system, blood forming system, bone and inner organs, in particular psoriasis, multiple sclerosis, and anemias.
The preferred relative amount of syrosingopine and metformin or other biguanides, dose quantity and kind of pharmaceutical composition, which are to be used in each case, depend on the type of cancer or autoimmune disease, the severity and progress of the disease, and the particular condition of the patient to be treated, and has to be determined accordingly by the medical doctor responsible for the treatment.
The invention further relates to the use of a combination of syrosingopine and metformin or other biguanides for the preparation of a pharmaceutical composition for the treatment of cancer or autoimmune disease, as explained above.
Especially, the invention provides a method for treatment of cancer or autoimmune disease, which comprises administering a combination of syrosingopine and mefformin or other biguanides, or of a pharmaceutical composition comprising syrosingopine and metformin or other biguanides, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
Rationale for the use of a combination of syrosingopine and metformin or other biguanides.
A combination screen was performed, where cells were co-treated with the anti-diabetic agent metformin plus over a thousand drugs and drug-like compounds. It was found that metformin and syrosingopine synergise to kill various cancer cells in vitro and in vivo. This effect is only observed when the two drugs are combined, with minimal cytotoxicity for each individual compound.
Mouse mast cell line 6.5 was used for a preliminary screen. 6.5 cells show many features of oncogenic transformation such as loss of growth-factor (1L3) dependence and signaling pathway addiction. They are addicted to the P13K-mTOR-Akt pathway as well as to the MAP kinase pathway as shown by inhibitor studies. These cells display exquisite sensitivity to many clinical drugs. A drug co-screen using a commercial drug library (Prestwick Chemical Library) on mouse 6.5 cells in the presence of metformin (2 mM) was performed to identify compounds that would act as a metformin co-drug to kill these cells synergistically.
The best hit identified was syrosingopine. Fig IA shows, that metformin alone at 5 mM triggers 20% inhibition of growth (left panel), while syrosingopine alone is virtually non-inhibitory (right panel, straight line). However, when increasing concentrations of syrosingopine are combined with 5 mM metformin (right panel, dashed line), a dramatic inhibition is seen with 2.5 pM syrosingopine. Similar findings were made with a series of human cancer lines, specifically the myeloma line OPM2 (Fig. I B), the myeloma line RPM18226 (Fig. I C), the T cell leukemia line Jurkat (Fig. I D), the chronic myelogenous leukemia line K562 (Fig. I E). Notably, in these cell lines the combined activity showed potent activity at a concentration range where each compound used singly had only a marginal effect. In human fibrosarcoma line HTI 080 (Fig. I F) as well as in two normal human fibroblast lines (Fig. IC, H) no inhibition of growth was observed, when cells were co-treated with both drugs. This is corroboration for a specific response rather than general cytotoxicity. Table 1 summarizes data from these and additional lines tested.
Table 1: Panel of human cancer cells tested for sensitivity to metformin and syrosingopine co-treatment.
Human Cancer Cell Source Sensitivity OPM2 Multiple myeloma YES RPM18226 Multiple myeloma YES A549 Lung cancer YES MDA-468 Breast cancer YES H1299 Lung cancer YES AN3CA Endometrial cancer YES Jurkat T cell leukaemia YES K562 CML YES HTI 080 Fibrosarcoma NO MDA-231 Breast cancer NO JUSO Melanoma NO ME-59 Melanoma NO NA-8 Melanoma NO A time course experiment of the combined treatment was performed on two sensitive human cancer cell lines, OPM2 (multiple myeloma) and A549 (lung cancer). No out-growth was observed after g-i 0 days of treatment (Fig. 2). To see whether the inhibition observed involved actual apoptotic cell death, drug-treated cells were analyzed for membrane surface expression of annexin V, a marker of apoptosis, and by propidium iodide (P1) staining, revealing cell death. The number of apoptotic cells was increased with a corresponding decrease in the viable cell population in OPM2 and RPM 18226 human multiple myeloma cells undergoing the combined drug treatment, indicating apoptotic induction as the mechanism of cell killing (Fig. 3). No apoptotic induction was observed when the compounds were used singly.
Syrosingopine of formula (IV) is an artificial derivative of reserpine of formula (Ill), an anti-hypertensive agent, and shares the rauwolfia-specific chemical backbone. Other rauwolfia-related compounds, such as reserpine, reserpinnic acid, rescinnnamine, yohimbinic acid, corynanthine HCI, ajmalicine, yohimbine HCI, and rauwolscine HCI do not show significant interaction with metformin of formula (I) in cancer test cell lines. To confirm the specificity for syrosingopine, reserpine was tested over a range of concentrations in 6.5 and OPM2 cells. No interaction of reserpine with metformin was observed (Fig. 4), suggesting that syrosingopine is acting in a novel fashion compared to other rauwolfia derivatives.
