CN111936125A - 穿透血脑屏障的方法 - Google Patents
穿透血脑屏障的方法 Download PDFInfo
- Publication number
- CN111936125A CN111936125A CN201980023885.8A CN201980023885A CN111936125A CN 111936125 A CN111936125 A CN 111936125A CN 201980023885 A CN201980023885 A CN 201980023885A CN 111936125 A CN111936125 A CN 111936125A
- Authority
- CN
- China
- Prior art keywords
- cancer
- cells
- cell
- carcinoma
- therapeutic agent
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 61
- 230000008499 blood brain barrier function Effects 0.000 title abstract description 34
- 210000001218 blood-brain barrier Anatomy 0.000 title abstract description 34
- 229930003658 monoterpene Natural products 0.000 claims abstract description 78
- 150000002773 monoterpene derivatives Chemical class 0.000 claims abstract description 75
- 235000002577 monoterpenes Nutrition 0.000 claims abstract description 75
- 210000004027 cell Anatomy 0.000 claims description 117
- 206010028980 Neoplasm Diseases 0.000 claims description 86
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Natural products CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 claims description 80
- 239000003814 drug Substances 0.000 claims description 79
- 229940124597 therapeutic agent Drugs 0.000 claims description 58
- 201000011510 cancer Diseases 0.000 claims description 54
- 229930007631 (-)-perillyl alcohol Natural products 0.000 claims description 41
- 235000005693 perillyl alcohol Nutrition 0.000 claims description 41
- 210000004556 brain Anatomy 0.000 claims description 39
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 36
- 239000002246 antineoplastic agent Substances 0.000 claims description 19
- 210000002865 immune cell Anatomy 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 229940127089 cytotoxic agent Drugs 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 14
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 210000003169 central nervous system Anatomy 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 208000005017 glioblastoma Diseases 0.000 claims description 8
- NTFOSUUWGCDXEF-UHFFFAOYSA-N 4-[5-(2,5-dimethylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide Chemical group CC1=CC=C(C)C(C=2N(N=C(C=2)C(F)(F)F)C=2C=CC(=CC=2)S(N)(=O)=O)=C1 NTFOSUUWGCDXEF-UHFFFAOYSA-N 0.000 claims description 6
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 6
- 239000012624 DNA alkylating agent Substances 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 6
- 229960004768 irinotecan Drugs 0.000 claims description 6
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 6
- 229960004964 temozolomide Drugs 0.000 claims description 6
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 4
- 239000002256 antimetabolite Substances 0.000 claims description 4
- 230000037396 body weight Effects 0.000 claims description 4
- 210000002472 endoplasmic reticulum Anatomy 0.000 claims description 4
- 239000002532 enzyme inhibitor Substances 0.000 claims description 4
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 claims description 4
- 229950005741 rolipram Drugs 0.000 claims description 4
- 230000000340 anti-metabolite Effects 0.000 claims description 3
- 229940100197 antimetabolite Drugs 0.000 claims description 3
- 229940045985 antineoplastic platinum compound Drugs 0.000 claims description 3
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 3
- 206010061311 nervous system neoplasm Diseases 0.000 claims description 3
- 150000003058 platinum compounds Chemical class 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 239000002464 receptor antagonist Substances 0.000 claims description 3
- 229940044551 receptor antagonist Drugs 0.000 claims description 3
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 3
- 125000002075 perillyl alcohol group Chemical group 0.000 claims 1
- 229930004725 sesquiterpene Natural products 0.000 abstract description 52
- 150000004354 sesquiterpene derivatives Chemical class 0.000 abstract description 52
- 239000000203 mixture Substances 0.000 description 67
- 201000009030 Carcinoma Diseases 0.000 description 56
- 239000007924 injection Substances 0.000 description 47
- 238000002347 injection Methods 0.000 description 47
- NDTYTMIUWGWIMO-SNVBAGLBSA-N (-)-perillyl alcohol Chemical compound CC(=C)[C@H]1CCC(CO)=CC1 NDTYTMIUWGWIMO-SNVBAGLBSA-N 0.000 description 46
- 238000001990 intravenous administration Methods 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 241000699670 Mus sp. Species 0.000 description 31
- 206010018338 Glioma Diseases 0.000 description 30
- -1 but not limited to Substances 0.000 description 30
- 238000011282 treatment Methods 0.000 description 30
- 206010038389 Renal cancer Diseases 0.000 description 27
- 239000000427 antigen Substances 0.000 description 23
- 108091007433 antigens Proteins 0.000 description 23
- 102000036639 antigens Human genes 0.000 description 23
- 208000006265 Renal cell carcinoma Diseases 0.000 description 22
- 229940079593 drug Drugs 0.000 description 21
- 201000010174 renal carcinoma Diseases 0.000 description 21
- 239000013543 active substance Substances 0.000 description 20
- 208000032612 Glial tumor Diseases 0.000 description 19
- 239000007925 intracardiac injection Substances 0.000 description 19
- 108700010039 chimeric receptor Proteins 0.000 description 18
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 17
- 101000603882 Homo sapiens Nuclear receptor subfamily 1 group I member 3 Proteins 0.000 description 17
- 238000009472 formulation Methods 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- 206010006187 Breast cancer Diseases 0.000 description 14
- 208000026310 Breast neoplasm Diseases 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 14
- 230000011664 signaling Effects 0.000 description 14
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 229960003699 evans blue Drugs 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 201000010099 disease Diseases 0.000 description 12
- 230000004083 survival effect Effects 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 201000001441 melanoma Diseases 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 10
- 102000001301 EGF receptor Human genes 0.000 description 10
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000003937 drug carrier Substances 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 201000003076 Angiosarcoma Diseases 0.000 description 9
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 9
- 206010004146 Basal cell carcinoma Diseases 0.000 description 9
- 108060006698 EGF receptor Proteins 0.000 description 9
- 208000001258 Hemangiosarcoma Diseases 0.000 description 9
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 9
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 9
- 206010039491 Sarcoma Diseases 0.000 description 9
- 201000008275 breast carcinoma Diseases 0.000 description 9
- 210000005240 left ventricle Anatomy 0.000 description 9
- 229940071648 metered dose inhaler Drugs 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 239000000443 aerosol Substances 0.000 description 8
- 210000000481 breast Anatomy 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 238000007917 intracranial administration Methods 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 230000035515 penetration Effects 0.000 description 8
- 210000000130 stem cell Anatomy 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 7
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 7
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 7
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 7
- 206010060862 Prostate cancer Diseases 0.000 description 7
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 7
- 229960003638 dopamine Drugs 0.000 description 7
- 239000006196 drop Substances 0.000 description 7
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 7