To test if the interaction also holds in an in vivo context, 6.5 cells were injected into immunocompatible DBA mice. Treatment was begun when the tumors reached 100 mm2 in size. Mice were injected intra-peritoneally daily with syrosingopine (2 mg/kg body weight), metformin (250 mg/kg body weight) or both for 15 days and sacrificed for tumor dissection and measurement. As seen in Fig. 5A, the dual treatment successfully arrested tumor growth. There was no significant difference in body weight between the treatment groups (Fig. SB) or any signs of overt toxicity.
Mefformin is a biguanide similar to phenformin (formula II), an antidiabetic compound which is rarely in clinical use today due to side effects (lactic acidosis). It was tested whether phenformin also synergizes with syrosingopine. As shown in Fig. 6, left panel, phenformin treatment alone leads to no growth inhibition at concentrations up to 10 IIM.
When phenformin at this concentration, however, is combined with increasing concentrations of syrosingopine (Fig. 6, right panel), a strong synergistic effect is seen. In fact, a dose dependent synergistic effect is observed at all concentrations of phenformin tested.
The triggering of an immune response by antigenic stimulation involves early proliferation of T cells. This T cell stimulation can be mimicked by polyclonal stimulators such as lectins, for example phytohaemagglutinin (PHA). The combination of metformin and syrosingopine also inhibits PHA-stimulated T cell proliferation. Leukocytes isolated from the peripheral blood of normal human blood donors were tested, and proliferation measured on day 3 after incubation with metformin, syrosingopine, or both. As shown in Fig. 7, right panel, PHA-stimulated proliferation is very sensitive to inhibition when syrosingopine is combined with metformin (4 mM) (dashed line), but considerably less so in absence of metformin (solid line). The left panel of Fig. 7 shows peripheral blood leukocytes cultured for 3 days in the absence of PHA, where cells hardly proliferate but survive. This survival is not affected by the presence of increasing concentrations of syrosingopine in presence of 4 mM metformin (dashed line).
Examples
Cell culture Mouse mast cell line 6.5 was cultured in IMDM, 10% FCS, 2 mM L-glutamine, 100 U/mI penicillin, 100 pg/mI streptomycin and 50 pM 2-mercaptoethanol, exogenous IL-3 was added as 1% conditioned medium from X63 murine lL3 secreting cells. Human leukemia cell lines Jurkat, K562, OPM2, RPM 18226 were grown in RPM I-I 640 medium supplemented with 10% FCS, 2 mM L-glutamine. Recombinant human IL-6 (Biomol) was added at 10 ng/ml to the media for OPM2 and RPM18226. Adherent human cancer lines MDA-MB468, MDA-MB231, A549, H1299, AN3CA, JUSO, HTI 080, ME-59 and NA-8 were grown in Iscove's medium containing 10% FCS, 2 mM L-glutamine and 50 pM 2-mercaptoethanol. All cells were grown at 37°C in 5% CO2.
Reagents Metformin (Sigma) was prepared as a I M stock in PBS and kept at 4°C, syrosingopine (Extrasynthese) and reserpine (Sigma) were prepared as 5 mM stocks in DMSO and stored at -20°C.
Mouse mast cell line 6.5 The cell line 6.5 has recently been described (Colombi et al., Oncogene 2010, doi:1 0.1 038/onc.201 0.539).
These cells were generated by treating 15V4 mast cells (Nair et al., Oncogene 1992, 7:1963-72) with mutagen ICRI9I, which led to loss of the Pten tumor suppressor gene.
This loss abrogated the lL-3 dependence of the cells and generated growth autonomous cells which formed tumors in syngeneic mice.
Inhibitor studies of mouse mast cell line 6.5 Mouse mast cell line 6.5 cells are addicted to the Pl3K-mTOR-Akt pathway as well as to the MAP kinase pathway as shown to their sensitive to nanomolar concentrations of the mTOR-inhibitor rapamycin (Colombi et al., Oncogene, 2010, bc. cit.) or the Mek inhibitor U0126.
Cell proliferation assay Cells were seeded at appropriate density (5,000-15,000 cells per well depending on cell type, 150 p1 medium per well) in flat-bottomed 96-well plates and compounds added at the desired concentrations. After 3 days, proliferation was assayed by adding 0.1 vol. AlamarBlue (lnvitrogen), and fluorescence was read at 535/595 nm excitation/emission after 4-6 hours of color development. Readings were normalized to non-treated control cells and growth expressed as percentage of control growth.