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 7
- 238000001361 intraarterial administration Methods 0.000 description 7
- 229960004891 lapatinib Drugs 0.000 description 7
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 230000003211 malignant effect Effects 0.000 description 7
- 239000006199 nebulizer Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 7
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 7
- RXBQNMWIQKOSCS-UHFFFAOYSA-N (7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl)methanol Chemical compound C1C2C(C)(C)C1CC=C2CO RXBQNMWIQKOSCS-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 208000003174 Brain Neoplasms Diseases 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 description 6
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- 206010025323 Lymphomas Diseases 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 206010033128 Ovarian cancer Diseases 0.000 description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 description 6
- MOYAFQVGZZPNRA-UHFFFAOYSA-N Terpinolene Chemical compound CC(C)=C1CCC(C)=CC1 MOYAFQVGZZPNRA-UHFFFAOYSA-N 0.000 description 6
- 208000009956 adenocarcinoma Diseases 0.000 description 6
- UAHWPYUMFXYFJY-UHFFFAOYSA-N beta-myrcene Chemical compound CC(C)=CCCC(=C)C=C UAHWPYUMFXYFJY-UHFFFAOYSA-N 0.000 description 6
- NEHNMFOYXAPHSD-UHFFFAOYSA-N citronellal Chemical compound O=CCC(C)CCC=C(C)C NEHNMFOYXAPHSD-UHFFFAOYSA-N 0.000 description 6
- QMVPMAAFGQKVCJ-UHFFFAOYSA-N citronellol Chemical compound OCCC(C)CCC=C(C)C QMVPMAAFGQKVCJ-UHFFFAOYSA-N 0.000 description 6
- 208000029742 colonic neoplasm Diseases 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 206010017758 gastric cancer Diseases 0.000 description 6
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- 230000004068 intracellular signaling Effects 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 201000010982 kidney cancer Diseases 0.000 description 6
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 6
- CDOSHBSSFJOMGT-UHFFFAOYSA-N linalool Chemical compound CC(C)=CCCC(C)(O)C=C CDOSHBSSFJOMGT-UHFFFAOYSA-N 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 6
- 208000029974 neurofibrosarcoma Diseases 0.000 description 6
- 201000002528 pancreatic cancer Diseases 0.000 description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000004936 stimulating effect Effects 0.000 description 6
- 201000011549 stomach cancer Diseases 0.000 description 6
- 229930006978 terpinene Natural products 0.000 description 6
- 150000003507 terpinene derivatives Chemical class 0.000 description 6
- 229950000578 vatalanib Drugs 0.000 description 6
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 5
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 5
- 208000009458 Carcinoma in Situ Diseases 0.000 description 5
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 5
- 208000015634 Rectal Neoplasms Diseases 0.000 description 5
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000000611 antibody drug conjugate Substances 0.000 description 5
- 229940049595 antibody-drug conjugate Drugs 0.000 description 5
- 229960000590 celecoxib Drugs 0.000 description 5
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000009977 dual effect Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 229960001433 erlotinib Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 229960005150 glycerol Drugs 0.000 description 5
- 201000004933 in situ carcinoma Diseases 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 5
- 239000004005 microsphere Substances 0.000 description 5
- 210000003928 nasal cavity Anatomy 0.000 description 5
- 239000003380 propellant Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 206010038038 rectal cancer Diseases 0.000 description 5
- 201000001275 rectum cancer Diseases 0.000 description 5
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 5
- WRYLYDPHFGVWKC-UHFFFAOYSA-N 4-terpineol Chemical compound CC(C)C1(O)CCC(C)=CC1 WRYLYDPHFGVWKC-UHFFFAOYSA-N 0.000 description 4
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 4
- 206010003571 Astrocytoma Diseases 0.000 description 4
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 4
- 208000006332 Choriocarcinoma Diseases 0.000 description 4
- 208000006168 Ewing Sarcoma Diseases 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 206010029260 Neuroblastoma Diseases 0.000 description 4
- KKMPSGJPCCJYRV-UHFFFAOYSA-N Nitidine Chemical compound C1=C2C3=[N+](C)C=C4C=C(OC)C(OC)=CC4=C3C=CC2=CC2=C1OCO2 KKMPSGJPCCJYRV-UHFFFAOYSA-N 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 206010070308 Refractory cancer Diseases 0.000 description 4
- 108091008605 VEGF receptors Proteins 0.000 description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 4
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 4
- CRPUJAZIXJMDBK-UHFFFAOYSA-N camphene Chemical compound C1CC2C(=C)C(C)(C)C1C2 CRPUJAZIXJMDBK-UHFFFAOYSA-N 0.000 description 4
- 230000005779 cell damage Effects 0.000 description 4
- 208000037887 cell injury Diseases 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 4
- 229960001625 furazolidone Drugs 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 229960002584 gefitinib Drugs 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 4
- 230000002055 immunohistochemical effect Effects 0.000 description 4
- 239000002955 immunomodulating agent Substances 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- XHWRWCSCBDLOLM-UHFFFAOYSA-N nolatrexed Chemical compound CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 XHWRWCSCBDLOLM-UHFFFAOYSA-N 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 229960005079 pemetrexed Drugs 0.000 description 4
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 4
- 239000003961 penetration enhancing agent Substances 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 4
- NDVASEGYNIMXJL-UHFFFAOYSA-N sabinene Chemical compound C=C1CCC2(C(C)C)C1C2 NDVASEGYNIMXJL-UHFFFAOYSA-N 0.000 description 4
- 229950003647 semaxanib Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 210000001578 tight junction Anatomy 0.000 description 4
- 229960000241 vandetanib Drugs 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 3
- 239000001490 (3R)-3,7-dimethylocta-1,6-dien-3-ol Substances 0.000 description 3
- QMVPMAAFGQKVCJ-SNVBAGLBSA-N (R)-(+)-citronellol Natural products OCC[C@H](C)CCC=C(C)C QMVPMAAFGQKVCJ-SNVBAGLBSA-N 0.000 description 3
- CDOSHBSSFJOMGT-JTQLQIEISA-N (R)-linalool Natural products CC(C)=CCC[C@@](C)(O)C=C CDOSHBSSFJOMGT-JTQLQIEISA-N 0.000 description 3
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 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 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 3
- 241000399988 Carinoma Species 0.000 description 3
- 208000005243 Chondrosarcoma Diseases 0.000 description 3
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000005792 Geraniol Substances 0.000 description 3
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 3
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RXBQNMWIQKOSCS-RKDXNWHRSA-N Myrtenol Natural products C1[C@H]2C(C)(C)[C@@H]1CC=C2CO RXBQNMWIQKOSCS-RKDXNWHRSA-N 0.000 description 3
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 3
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 3
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 201000000582 Retinoblastoma Diseases 0.000 description 3
- 108091008874 T cell receptors Proteins 0.000 description 3
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 3
- 229940123237 Taxane Drugs 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- VYBREYKSZAROCT-UHFFFAOYSA-N alpha-myrcene Natural products CC(=C)CCCC(=C)C=C VYBREYKSZAROCT-UHFFFAOYSA-N 0.000 description 3
- KQAZVFVOEIRWHN-UHFFFAOYSA-N alpha-thujene Natural products CC1=CCC2(C(C)C)C1C2 KQAZVFVOEIRWHN-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 229960003005 axitinib Drugs 0.000 description 3
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 3
- 210000000270 basal cell Anatomy 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- JGQFVRIQXUFPAH-UHFFFAOYSA-N beta-citronellol Natural products OCCC(C)CCCC(C)=C JGQFVRIQXUFPAH-UHFFFAOYSA-N 0.000 description 3
- 210000004782 brain capillary endothelium Anatomy 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 210000000621 bronchi Anatomy 0.000 description 3
- 229960004117 capecitabine Drugs 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000025084 cell cycle arrest Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 238000002659 cell therapy Methods 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229930003633 citronellal Natural products 0.000 description 3
- 235000000983 citronellal Nutrition 0.000 description 3
- 235000000484 citronellol Nutrition 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 3
- 229950009429 exatecan Drugs 0.000 description 3
- 239000008273 gelatin 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
- 229940113087 geraniol Drugs 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 208000014829 head and neck neoplasm Diseases 0.000 description 3
- 201000005787 hematologic cancer Diseases 0.000 description 3
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 235000001510 limonene Nutrition 0.000 description 3
- 229940087305 limonene Drugs 0.000 description 3
- 229930007744 linalool Natural products 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229940041616 menthol Drugs 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 230000006618 mitotic catastrophe Effects 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 229950008835 neratinib Drugs 0.000 description 3
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229950000891 nolatrexed Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 150000002977 perillyl alcohol derivatives Chemical class 0.000 description 3
- 150000007875 phellandrene derivatives Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 229960004641 rituximab Drugs 0.000 description 3
- 208000000649 small cell carcinoma Diseases 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 229960003787 sorafenib Drugs 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229960001796 sunitinib Drugs 0.000 description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 150000003505 terpenes Chemical class 0.000 description 3
- 235000007586 terpenes Nutrition 0.000 description 3
- 239000003734 thymidylate synthase inhibitor Substances 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 3
- XJPBRODHZKDRCB-UHFFFAOYSA-N trans-alpha-ocimene Natural products CC(=C)CCC=C(C)C=C XJPBRODHZKDRCB-UHFFFAOYSA-N 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 3
- FQTLCLSUCSAZDY-UHFFFAOYSA-N (+) E(S) nerolidol Natural products CC(C)=CCCC(C)=CCCC(C)(O)C=C FQTLCLSUCSAZDY-UHFFFAOYSA-N 0.000 description 2
- NDTYTMIUWGWIMO-JTQLQIEISA-N (+)-perillyl alcohol Chemical compound CC(=C)[C@@H]1CCC(CO)=CC1 NDTYTMIUWGWIMO-JTQLQIEISA-N 0.000 description 2
- NDVASEGYNIMXJL-NXEZZACHSA-N (+)-sabinene Natural products C=C1CC[C@@]2(C(C)C)[C@@H]1C2 NDVASEGYNIMXJL-NXEZZACHSA-N 0.000 description 2
- YHRUHBBTQZKMEX-YFVJMOTDSA-N (2-trans,6-trans)-farnesal Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\C=O YHRUHBBTQZKMEX-YFVJMOTDSA-N 0.000 description 2
- YHRUHBBTQZKMEX-UHFFFAOYSA-N (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-al Natural products CC(C)=CCCC(C)=CCCC(C)=CC=O YHRUHBBTQZKMEX-UHFFFAOYSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 2
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 2
- ARIWANIATODDMH-AWEZNQCLSA-N 1-lauroyl-sn-glycerol Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)CO ARIWANIATODDMH-AWEZNQCLSA-N 0.000 description 2
- 239000001169 1-methyl-4-propan-2-ylcyclohexa-1,4-diene Substances 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 2
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 2
- XZOBEDLKVOHSSH-UHFFFAOYSA-N 4-prop-1-en-2-ylcyclohexane-1-carboxylic acid Chemical compound CC(=C)C1CCC(C(O)=O)CC1 XZOBEDLKVOHSSH-UHFFFAOYSA-N 0.000 description 2
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 2
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 2
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000003847 Carboxypeptidase B2 Human genes 0.000 description 2
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 2
- BAVONGHXFVOKBV-UHFFFAOYSA-N Carveol Chemical compound CC(=C)C1CC=C(C)C(O)C1 BAVONGHXFVOKBV-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- 241000723346 Cinnamomum camphora Species 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- 206010073140 Clear cell sarcoma of soft tissue Diseases 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 2
- 208000008743 Desmoplastic Small Round Cell Tumor Diseases 0.000 description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 2
- YHRUHBBTQZKMEX-FBXUGWQNSA-N E,E-Farnesal Natural products CC(C)=CCC\C(C)=C/CC\C(C)=C/C=O YHRUHBBTQZKMEX-FBXUGWQNSA-N 0.000 description 2
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 102400001047 Endostatin Human genes 0.000 description 2
- 108010079505 Endostatins Proteins 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 206010015548 Euthanasia Diseases 0.000 description 2
- GVVPGTZRZFNKDS-YFHOEESVSA-N Geranyl diphosphate Natural products CC(C)=CCC\C(C)=C/COP(O)(=O)OP(O)(O)=O GVVPGTZRZFNKDS-YFHOEESVSA-N 0.000 description 2
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 2
- 102000006354 HLA-DR Antigens Human genes 0.000 description 2
- 108010058597 HLA-DR Antigens Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical group CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- GLZPCOQZEFWAFX-JXMROGBWSA-N Nerol Natural products CC(C)=CCC\C(C)=C\CO GLZPCOQZEFWAFX-JXMROGBWSA-N 0.000 description 2
- FQTLCLSUCSAZDY-ATGUSINASA-N Nerolidol Chemical compound CC(C)=CCC\C(C)=C\CC[C@](C)(O)C=C FQTLCLSUCSAZDY-ATGUSINASA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- IAPCTXZQXAVYNG-UHFFFAOYSA-M Potassium 2,6-dihydroxytriazinecarboxylate Chemical compound [K+].[O-]C(=O)C1=NC(=O)NC(=O)N1 IAPCTXZQXAVYNG-UHFFFAOYSA-M 0.000 description 2
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 2
- PXRCIOIWVGAZEP-UHFFFAOYSA-N Primaeres Camphenhydrat Natural products C1CC2C(O)(C)C(C)(C)C1C2 PXRCIOIWVGAZEP-UHFFFAOYSA-N 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 2
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 2
- 190014017285 Satraplatin Chemical compound 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 206010043515 Throat cancer Diseases 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 190014017283 Triplatin tetranitrate Chemical compound 0.000 description 2
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 2
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 208000008524 alveolar soft part sarcoma Diseases 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 229960003896 aminopterin Drugs 0.000 description 2
- 229960002550 amrubicin Drugs 0.000 description 2
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 2
- 229950001858 batimastat Drugs 0.000 description 2
- 229960002707 bendamustine Drugs 0.000 description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 2
- SEXRCKWGFSXUOO-UHFFFAOYSA-N benzo[a]phenazine Chemical class C1=CC=C2N=C3C4=CC=CC=C4C=CC3=NC2=C1 SEXRCKWGFSXUOO-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 229930003642 bicyclic monoterpene Natural products 0.000 description 2
- 201000009036 biliary tract cancer Diseases 0.000 description 2
- 208000020790 biliary tract neoplasm Diseases 0.000 description 2
- 239000000227 bioadhesive Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229930006739 camphene Natural products 0.000 description 2
- ZYPYEBYNXWUCEA-UHFFFAOYSA-N camphenilone Natural products C1CC2C(=O)C(C)(C)C1C2 ZYPYEBYNXWUCEA-UHFFFAOYSA-N 0.000 description 2
- 229930008380 camphor Natural products 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 2
- 229960000830 captopril Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- WNRZHQBJSXRYJK-UHFFFAOYSA-N carboxyamidotriazole Chemical compound NC1=C(C(=O)N)N=NN1CC(C=C1Cl)=CC(Cl)=C1C(=O)C1=CC=C(Cl)C=C1 WNRZHQBJSXRYJK-UHFFFAOYSA-N 0.000 description 2
- 229960002412 cediranib Drugs 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000019522 cellular metabolic process Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229950009003 cilengitide Drugs 0.000 description 2
- AMLYAMJWYAIXIA-VWNVYAMZSA-N cilengitide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]1CC1=CC=CC=C1 AMLYAMJWYAIXIA-VWNVYAMZSA-N 0.000 description 2
- 229940043350 citral Drugs 0.000 description 2
- WTEVQBCEXWBHNA-YFHOEESVSA-N citral B Natural products CC(C)=CCC\C(C)=C/C=O WTEVQBCEXWBHNA-YFHOEESVSA-N 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 201000000292 clear cell sarcoma Diseases 0.000 description 2
- 229960000928 clofarabine Drugs 0.000 description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 201000010918 connective tissue cancer Diseases 0.000 description 2
- 230000000139 costimulatory effect Effects 0.000 description 2
- 201000011063 cribriform carcinoma Diseases 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- SQIFACVGCPWBQZ-UHFFFAOYSA-N delta-terpineol Natural products CC(C)(O)C1CCC(=C)CC1 SQIFACVGCPWBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229960001776 edrecolomab Drugs 0.000 description 2
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 2
- 229950002339 elsamitrucin Drugs 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 208000037828 epithelial carcinoma Diseases 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 210000003722 extracellular fluid Anatomy 0.000 description 2
- 208000024519 eye neoplasm Diseases 0.000 description 2
- 206010016629 fibroma Diseases 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 229960004783 fotemustine Drugs 0.000 description 2
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 2
- 210000001652 frontal lobe Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- GVVPGTZRZFNKDS-JXMROGBWSA-N geranyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O GVVPGTZRZFNKDS-JXMROGBWSA-N 0.000 description 2
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 208000029824 high grade glioma Diseases 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003601 intercostal effect Effects 0.000 description 2
- 238000000185 intracerebroventricular administration Methods 0.000 description 2
- 229940084651 iressa Drugs 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229950005692 larotaxel Drugs 0.000 description 2
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 229940100491 laureth-2 Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 206010024627 liposarcoma Diseases 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 229960003538 lonidamine Drugs 0.000 description 2
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 2
- 210000005244 lower chamber Anatomy 0.000 description 2
- FBQPGGIHOFZRGH-UHFFFAOYSA-N lucanthone Chemical compound S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC FBQPGGIHOFZRGH-UHFFFAOYSA-N 0.000 description 2
- 229950005239 lucanthone Drugs 0.000 description 2
- 208000016992 lung adenocarcinoma in situ Diseases 0.000 description 2
- 201000000966 lung oat cell carcinoma Diseases 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 201000011614 malignant glioma Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229950008959 marimastat Drugs 0.000 description 2
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 2
- 229960005485 mitobronitol Drugs 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229930008383 myrcenol Natural products 0.000 description 2
- DUNCVNHORHNONW-UHFFFAOYSA-N myrcenol Chemical compound CC(C)(O)CCCC(=C)C=C DUNCVNHORHNONW-UHFFFAOYSA-N 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229950007221 nedaplatin Drugs 0.000 description 2
- 230000017095 negative regulation of cell growth Effects 0.000 description 2
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
- 229960000884 nelfinavir Drugs 0.000 description 2
- WASNIKZYIWZQIP-AWEZNQCLSA-N nerolidol Natural products CC(=CCCC(=CCC[C@@H](O)C=C)C)C WASNIKZYIWZQIP-AWEZNQCLSA-N 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 2
- 229960001420 nimustine Drugs 0.000 description 2
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 150000007823 ocimene derivatives Chemical class 0.000 description 2
- 201000008106 ocular cancer Diseases 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 238000012634 optical imaging Methods 0.000 description 2
- 230000002188 osteogenic effect Effects 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- CDSMSBUVCWHORP-UHFFFAOYSA-N perillic acid Chemical compound CC(=C)C1CCC(C(O)=O)=CC1 CDSMSBUVCWHORP-UHFFFAOYSA-N 0.000 description 2
- RUMOYJJNUMEFDD-UHFFFAOYSA-N perillyl aldehyde Chemical compound CC(=C)C1CCC(C=O)=CC1 RUMOYJJNUMEFDD-UHFFFAOYSA-N 0.000 description 2
- 150000005052 perimidines Chemical class 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 238000010837 poor prognosis Methods 0.000 description 2
- 229960004694 prednimustine Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 2
- 229950009213 rubitecan Drugs 0.000 description 2
- 229930006696 sabinene Natural products 0.000 description 2
- 229960005399 satraplatin Drugs 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000011272 standard treatment Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- 229940116411 terpineol Drugs 0.000 description 2
- MODVSQKJJIBWPZ-VLLPJHQWSA-N tesetaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3CC[C@@]2(C)[C@H]2[C@@H](C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C(=CC=CN=4)F)C[C@]1(O)C3(C)C)O[C@H](O2)CN(C)C)C(=O)C1=CC=CC=C1 MODVSQKJJIBWPZ-VLLPJHQWSA-N 0.000 description 2
- 229950009016 tesetaxel Drugs 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 2
- 229960000977 trabectedin Drugs 0.000 description 2
- 230000037317 transdermal delivery Effects 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 150000004654 triazenes Chemical class 0.000 description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
- 229950002860 triplatin tetranitrate Drugs 0.000 description 2
- 238000012285 ultrasound imaging Methods 0.000 description 2
- 229960001055 uracil mustard Drugs 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 229960000653 valrubicin Drugs 0.000 description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229940099039 velcade Drugs 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 2
- 229960000922 vinflunine Drugs 0.000 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- IHPKGUQCSIINRJ-UHFFFAOYSA-N β-ocimene Natural products CC(C)=CCC=C(C)C=C IHPKGUQCSIINRJ-UHFFFAOYSA-N 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- BAVONGHXFVOKBV-ZJUUUORDSA-N (-)-trans-carveol Natural products CC(=C)[C@@H]1CC=C(C)[C@@H](O)C1 BAVONGHXFVOKBV-ZJUUUORDSA-N 0.000 description 1
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- WJHFZYAELPOJIV-IJFRVEDASA-N (2E,6E)-farnesoic acid Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\C(O)=O WJHFZYAELPOJIV-IJFRVEDASA-N 0.000 description 1
- VQQFQUXKIKUEIU-DFWYDOINSA-N (2s)-5-oxopyrrolidine-2-carboxylic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.OC(=O)[C@@H]1CCC(=O)N1 VQQFQUXKIKUEIU-DFWYDOINSA-N 0.000 description 1
- GTXSRFUZSLTDFX-HRCADAONSA-N (2s)-n-[(2s)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-4-methyl-2-[[(2s)-2-sulfanyl-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butanoyl]amino]pentanamide Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](S)CCN1C(=O)N(C)C(C)(C)C1=O GTXSRFUZSLTDFX-HRCADAONSA-N 0.000 description 1
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- WUIFRGYQELQKDN-NTMALXAHSA-N (E)-Ocimene Natural products CC(C)CC\C=C(\C)C=C WUIFRGYQELQKDN-NTMALXAHSA-N 0.000 description 1
- IHPKGUQCSIINRJ-CSKARUKUSA-N (E)-beta-ocimene Chemical compound CC(C)=CC\C=C(/C)C=C IHPKGUQCSIINRJ-CSKARUKUSA-N 0.000 description 1
- TYDDWHVJHGIJCW-OLKPEBQYSA-N (Z)-Ocimene Natural products O[C@@H](C(=C)C)C/C=C(/C=C)\C TYDDWHVJHGIJCW-OLKPEBQYSA-N 0.000 description 1
- IHPKGUQCSIINRJ-NTMALXAHSA-N (Z)-beta-ocimene Chemical compound CC(C)=CC\C=C(\C)C=C IHPKGUQCSIINRJ-NTMALXAHSA-N 0.000 description 1
- FABAOYOFJNAVHB-KVVVOXFISA-N (z)-octadec-9-enoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O FABAOYOFJNAVHB-KVVVOXFISA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- RLXAQIXESOWNGY-UHFFFAOYSA-N 1-methyl-4-propan-2-ylbenzene Chemical compound CC(C)C1=CC=C(C)C=C1.CC(C)C1=CC=C(C)C=C1 RLXAQIXESOWNGY-UHFFFAOYSA-N 0.000 description 1
- HYYDHUILGLWOOP-UHFFFAOYSA-N 1-phenyl-2-(pyridin-2-ylamino)ethanol;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(O)CNC1=CC=CC=N1 HYYDHUILGLWOOP-UHFFFAOYSA-N 0.000 description 1
- AZLWQVJVINEILY-UHFFFAOYSA-N 2-(2-dodecoxyethoxy)ethanol Chemical compound CCCCCCCCCCCCOCCOCCO AZLWQVJVINEILY-UHFFFAOYSA-N 0.000 description 1
- QXRCPJZJWJTNCJ-UHFFFAOYSA-N 2-(2-dodecoxyethoxy)ethyl acetate Chemical compound CCCCCCCCCCCCOCCOCCOC(C)=O QXRCPJZJWJTNCJ-UHFFFAOYSA-N 0.000 description 1
- OAHKIYOTXOCPNI-UHFFFAOYSA-N 2-(2-dodecoxyethoxy)ethyl benzoate Chemical compound CCCCCCCCCCCCOCCOCCOC(=O)C1=CC=CC=C1 OAHKIYOTXOCPNI-UHFFFAOYSA-N 0.000 description 1
- MXWHMTNPTTVWDM-UHFFFAOYSA-N 2-[1-(diaminomethylidenehydrazinylidene)propan-2-ylideneamino]guanidine Chemical compound NC(N)=NN=C(C)C=NN=C(N)N MXWHMTNPTTVWDM-UHFFFAOYSA-N 0.000 description 1
- VUCGAFPTLRWSEB-UHFFFAOYSA-N 2-[2-(2-dodecoxyethoxy)ethoxy]acetic acid Chemical compound CCCCCCCCCCCCOCCOCCOCC(O)=O VUCGAFPTLRWSEB-UHFFFAOYSA-N 0.000 description 1
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 1
- NGOZDSMNMIRDFP-UHFFFAOYSA-N 2-[methyl(tetradecanoyl)amino]acetic acid Chemical compound CCCCCCCCCCCCCC(=O)N(C)CC(O)=O NGOZDSMNMIRDFP-UHFFFAOYSA-N 0.000 description 1
- PJKVJJYMWOCLIJ-UHFFFAOYSA-N 2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1h-quinazolin-4-one;hydron;dichloride Chemical compound Cl.Cl.CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 PJKVJJYMWOCLIJ-UHFFFAOYSA-N 0.000 description 1
- IXHQRYNLQLEBAI-UHFFFAOYSA-N 2-hydroxy-2-methyl-3-oxooctanoic acid Chemical compound CCCCCC(=O)C(C)(O)C(O)=O IXHQRYNLQLEBAI-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- XUSKJHCMMWAAHV-SANMLTNESA-N 220913-32-6 Chemical compound C1=C(O)C=C2C([Si](C)(C)C(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 XUSKJHCMMWAAHV-SANMLTNESA-N 0.000 description 1
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 description 1
- VVEPUJCLNRDIEQ-UHFFFAOYSA-N 3,8,9-trimethoxy-5-methylbenzo[c]phenanthridin-5-ium-2-ol;chloride Chemical compound [Cl-].C1=C(OC)C(OC)=CC2=C[N+](C)=C3C(C=C(C(=C4)O)OC)=C4C=CC3=C21 VVEPUJCLNRDIEQ-UHFFFAOYSA-N 0.000 description 1
- AEDQNOLIADXSBB-UHFFFAOYSA-N 3-(dodecylazaniumyl)propanoate Chemical compound CCCCCCCCCCCCNCCC(O)=O AEDQNOLIADXSBB-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- WRYLYDPHFGVWKC-SNVBAGLBSA-N 4-Terpineol Natural products CC(C)[C@]1(O)CCC(C)=CC1 WRYLYDPHFGVWKC-SNVBAGLBSA-N 0.000 description 1
- UICBHOXXGLYZJH-UHFFFAOYSA-N 5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium Chemical class C1=CC=C2CC[N+]3=CC4=CC=CC=C4C=C3C2=C1 UICBHOXXGLYZJH-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- IOAISUCAQCEHTA-UHFFFAOYSA-N 5-methyl-2-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(C)C=C1O.CC(C)C1=CC=C(C)C=C1O IOAISUCAQCEHTA-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 108090000644 Angiozyme Proteins 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000003609 Bile Duct Adenoma Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VUQAJHUAVIQPGY-UHFFFAOYSA-N CCO.CCO.CCCCCCCCCCCC(N)=O Chemical compound CCO.CCO.CCCCCCCCCCCC(N)=O VUQAJHUAVIQPGY-UHFFFAOYSA-N 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102400000730 Canstatin Human genes 0.000 description 1
- 101800000626 Canstatin Proteins 0.000 description 1
- LKUNXBRZDFMZOK-GFCCVEGCSA-N Capric acid monoglyceride Natural products CCCCCCCCCC(=O)OC[C@H](O)CO LKUNXBRZDFMZOK-GFCCVEGCSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102100031186 Chromogranin-A Human genes 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000134874 Geraniales Species 0.000 description 1
- ZPLQIPFOCGIIHV-UHFFFAOYSA-N Gimeracil Chemical compound OC1=CC(=O)C(Cl)=CN1 ZPLQIPFOCGIIHV-UHFFFAOYSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010018833 Haematocoele Diseases 0.000 description 1
- 208000005873 Hematocele Diseases 0.000 description 1
- 206010073069 Hepatic cancer Diseases 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
- 241001272567 Hominoidea Species 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- JZUTXVTYJDCMDU-MOPGFXCFSA-N Hydrastine Chemical compound CN1CCC2=CC=3OCOC=3C=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 JZUTXVTYJDCMDU-MOPGFXCFSA-N 0.000 description 1
- CRAVBINFWZGLSC-UHFFFAOYSA-N Hydrastine Natural products COC1=C(OC)C2C(C=C1)C(OC2=O)C3N(C)CCc4cc5OCOc5cc34 CRAVBINFWZGLSC-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- 102000006503 Janus Kinase 2 Human genes 0.000 description 1
- 108010019437 Janus Kinase 2 Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- 229920002884 Laureth 4 Polymers 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 102000013967 Monokines Human genes 0.000 description 1
- 108010050619 Monokines Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 241000581058 Myxodes Species 0.000 description 1
- 206010073137 Myxoid liposarcoma Diseases 0.000 description 1
- BACYUWVYYTXETD-UHFFFAOYSA-N N-Lauroylsarcosine Chemical compound CCCCCCCCCCCC(=O)N(C)CC(O)=O BACYUWVYYTXETD-UHFFFAOYSA-N 0.000 description 1
- WPPOGHDFAVQKLN-UHFFFAOYSA-N N-Octyl-2-pyrrolidone Chemical compound CCCCCCCCN1CCCC1=O WPPOGHDFAVQKLN-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000004264 Osteopontin Human genes 0.000 description 1
- 108010081689 Osteopontin Proteins 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 102100032341 PCNA-interacting partner Human genes 0.000 description 1
- 101710196737 PCNA-interacting partner Proteins 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 208000031839 Peripheral nerve sheath tumour malignant Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000004211 Platelet factor 4 Human genes 0.000 description 1
- 108090000778 Platelet factor 4 Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- KGZHFKDNSAEOJX-WIFQYKSHSA-N Ramoplanin Chemical compound C([C@H]1C(=O)N[C@H](CCCN)C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C)C(=O)N[C@H](C(=O)O[C@@H]([C@@H](C(N[C@@H](C(=O)N[C@H](CCCN)C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)[C@H](C)O)C=1C=CC(O)=CC=1)C=1C=CC(O)=CC=1)[C@@H](C)O)C=1C=CC(O)=CC=1)=O)NC(=O)[C@H](CC(N)=O)NC(=O)\C=C/C=C/CC(C)C)C(N)=O)C=1C=C(Cl)C(O)=CC=1)C=1C=CC(O)=CC=1)[C@@H](C)O)C=1C=CC(O[C@@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=1)C1=CC=CC=C1 KGZHFKDNSAEOJX-WIFQYKSHSA-N 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 102400001051 Restin Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- 201000001542 Schneiderian carcinoma Diseases 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010042658 Sweat gland tumour Diseases 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- VRGWBRLULZUWAJ-XFFXIZSCSA-N [(2s)-2-[(1r,3z,5s,8z,12z,15s)-5,17-dihydroxy-4,8,12,15-tetramethyl-16-oxo-18-bicyclo[13.3.0]octadeca-3,8,12,17-tetraenyl]propyl] acetate Chemical compound C1\C=C(C)/CC\C=C(C)/CC[C@H](O)\C(C)=C/C[C@@H]2C([C@@H](COC(C)=O)C)=C(O)C(=O)[C@]21C VRGWBRLULZUWAJ-XFFXIZSCSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 229930003651 acyclic monoterpene Natural products 0.000 description 1
- 150000002841 acyclic monoterpene derivatives Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002487 adenosine deaminase inhibitor Substances 0.000 description 1
- 208000018234 adnexal spiradenoma/cylindroma of a sweat gland Diseases 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 230000000964 angiostatic effect Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000001740 anti-invasion Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 239000000987 azo dye Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 150000001604 bicyclic monoterpene derivatives Chemical class 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 201000005200 bronchus cancer Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229930006737 car-3-ene Natural products 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 229930007796 carene Natural products 0.000 description 1
- BQOFWKZOCNGFEC-UHFFFAOYSA-N carene Chemical compound C1C(C)=CCC2C(C)(C)C12 BQOFWKZOCNGFEC-UHFFFAOYSA-N 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 229930007646 carveol Natural products 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229960000419 catumaxomab Drugs 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- ZXFCRFYULUUSDW-OWXODZSWSA-N chembl2104970 Chemical compound C([C@H]1C2)C3=CC=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2CC(O)=C(C(=O)N)C1=O ZXFCRFYULUUSDW-OWXODZSWSA-N 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- WDOGQTQEKVLZIJ-WAYWQWQTSA-N combretastatin a-4 phosphate Chemical compound C1=C(OP(O)(O)=O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 WDOGQTQEKVLZIJ-WAYWQWQTSA-N 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000010226 confocal imaging Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 108010038764 cytoplasmic linker protein 170 Proteins 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- JZUTXVTYJDCMDU-UHFFFAOYSA-N d-alpha-hydrastine Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 JZUTXVTYJDCMDU-UHFFFAOYSA-N 0.000 description 1
- 229960004969 dalteparin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- ODCCQUXDUXHSBP-UHFFFAOYSA-N decanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCC(O)=O ODCCQUXDUXHSBP-UHFFFAOYSA-N 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- UWLPCYBIJSLGQO-UHFFFAOYSA-N dodecanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCC(O)=O UWLPCYBIJSLGQO-UHFFFAOYSA-N 0.000 description 1
- HJXPPCPJEYUQFQ-HNNXBMFYSA-N dodecyl (2s)-5-oxopyrrolidine-2-carboxylate Chemical compound CCCCCCCCCCCCOC(=O)[C@@H]1CCC(=O)N1 HJXPPCPJEYUQFQ-HNNXBMFYSA-N 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- BKJIXTWSNXCKJH-UHFFFAOYSA-N elesclomol Chemical compound C=1C=CC=CC=1C(=S)N(C)NC(=O)CC(=O)NN(C)C(=S)C1=CC=CC=C1 BKJIXTWSNXCKJH-UHFFFAOYSA-N 0.000 description 1
- 229950003247 elesclomol Drugs 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000008472 epithelial growth Effects 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930002886 farnesol Natural products 0.000 description 1
- 229940043259 farnesol Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000009459 flexible packaging Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 210000005200 frontal scalp Anatomy 0.000 description 1
- VRGWBRLULZUWAJ-UHFFFAOYSA-N fusaproliferin Natural products C1C=C(C)CCC=C(C)CCC(O)C(C)=CCC2C(C(COC(C)=O)C)=C(O)C(=O)C21C VRGWBRLULZUWAJ-UHFFFAOYSA-N 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 210000001654 germ layer Anatomy 0.000 description 1
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 1
- 229950009073 gimatecan Drugs 0.000 description 1
- 229950009822 gimeracil Drugs 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 201000007574 granular cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000004920 hematocele of tunica vaginalis testis Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 102000052196 human PF4 Human genes 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 229930005369 hydrastine Natural products 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 229940096397 interleukin-8 Drugs 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229940061515 laureth-4 Drugs 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229950001845 lestaurtinib Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 230000035168 lymphangiogenesis Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 229960000733 mannosulfan Drugs 0.000 description 1
- UUVIQYKKKBJYJT-ZYUZMQFOSA-N mannosulfan Chemical compound CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](OS(C)(=O)=O)COS(C)(=O)=O UUVIQYKKKBJYJT-ZYUZMQFOSA-N 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930003647 monocyclic monoterpene Natural products 0.000 description 1
- 150000002767 monocyclic monoterpene derivatives Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- 208000022669 mucinous neoplasm Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- VIJMMQUAJQEELS-UHFFFAOYSA-N n,n-bis(ethenyl)ethenamine Chemical compound C=CN(C=C)C=C VIJMMQUAJQEELS-UHFFFAOYSA-N 0.000 description 1
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 description 1
- KUFCYNGJQRKYSQ-LJQANCHMSA-N n-[5-[[(1r)-3-amino-1-(3-chlorophenyl)propyl]carbamoyl]-2-chlorophenyl]-2-methoxy-7-oxo-8h-pyrido[2,3-d]pyrimidine-6-carboxamide Chemical compound C1([C@@H](CCN)NC(=O)C=2C=C(C(=CC=2)Cl)NC(=O)C2=CC3=CN=C(N=C3NC2=O)OC)=CC=CC(Cl)=C1 KUFCYNGJQRKYSQ-LJQANCHMSA-N 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 210000000441 neoplastic stem cell Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- SQABAALQCGKFFO-UHFFFAOYSA-N octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O SQABAALQCGKFFO-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002475 olfactory pathway Anatomy 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- BWKDAMBGCPRVPI-ZQRPHVBESA-N ortataxel Chemical compound O([C@@H]1[C@]23OC(=O)O[C@H]2[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]2(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]21)OC(C)=O)C3(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC(C)C)C(=O)C1=CC=CC=C1 BWKDAMBGCPRVPI-ZQRPHVBESA-N 0.000 description 1
- 229950001094 ortataxel Drugs 0.000 description 1
- 229950000193 oteracil Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229940043138 pentosan polysulfate Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 150000005041 phenanthrolines Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000008884 pinocytosis Effects 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 229940037129 plain mineralocorticoids for systemic use Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 210000004986 primary T-cell Anatomy 0.000 description 1
- 229950003608 prinomastat Drugs 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229930185346 proliferin Natural products 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 229930001510 protoberberine alkaloid Natural products 0.000 description 1
- 208000020016 psychiatric disease Diseases 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
- LKUNXBRZDFMZOK-UHFFFAOYSA-N rac-1-monodecanoylglycerol Chemical compound CCCCCCCCCC(=O)OCC(O)CO LKUNXBRZDFMZOK-UHFFFAOYSA-N 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229950003551 ramoplanin Drugs 0.000 description 1
- 108010076689 ramoplanin Proteins 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 208000009146 rhinoscleroma Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 108700004121 sarkosyl Proteins 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 201000008157 scrotal carcinoma Diseases 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940111630 tea tree oil Drugs 0.000 description 1