Apoptosis assay Apoptosis was determined by Annexin V-FITC (Invitrogen) and propidium iodide counter-staining, and cells were analysed by FACS to distinguish between viable / early apoptotic / late apoptotic cell sub-populations. Cells were seeded at a density of 100,000 cells / 5 ml medium with addition of compounds as indicated. 500 p1 of culture was harvested after 3 days and the cells were washed and stained with PI/Annexin V before FACs analysis.
Mouse syngeneic tumor model 4 x 106.5 cells were injected in 150 p1 of PBS into the flanks of immuno-compatible DBA mice. Tumor progression was monitored and treatment was started when tumor area reached 100 mm2 in size. Mice were injected intra-peritoneally daily with metformin (250 mg/kg body weight), syrosingopine (2 mg/kg body weight) or combined for 15 days before being sacrificed for tumor tissue measurements.
A combination of metformin and syrosingopine kills mouse mast cells 6.5 A drug co-screen was performed using a commercial drug library (Prestwick Chemical Library) on mouse 6.5 cells in the presence of metformin (2 mM) to identify compounds that would act as a metformin co-drug to kill these cells synergistically.
Effect of metformin and sysrosingopine on pl-iytohaemagglutinin-stimulated T cell proliferation Normal human buffy coat cells were obtained from a local blood donation center in accordance with the rules. 80 ml of blood was diluted with 200 ml of lscove's medium and overlayed on a Ficoll gradient. The gradient was centrifuged at 1400 x g for 5 minutes to separate the leukocyte fraction from erythrocytes. Cells were plated on coated tissue culture dishes for 1 hour to remove adherent cells, and the remaining suspension cells were collected by centrifugation and counted with a haemocytometer. 50,000 cells were seeded per well in 96-well dishes and compounds were added according to the various treatment regimes to a final medium volume of 150 uI. For stimulation, phytohemagglutinin was added to a final concentration of 10 jig/mI. At day 3, proliferation was determined by AlamarBlue assay.
Claims (13)
- Claims 1. A pharmaceutical composition comprising syrosingopine and metformin or another biguanide.
- 2. The pharmaceutical composition of claim I comprising syrosingopine and metformin or phenformin.
- 3. The pharmaceutical composition of claim I comprising syrosingopine and metformin.
- 4. The pharmaceutical composition of claim 3 wherein the relative amount (weight per weight) of syrosingopine and metformin is between Ito 10 and Ito 1'OOO.
- 5. The pharmaceutical composition of claim 3 wherein the relative amount (weight per IS weight) of syrosingopine and metformin is between I to 10 and I to 200.
- 6. A combination of syrosingopine and metformin or another biguanide for use in the treatment of cancer or autoimmune diseases.
- 7. The combination of metformin and syrosingopine according to claim 6 for use in the treatment of carcinoma, sarcoma, leukemia, myeloma, lymphoma, and cancers of the nervous system.
- 8. The combination of metformin and syrosingopine according to claim 6 for use in immunosuppressive treatment.
- 9. The combination of metformin and syrosingopine according to claim 8 for use in the treatment of autoimmune diseases of the skin, nervous system, connective tissue, muscle, nervous system, blood forming system, bone and inner organs.
- 10. The combination of metformin and syrosingopine according to anyone of claims 6 to 9, wherein metformin and syrosingopine are part of the same pharmaceutical composition.
- 11. The combination of metformin and syrosingopine according to anyone of claims 6 to 9, wherein metformin and syrosingopine are in different pharmaceutical compositions.
- 12. Use of a combination of syrosingopine and metformin or another biguanide for the preparation of a pharmaceutical composition for the treatment of cancer or autoimmune disease.