- 239000010677 tea tree oil Substances 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 150000007873 thujene derivatives Chemical class 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- RBNWAMSGVWEHFP-UHFFFAOYSA-N trans-p-Menthane-1,8-diol Chemical compound CC(C)(O)C1CCC(C)(O)CC1 RBNWAMSGVWEHFP-UHFFFAOYSA-N 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- RRBYUSWBLVXTQN-VZCHMASFSA-N tricyclene Natural products C([C@@H]12)C3C[C@H]1C2(C)C3(C)C RRBYUSWBLVXTQN-VZCHMASFSA-N 0.000 description 1
- RRBYUSWBLVXTQN-UHFFFAOYSA-N tricyclene Chemical compound C12CC3CC2C1(C)C3(C)C RRBYUSWBLVXTQN-UHFFFAOYSA-N 0.000 description 1
- 229930007794 tricyclic monoterpene Natural products 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000005102 tumor initiating cell Anatomy 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 0.000 description 1
- 108010060757 vasostatin Proteins 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- 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
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464411—Immunoglobulin superfamily
- A61K39/464412—CD19 or B4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/16—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring
- C07C13/23—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring with a cyclohexadiene ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/543—Mucosal route intranasal
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/544—Mucosal route to the airways
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P5/00—Preparation of hydrocarbons or halogenated hydrocarbons
- C12P5/007—Preparation of hydrocarbons or halogenated hydrocarbons containing one or more isoprene units, i.e. terpenes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Otolaryngology (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Endocrinology (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Dispersion Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Toxicology (AREA)
Abstract
本发明涉及使用单萜或倍半萜来穿透血脑屏障。
Description
技术领域
本发明涉及使用单萜或倍半萜来穿透血脑屏障。
背景技术
血脑屏障(BBB)是脑的血液、间质液(IF)和脑脊液(CSF)之间的连续边界。它由一层内皮细胞组成,即脑毛细血管内皮,是阻止高、低分子量血清成分进入脑组织的有效屏障。限制这类物质进入脑和CSF是由于脑毛细血管内皮的独特结构。尽管在其他器官中内皮层的细胞之间有贯穿整个内皮层的间隙和通道,这类通道在脑毛细血管内皮中缺乏,脑毛细血管内皮在其细胞之间的解剖学紧密连接以及罕见胞饮小泡(在其他内皮中常见)方面都是独一无二的。
在正常(健康)状态下,只有能够穿过BBB的物质才能进入脑,并且这类物质往往是相对疏水的(脂质样的)。亲水性(水溶性)的物质穿透BBB的效果要差得多,甚至根本没有。这类水溶性和穿透性差的物质包括一系列分子,从大到白蛋白的分子到小到钠的离子,以及化疗剂、药物、诊断成像化合物和具有潜在治疗用途的蛋白质。虽然有些治疗剂具有足够的脂溶性来穿透BBB,但绝大多数药物(例如青霉素)和其他治疗有用物质的脂溶性有限,因此不能很好地穿透BBB。许多潜在有用的药物对BBB的穿透性差,严重限制了脑组织和脑脊液疾病的治疗。因此,开发能够“打开”BBB的产品和方法,以允许已知在治疗或诊断脑障碍方面有效但自身无法穿过BBB的药物进入脑组织和脑脊液,将具有极其重要的临床意义。
恶性神经胶质瘤是中枢神经系统(CNS)癌症的最常见形式,目前认为基本不能治愈。在多种恶性神经胶质瘤中,间变性星形细胞瘤(III级)和多形性胶质母细胞瘤(GBM;IV级)预后特别差,这是由于它们的侵略性生长和对当前可用治疗的抗性。恶性神经胶质瘤的现有标准治疗包括手术、电离放疗和化疗。尽管近来在医学上的进展,但过去50年在恶性神经胶质瘤的预后上并未看到任何明显改善。Wen等Malignant gliomas in adults.New England J Med.359:492-507,2008。Stupp等Radiotherapy plus concomitant andadjuvant temozolomide for glioblastoma.New England J Med.352:987-996,2005。
恶性神经胶质瘤预后差的一个主要原因是难以递送足量化疗剂到脑。药物进入脑受到血脑屏障(BBB)的限制。最终到达脑的药物浓度通过肝脏的首关代谢和尿液排泄进一步降低。因此,往往需要侵入性手术,如肿瘤切除,立体定向注射抗肿瘤药物,或放置导管用于药物的对流增强递送。
鼻内递送药物提供了一种新的非侵入性治疗方法,可以绕过血脑屏障,迅速将药物直接递送到CNS。鼻内施用的药物在几分钟内到达脑实质组织、脊髓和/或脑脊液(CSF)。除了通过嗅束和三叉神经递送外,动物研究显示,治疗药物也通过鼻血管系统进行全身递送。Hashizume等New therapeutic approach for brain tumors:intranasal deliveryof telomerase inhibitor GRN163.Neuro-oncology 10:112-120,2008。Thorne等Delivery of insulin-like growth factor-1to the rat brain and spinal cordalong olfactory and trigeminal pathways following intranasaladministration.Neuroscience 127:481-496,2004。鼻内递送治疗剂可为其他类型的癌症,如肺癌、前列腺癌、乳腺癌、血液癌和卵巢癌等提供全身治疗方法。
尽管尝试了几十年,癌症的治愈性免疫治疗一直很难实现,其基本基础是抗原识别能力,无论是通过抗体还是通过T细胞(通过T细胞受体)(Cousin-Frankel,Science(2013)342:1432)。基于抗体的免疫治疗已广泛用于抗癌,当与正常细胞相比靶抗原在肿瘤细胞中上调(例如,在Her-2扩增型乳腺癌中的Her-2)的情况下,或当肿瘤细胞表达可被抗体或抗体-毒素缀合物(例如,抗CD20的利妥昔单抗(Rituximab))识别的抗原的情况下(Baselga等,Annals Oncology(2001)12:S35)。虽然使用基于抗体的免疫治疗的临床试验表明,在有限数量的癌症类型中(通常在与标准化疗联合时),患者生存率有所提高,但这些效果往往伴随着显著的安全性和有效性问题(Cousin-Frankel Cancer,Science(2013)342:1432)。
针对癌症的有效T细胞治疗在临床上更难以实现(Schmitt等,Hum.Gene Ther.(2009)20(11):1240)。有效的抗癌T细胞治疗依赖于对癌细胞上的抗原具有高亲和力结合的T细胞。嵌合抗原受体T细胞(CAR T细胞)广泛用于识别细胞上的抗原,具有高亲和力和特异性,不需要辅助识别分子,如HLA抗原来“呈递”肽。CAR T细胞的T细胞受体被结合抗原的重链和轻链“交换”,因此不需要HLA辅助分子。重组CAR T受体与信号传导结构域融合,导致T细胞在CAR T受体与靶抗原结合时活化。
紫苏醇(POH)是一种天然存在的单萜,已表明它是治疗包括CNS癌、乳腺癌、胰腺癌、肺癌、黑色素瘤和结肠癌的多种癌症的有效药物。Gould,M.Cancer chemopreventionand therapy by monoterpenes.Environ Health Perspect.1997,105(Suppl 4):977–979。制备了含有紫苏醇和类视黄醇的杂合分子,以提高细胞凋亡诱导活性。Das等Designand synthesis of potential new apoptosis agents:hybrid compounds containingperillyl alcohol and new constrained retinoids.Tetrahedron Letters 2010,51,1462–1466。
在癌症如恶性神经胶质瘤以及其他脑障碍如帕金森病和阿尔茨海默病的治疗中,仍然需要穿透血脑屏障来递送多种治疗剂。
发明概述
本发明提供对哺乳动物(例如人类)的中枢神经系统施用治疗剂的方法,该方法包括在治疗剂之前、之后或并行施用单萜。
中枢神经系统可以是脑。
单萜可以是紫苏醇。
可将单萜(例如,紫苏醇)施用入哺乳动物的血管系统,如动脉内(例如注射入动脉)。单萜(例如,紫苏醇)可通过吸入、鼻内、口服、静脉内、皮下或肌内施用。
单萜(例如,紫苏醇)可按约0.050mg/kg至约500mg/kg体重范围内的剂量施用。
单萜(例如,紫苏醇)可在施用治疗剂之前约0.2分钟至约60分钟、或约1分钟至约15分钟施用。
单萜和治疗剂可分开施用。
单萜和治疗剂可并行施用。在一个实施方案中,单萜和治疗剂在药物组合物(例如溶液)中一起施用。
治疗剂可以是化疗剂。化疗剂的非限制性实例包括DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、酶抑制剂、受体拮抗剂、治疗性抗体及其组合。化疗剂可以是二甲基塞来昔布(DMC)、伊立替康(CPT-11)、替莫唑胺或咯利普兰。
治疗剂可以是抗体或抗体片段。
治疗剂可以是表达嵌合抗原受体的免疫细胞。该免疫细胞可以是T细胞。在一个实施方案中,该治疗剂是CAR-T细胞。
哺乳动物可以患有癌症,如神经系统肿瘤(如胶质母细胞瘤)。
所述方法可以进一步包括用辐射治疗该哺乳动物的步骤。
附图简述
图1显示Lym-1 CAR和CD19(FMC 63)CAR构建体的示意图。
图2A显示脑肿瘤内人CAR T细胞的累积。图2A显示免疫组化(IHC)染色,以检测人CAR T细胞在脑和所形成的肿瘤(GL261小鼠神经胶质瘤)内的渗透。用抗人CD3抗体(CD3ε(D7A6ETM)兔mAb(#85061)(Cell Signaling,Boston,MA)一抗识别人源CD3阳性细胞。
图2B显示培养的人CAR T细胞上的CD3表达。
图2C显示正常C57 BL/6脑切片中的CD3染色。
图2D显示,在通过静脉内(IV)注射提供Lym-1人CAR T细胞时,具有GL261小鼠神经胶质瘤的脑中CD3的表达。
图2E显示,在IC注射3%NEO100后IV注射Lym-1人CAR T细胞时,具有GL261小鼠神经胶质瘤的脑中CD3的表达。
图2F显示,在通过静脉内(IV)注射提供抗CD19人CAR T细胞时,具有GL261小鼠神经胶质瘤的脑中CD3的表达。
图2G显示,在IC注射3%NEO100后IV注射抗CD19人CAR T细胞时,具有GL261小鼠神经胶质瘤的脑中CD3的表达。
图2H显示带有GL261肿瘤的脑的正常部分中CD3阳性细胞的比较。
图3显示存活率,反映没有或存在紫苏醇的情况下在带有同基因小鼠GBM(GL261)的C57 BL/6中抗小鼠PD-1抗体介导的治疗效果。
图4A-4D显示,NEO100可应用于跨过体外BBB模型,并瞬时允许标记抗体跨过该模型。图4A显示体外脑屏障紧密连接模型。标记组分为Transwell趋化室、上室、多孔膜和下室。Transwell培养室(孔径:0.8μm)。Madin-Darby犬肾(MDCK)细胞是上皮细胞。TEER:跨上皮/跨内皮电阻。荧光Ab:Alexa488;驴抗大鼠IgG(H+L)。在大约120分钟内测量下室中的荧光。图4B显示随着浓度的增加,荧光标记抗体穿过上室的渗透增强。图4C显示使用浓度2mM的NEO100后,TEER的减少。图4D显示应用NEO100后TEER的恢复时间。
图5A显示NEO100(不同浓度)和2%埃文斯蓝(EB)混合物的心内注射(IC)。
图5B显示通过IC(心内注射)或IV注射应用NEO100后EB在脑中的透入。
图6显示NEO100破坏脑中的紧密连接。
图7显示NEO100介导多巴胺递送通过破坏的血脑屏障。
图8显示BBB打开和关闭时间的测量。
图9显示在没有或存在紫苏醇的情况下抗小鼠IgG抗体的递送。
图10显示在没有或存在紫苏醇的情况下抗PD-1抗体的递送。
图11显示NEO100介导的人CAR T细胞(Lym-1 CAR)递送治疗NSG小鼠颅内Raji淋巴瘤异种移植后的Kaplan-Meier存活曲线。
本文所用的术语“NEO100”指紫苏醇。
发明详述
本发明提供使用单萜或倍半萜或其衍生物(例如紫苏醇或POH、异紫苏醇、或紫苏醇衍生物)来穿透血脑屏障的方法。因此,单萜或倍半萜可用于递送至少一种治疗剂跨过BBB。
单萜(或倍半萜)的纯度可大于约98.5%(w/w)、大于约99.0%(w/w)或大于约99.5%(w/w)。
可在存在或不存在治疗剂的情况下将单萜(或倍半萜)配制为药物组合物,其中单萜(或倍半萜)以约0.01%(w/w)至约100%(w/w)、约0.1%(w/w)至约80%(w/w)、约1%(w/w)至约70%(w/w)、约10%(w/w)至约60%(w/w),约1%(w/w)至约10%(w/w)、约1%(w/w)至约5%(w/w)、约1%(w/w)至约3%(w/w)、约3%(w/w)至约10%(w/w)、或约0.1%(w/w)至约20%(w/w)的量存在。
单萜(例如,紫苏醇)可以按约0.050mg/kg至约500mg/kg体重范围内的剂量施用。其他范围包括约0.1mg/kg至约100mg/kg、约1mg/kg至约50mg/kg、约5mg/kg至约25mg/kg以及约10mg/kg至约15mg/kg。
单萜或倍半萜可与至少一种治疗剂联合使用,该治疗剂包括但不限于化疗剂、免疫治疗剂、免疫调节剂、抗体(例如,单克隆抗体)、免疫细胞(例如,CAR-T细胞)、疫苗、抗体-药物缀合物、抗病毒剂、消炎剂、抗细菌剂、抗微生物剂、抗生素及其组合。
可以与纯化的单萜或倍半萜联合使用的抗癌剂可对癌细胞或个体具有以下一种或多种作用:细胞死亡;细胞增殖减少;细胞数量减少;细胞生长抑制;凋亡;坏死;有丝分裂灾难(mitotic catastrophe);细胞周期阻滞(cell cycle arrest);细胞大小减小;细胞分裂减少;细胞存活率降低;细胞代谢减少;细胞损伤或细胞毒性的标志物;细胞损伤或细胞毒性的间接指标,如肿瘤缩小;个体生存率提高;或与非期望的、不需要的或异常的细胞增殖相关的标志物的消失。美国专利公开号20080275057。
治疗剂可溶解于紫苏醇中。本发明的组合物可单独施用,或可与放射或另一活性剂(例如,化疗剂)一起共同施用,以治疗诸如癌症的疾病。
在一些实施方案中,该活性剂是抗体-药物缀合物。在一些实施方案中,抗体-药物缀合物包含抗原结合片段和在靶细胞中诱导细胞毒性的毒素或药物。可用于抗体-药物缀合物的毒素或药物为本领域公知,且对本领域普通技术人员而言显而易见。参见例如Peters et al.Biosci.Rep.(2015)35(4):e00225。在一些实施方案中,抗体-药物缀合物可进一步包含连接抗体和药物分子的接头(例如,肽接头,例如可切割接头)。
治疗可以是顺次的,单萜(或倍半萜)可以在施用治疗剂之前或之后施用。备选地,单萜(或倍半萜)和治疗剂可并行施用。
单萜(或倍半萜)和至少一种治疗剂可同时、分开或顺次施用。它们可以发挥有利的联合效应(例如,加和或协同效应)。
对于顺次施用,可以先施用单萜(或倍半萜),然后施用治疗剂,或者先施用治疗剂,然后施用单萜(或倍半萜)。在单萜(或倍半萜)和治疗剂分开施用的实施方案中,单萜(或倍半萜)的施用可以在施用治疗剂之前或备选地在施用治疗剂之后数秒、数分钟、数小时、数日或数周。非同时施用中的时间差可以大于1分钟,并且可以例如精确地为至少、至多或小于5分钟、10分钟、15分钟、30分钟、45分钟、60分钟、2小时、3小时、6小时、9小时、12小时、24小时、36小时或48小时,或超过48小时。所述两种或两种以上活性剂可在彼此相隔数分钟内或在彼此相隔约0.5、约1、约2、约3、约4、约6、约9、约12、约15、约18、约24或约36小时内,或在彼此相隔约1、2、3、4、5、6、7、8、9、10、12、14天内、或在彼此相隔约2、3、4、5、6、7、8、9或10周内施用。在某些情况下,间隔可以更长。
本公开还提供药物组合物,其包含(i)至少一种单萜(或倍半萜);和(ii)至少一种治疗剂。
给药途径可以不同,并且可以包括动脉内给药、吸入、鼻内、口服、经皮、静脉内、皮下或肌内注射。
本发明还提供用于治疗诸如癌症的疾病的方法,其包括将本发明的组合物递送给患者的步骤。
本发明组合物可以含有一种或多种类型的单萜(或倍半萜)。单萜包括具有两个异戊二烯单元并且分子式为C10H16的萜烯。单萜可以是线性的(无环的)或含有环。通过生物化学修饰例如单萜氧化或重排产生的类单萜、以及单萜或类单萜的可药用盐,也为本发明所涵盖。单萜和类单萜的实例包括紫苏醇(S(-)和R(+))(perillyl alcohol)、焦磷酸香叶酯(geranyl pyrophosphate)、罗勒烯(ocimene)、月桂烯(myrcene)、香叶醇(geraniol)、柠檬醛(citral)、香茅醇(citronellol)、香茅醛(citronellal)、芳樟醇(linalool)、蒎烯(pinene)、萜品醇(terpineol)、萜品烯(terpinen)、柠檬烯(limonene)、松油烯(terpinenes)、水芹烯(phellandrenes)、萜品油烯(terpinolene)、松油烯-4-醇(或茶树油)(terpinen-4-ol)、蒎烯、萜品醇、萜品烯;类萜化合物,如p-伞花烃(p-cymene),其源自于单环萜如薄荷醇(menthol)、百里香酚(thymol)和香芹酚(carvocrol);双环类单萜化合物,如樟脑(camphor)、冰片(borneol)和桉树脑(eucalyptol)。
单萜可以通过碳骨架结构来区分,且可以分组为无环单萜(例如月桂烯、(Z)-和(E)-罗勒烯、芳樟醇、香叶醇、橙花醇(nerol)、香茅醇、月桂烯醇(myrcenol)、香叶醛、柠檬醛a、橙花醛、柠檬醛b、香茅醛等)、单环单萜(例如柠檬烯、松油烯、水芹烯、萜品油烯、薄荷醇、香芹醇等)、双环单萜(例如蒎烯、桃金娘烯醇(myrtenol)、桃金娘烯醛(myrtenal)、马鞭草烷醇(verbanol)、马鞭烷酮(verbanon)、松香芹醇(pinocarveol)、蒈烯(carene)、桧烯(sabinene)、莰烯(camphene)、侧柏烯(thujene)等)、和三环单萜(例如三环萜(tricyclene))。参见Encyclopedia of Chemical Technology,第4版,23卷,834-835页。
本发明的倍半萜包括具有三个异戊二烯单元并且分子式为C15H24的萜烯。倍半萜可以是线性的(无环的)或含有环。通过生物化学修饰如倍半萜的氧化或重排产生的类倍半萜也为本发明所涵盖。倍半萜的实例包括法尼醇(farnesol)、法尼醛(farnesal)、法尼酸(farnesylic acid)和橙花叔醇(nerolidol)。
单萜(或倍半萜)的衍生物包括但不限于单萜(或倍半萜)的酯、醇、醛和酮。单萜(倍半萜)醇可以衍生成酯、醛或酸。
本发明的单萜(或倍半萜)醇的酯可以从无机酸或有机酸衍生得到。无机酸包括但不限于磷酸、硫酸和硝酸。有机酸包括但不限于羧酸,如苯甲酸、脂肪酸、乙酸和丙酸。单萜(或倍半萜)醇的酯的实例包括但不限于羧酸酯(如苯甲酸酯、脂肪酸酯(例如棕榈酸酯和亚油酸酯)、乙酸酯、丙酸酯(propionates或propanoates)和甲酸酯)、磷酸酯、硫酸酯和氨基甲酸酯(例如Ν,Ν-二甲氨基碳酰)。维基百科-酯,获自URL:http://en.wikipedia.org/wiki/Ester。
可用于本发明的单萜的具体实例是紫苏醇(通常缩写为POH)。本发明的紫苏醇组合物可以含有(S)-紫苏醇、(R)-紫苏醇、或(S)-紫苏醇和(R)-紫苏醇的混合物。
术语“嵌合受体”、“嵌合抗原受体”或备选地“CAR”在本文中可互换使用,是指至少包含胞外抗原结合结构域、跨膜结构域及含有下文定义的刺激分子的功能性信号传导结构域的胞质信号传导结构域(在本文中也称为“胞内信号传导结构域”)的重组多肽构建体。Lee等,Clin.Cancer Res.(2012)18(10):2780;Jensen等,Immunol Rev.(2014)257(1):127;www.cancer.gov/about-cancer/treatment/research/car-t-cells。在一个实施方案中,刺激分子是与T细胞受体复合物结合的ζ链。在一方面,该胞质信号传导结构域还包含源自下文定义的至少一个共刺激分子的一个或多个功能性信号传导结构域。共刺激分子也可以是4-1BB(即CD137)、CD27和/或CD28或这些分子的片段。在另一方面,CAR包含嵌合融合蛋白,该嵌合融合蛋白包含胞外抗原识别结构域、跨膜结构域和含有源自刺激分子的功能性信号传导结构域的胞内信号传导结构域。CAR包含嵌合融合蛋白,该嵌合融合蛋白包含胞外抗原识别结构域、跨膜结构域和胞内信号传导结构域,该胞内信号传导结构域包含源自共刺激分子的功能性信号传导结构域和源自刺激分子的功能性信号传导结构域。备选地,CAR包含嵌合融合蛋白,该嵌合融合蛋白包含胞外抗原识别结构域、跨膜结构域和胞内信号传导结构域,该胞内信号传导结构域包含源自一个或多个共刺激分子的两个功能性信号传导结构域和源自刺激分子的一个功能性信号传导结构域。CAR还可以包含嵌合融合蛋白,该嵌合融合蛋白包含胞外抗原识别结构域、跨膜结构域和胞内信号传导结构域,该胞内信号传导结构域包含源自一个或多个共刺激分子的至少两个功能性信号传导结构域和源自刺激分子的一个功能性信号传导结构域。CAR的抗原识别部分可包含任何抗原结合抗体片段。抗体片段可包含一个或多个CDR、可变区(或其部分)、恒定区(或其部分)或上述任一者的组合。
如本文所用,嵌合受体是指可在宿主细胞表面表达并包含抗原结合片段的非天然存在的分子。一般而言,嵌合受体包含源自不同分子的至少两个结构域。除了本文所述的抗原结合片段外,嵌合受体可进一步包含铰链结构域、跨膜结构域、至少一个共刺激结构域和胞质信号传导结构域中的一个或多个。在一些实施方案中,嵌合受体从N端到C端包含抗原结合片段、铰链结构域、跨膜结构域和胞质信号传导结构域。在一些实施方案中,嵌合受体还包含至少一个共刺激结构域。
在一些实施方案中,本文所述的嵌合受体包含铰链结构域,其可位于抗原结合片段和跨膜结构域之间。铰链结构域是氨基酸片段,其通常见于蛋白质的两个结构域之间,可允许蛋白质的柔性和两个结构域中的一个或两者相对于彼此的运动。提供这种柔性和抗原结合片段相对于嵌合受体的另一个结构域的运动性的任何氨基酸序列都可以使用。
本文所述的嵌合受体中的任一个都可以通过常规技术引入合适的免疫细胞中进行表达。在一些实施方案中,免疫细胞是T细胞,如原代T细胞或T细胞系。备选地,免疫细胞可以是NK细胞,如建立的NK细胞系(例如NK-92细胞)。在一些实施方案中,免疫细胞是表达CD8(CD8+)或CD8和CD4(CD8+/CD4+)的T细胞。在一些实施方案中,T细胞是已建立的T细胞系的T细胞,例如293T细胞或Jurkat细胞。
在一些实施方案中,按有效量对个体施用表达本文所述的任意嵌合受体的免疫细胞,以将靶细胞(例如癌细胞)的数量减少至少20%,例如50%、80%、100%、2倍、5倍、10倍、20倍、50倍、100倍或更多。
向哺乳动物(例如人)施用的细胞(例如免疫细胞(如CAR T细胞))的典型量可以例如,在100万至1000亿个细胞的范围内;然而,低于或高于此示例性范围的量也在本公开的范围内。例如,细胞的每日剂量可为约100万至约500亿个细胞(例如约500万个细胞、约2500万个细胞、约5亿个细胞、约10亿个细胞、约50亿个细胞、约200亿个细胞、约300亿个细胞、约400亿个细胞,或由上述任何两个值定义的范围),优选约1000万到1000亿个细胞(例如约2000万个细胞,约3000万个细胞、约4000万个细胞、约6000万个细胞、约7000万个细胞、约8000万个细胞、约9000万个细胞、约100亿个细胞、约250亿个细胞、约500亿个细胞、约750亿个细胞、约900亿个细胞,或由上述任何两个值定义的范围),更优选约1亿个细胞至约500亿个细胞(例如约1.2亿个细胞、约2.5亿个细胞、约3.5亿个细胞、约4.5亿个细胞、约6.5亿个细胞、约8亿个细胞、约9亿个细胞、约30亿个细胞,约300亿个细胞,约450亿个细胞,或由上述任何两个值定义的范围)。
在一个实施方案中,将嵌合受体(例如编码嵌合受体的核酸)引入免疫细胞,并且个体(例如人患者)接受表达该嵌合受体的免疫细胞的初始施用或剂量。可在前一次施用后间隔15天、14天、13天、12天、11天、10天、9天、8天、7天、6天、5天、4天、3天或2天向患者提供一次或多次后续的活性剂(例如表达嵌合受体的免疫细胞)施用。每周可对个体施用一个以上剂量的活性剂,例如2、3、4或多剂的活性剂施用。个体每周可接受一个以上剂量的活性剂(例如表达嵌合受体的免疫细胞),随后一周不施用活性剂,最后再接受一个或多个附加剂量的活性剂(例如每周多剂施用表达嵌合受体的免疫细胞)。表达嵌合受体的免疫细胞可每隔一天施用,每周施用3次,持续2、3、4、5、6、7、8或更多周。
在本发明中,就其与本文所述的任何疾病状况有关而言,术语“治疗”等意指减轻或缓解与这种状况相关的至少一种症状,或减缓或逆转这种状况的进展。在本发明中,术语“治疗”还表示阻止、延迟发病(即疾病临床表现之前的时期)和/或降低疾病发展或恶化的风险。例如,与癌症有关的术语“治疗”可以指消除或减轻患者的肿瘤负担,或预防、延迟或抑制转移等。
本文所述的方法和组合物可用于治疗,但不限于,脑瘤、肺癌、耳鼻喉癌、血液癌、结肠癌、黑色素瘤、胰腺癌、乳腺癌、前列腺癌、乳房癌、卵巢癌、基底细胞癌、胆道癌;膀胱癌;骨癌;乳腺癌;宫颈癌;绒毛膜癌;结肠和直肠癌;结缔组织癌;消化系统癌;子宫内膜癌;食管癌;眼癌;头颈癌;胃癌;上皮内肿瘤;肾癌;喉癌;肝癌;纤维瘤、神经母细胞瘤;口腔癌(例如唇、舌、口、咽);卵巢癌;胰腺癌;前列腺癌;视网膜母细胞瘤;横纹肌肉瘤;直肠癌;肾癌;呼吸系统癌;肉瘤;皮肤癌;胃癌;睾丸癌;甲状腺癌;子宫癌;泌尿系癌、以及其他上皮癌和肉瘤。
上皮癌(Carcinomas)是上皮来源的癌症。旨在用本公开方法治疗的上皮癌包括但不限于腺泡癌(acinar carcinoma)、腺泡状癌(acinous carcinoma)、肺泡腺癌(alveolaradenocarcinoma)(也称为腺囊性癌(adenocystic carcinoma)、腺肌上皮瘤(adenomyoepithelioina)、筛状癌(cribriform carcinoma)和圆柱状瘤(cylindroma))、腺瘤性癌(carcinoma adenomatosum)、腺癌(adenocarcinoma)、肾上腺皮质癌(carcinoma ofadrenal cortex),肺泡癌(alveolar carcinoma)、肺泡细胞癌(alveolar cellcarcinoma)(又称支气管肺泡癌(bronchiolar carcinoma)、肺泡细胞瘤(alveolar celltumor)和肺腺瘤病(pulmonary adenomatosis))、基底细胞癌(basal cell carcinoma)、基底细胞癌(carcinoma basocellulare)(又称基底细胞瘤(basaloma)或基细胞癌(basiloma)和发母质癌(hair matrix carcinoma))、基底细胞样癌(basaloidcarcinoma)、基底鳞状细胞癌(basosquamous cell carcinoma)、乳腺癌(breastcarcinoma)、细支气管肺泡癌(bronchioalveolar carcinoma),细支气管癌(bronchiolarcarcinoma)、支气管源性癌(bronchogenic carcinoma)、脑样癌(cerebriformcarcinoma)、胆管细胞癌(cholangiocellular carcinoma)(又称胆管癌(cholangioma)和胆管腺瘤(cholangiocarcinoma))、绒毛膜癌(chorionic carcinoma)、胶样癌(colloidcarcinoma)、粉刺性癌(comedo carcinoma)、子宫体癌(corpus carcinoma)、筛状癌(cribriform carcinoma)、胸甲癌(carcinoma en cuirasse)、癌疮(carcinomacutaneum)、柱状癌(cylindrical carcinoma)、柱状细胞癌(cylindrical cellcarcinoma)、管癌(duct carcinoma)、硬癌(carcinoma durum)、胚胎癌(embryonalcarcinoma)、脑样癌(encephaloid carcinoma)、眼球上癌(epibulbar carcinoma)、表皮样癌(epidermoid carcinoma)、腺样上皮癌(carcinoma epitheliale adenoides)、溃疡性癌(carcinoma exulcere)、纤维癌(carcinoma fibrosum)、明胶样癌(gelatiniformcarcinoma)、胶样癌(gelatinous carcinoma)、巨细胞癌(giant cell carcinoma)、巨细胞癌(gigantocellulare)、腺癌(glandular carcinoma)、颗粒细胞癌(granulosa cellcarcinoma)、发母质癌(hair-matrix carcinoma)、血样癌(hematoid carcinoma)、肝细胞癌(hepatocellular carcinoma)(亦称肝细胞瘤(hepatoma)、恶性肝细胞瘤(malignanthepatoma)、肝癌(hepatocarcinoma))、Huirthle细胞癌(Huirthle cell carcinoma)、透明癌(hyaline carcinoma)、高肾样癌(hypernephroid carcinoma)、幼稚性胚胎性癌(infantile embryonal carcinoma)、原位癌(carcinoma in situ)、表皮内癌(intraepidermal carcinoma)、上皮内癌(intraepithelial carcinoma)、Krompecher癌、Kulchitzky细胞癌、豆状癌(lenticular carcinoma)、豆状细胞癌(carcinomalenticulare)、脂瘤样癌(lipomatous carcinoma)、淋巴上皮癌(lymphoepithelialcarcinoma)、乳腺炎性癌(carcinoma mastitoides)、软癌(carcinoma medullare)、髓样癌(medullary carcinoma)、黑色素癌(carcinoma melanodes)、黑素癌(melanoticcarcinoma)、粘液癌(mucinous carcinoma)、粘液癌(carcinoma muciparum)、粘液细胞癌(carcinoma mucocellulare)、粘液表皮样癌(mucoepidermoid carcinoma)、粘液腺癌(carcinoma mucosum)、粘液瘤(mucous carcinoma)、粘液瘤样癌(carcinomamyxomatodes)、鼻咽癌(nasopharyngeal carcinoma)、黑色素癌(carcinoma nigrum)、燕麦细胞癌(oat cell carcinoma)、骨化性癌(carcinoma ossificans)、骨样癌(osteoidcarcinoma)、卵巢癌(ovarian carcinoma)、乳头状癌(papillary carcinoma)、门脉周癌(periportal carcinoma)、浸润前癌(preinvasive carcinoma)、前列腺癌(prostatecarcinoma)、肾脏的肾细胞癌(renal cell carcinoma)(又称肾腺癌(adenocarcinoma ofkidney)和hypemephoroid carcinoma)、储备细胞癌(reserve cell carcinoma)、癌肉瘤(carcinoma sarcomatodes)、施奈德癌(scheinderian carcinoma)、硬癌(scirrhouscarcinoma)、阴囊癌(carcinoma scroti)、印戒细胞癌(signet-ring cell carcinoma)、单纯癌(carcinoma simplex)、小细胞癌(small-cell carcinoma)、马铃薯状癌(solanoidcarcinoma)、球状细胞癌(spheroidal cell carcinoma)、梭形细胞癌(spindle cellcarcinoma)、海绵状细胞癌(carcinoma spongiosum)、鳞状癌(squamous carcinoma)、鳞状细胞癌(squamous cell carcinoma)、string carcinoma、毛细血管扩张性癌(carcinomatelangiectaticum)、毛细血管扩张癌(carcinoma telangiectodes)、移行细胞癌(transitional cell carcinoma)、结节性癌(carcinoma tuberosum)、结节性癌(tuberouscarcinoma)、疣状癌(verrucous carcinoma)、carcinoma vilosum。在优选实施方案中,本公开的方法用于治疗患有乳腺癌、宫颈癌、卵巢癌、前列腺癌、肺癌、结肠和直肠癌、胰腺癌、胃癌或肾癌的个体。
肉瘤是发生在骨骼和软组织中的间