- 13. A method for treatment of cancer or autoimmune disease, which comprises administering a combination of syrosingopine and metformin or another biguanide, or of a pharmaceutical composition comprising syrosingopine and metformin or another biguanide, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1100404.1A GB2487351A (en) | 2011-01-11 | 2011-01-11 | Combination of syrosingopine and a biguanide |
JP2013548805A JP5940559B2 (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
KR1020137016147A KR20130142164A (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
CA2824096A CA2824096A1 (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
CN201280005080.9A CN103442705B (en) | 2011-01-11 | 2012-01-09 | Be used for the treatment of the combination of cancer and immunosuppressant syrosingopine and mitochondrial inhibitors |
US13/977,811 US8993587B2 (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
RU2013137380/14A RU2602937C2 (en) | 2011-01-11 | 2012-01-09 | Combination of sirosingopin and mitochondrial inhibitors for treatment of cancer and for immunosuppression |
BR112013017499A BR112013017499A2 (en) | 2011-01-11 | 2012-01-09 | combination of sirosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
MX2013007835A MX2013007835A (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression. |
AU2012206649A AU2012206649A1 (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
EP12700325.9A EP2663298A1 (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
PCT/EP2012/050216 WO2012095379A1 (en) | 2011-01-11 | 2012-01-09 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
US14/627,283 US20150157623A1 (en) | 2011-01-11 | 2015-02-20 | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1100404.1A GB2487351A (en) | 2011-01-11 | 2011-01-11 | Combination of syrosingopine and a biguanide |
Publications (2)
Publication Number | Publication Date |
---|---|
GB201100404D0 GB201100404D0 (en) | 2011-02-23 |
GB2487351A true GB2487351A (en) | 2012-07-25 |
Family
ID=43664065
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB1100404.1A Withdrawn GB2487351A (en) | 2011-01-11 | 2011-01-11 | Combination of syrosingopine and a biguanide |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2487351A (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009029206A1 (en) * | 2007-08-24 | 2009-03-05 | Wake Forest University Health Sciences | Chemotherapeutic for inducing an msh2-dependent apoptotic pathway |
CN101691344A (en) * | 2009-10-26 | 2010-04-07 | 漆又毛 | Metformin acidic double salt compound and preparation method |
-
2011
- 2011-01-11 GB GB1100404.1A patent/GB2487351A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009029206A1 (en) * | 2007-08-24 | 2009-03-05 | Wake Forest University Health Sciences | Chemotherapeutic for inducing an msh2-dependent apoptotic pathway |
CN101691344A (en) * | 2009-10-26 | 2010-04-07 | 漆又毛 | Metformin acidic double salt compound and preparation method |
Also Published As
Publication number | Publication date |
---|---|
GB201100404D0 (en) | 2011-02-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8993587B2 (en) | Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression | |
AU2004296868B2 (en) | Methods for suppressing an immune response or treating a proliferative disorder | |
JP6911019B2 (en) | A therapeutic agent for lung cancer that has acquired EGFR-TKI resistance | |
TWI674898B (en) | Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof | |
TWI759316B (en) | Combination of a bcl-2 inhibitor and a mcl1 inhibitor, uses and pharmaceutical compositions thereof | |
EP3703755A1 (en) | Combination comprising at least one spliceosome modulator and at least one inhibitor chosen from bcl2 inhibitors, bcl2/bclxl inhibitors, and bclxl inhibitors and methods of use | |
JP2022145948A (en) | Combination treatment for hematological cancers | |
WO2014083095A1 (en) | Combinations of metformin with other compounds for the treatment of cancer and for immunosuppression | |
KR20160090814A (en) | Combination therapy comprising an inhibitor of jak, cdk and pim | |
WO2020000704A1 (en) | Use of ampk inhibitor, compound c, in drug for treating tumors | |
KR101882790B1 (en) | Pharmaceutical Composition Containing DUSP1 Inhibitor | |
GB2487351A (en) | Combination of syrosingopine and a biguanide | |
CN108992463B (en) | Composition and medicinal preparation for treating lung cancer | |
Chung et al. | Potentiation of Bortezomib-Induced Apoptosis by TGF-β in Cultured Human Tenon's Fibroblasts: Contribution of the PI3K/Akt Signaling Pathway | |
EP3565547B1 (en) | Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof | |
CN111228272B (en) | Medicine mixture and application thereof in preparation of medicine for reversing liver cancer sorafenib drug resistance | |
RU2784809C2 (en) | Combined product containing dicycloplatin and method for its production and use | |
TW201235037A (en) | Sensitizer, pharmaceutical composition, kit and use for target therapy | |
US20200009108A1 (en) | Compositions and Methods for Treating Epithelial Cancer | |
JP2020176145A (en) | Combination treatment for hematological cancers | |
JPH04182427A (en) | Antitumor agent containing xanthocillin x dimethyl ether | |
CN114642666A (en) | Pharmaceutical composition containing palbociclib and paclitaxel and application | |
CN114984015A (en) | Pharmaceutical combination composition for the treatment of proliferative diseases | |
JP2005507410A (en) | Combination of ATP competitive inhibitor of Bcr / abl kinase activity and tyrophostin analogue | |
CN110882273A (en) | Sensitization composition of antitumor drug and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |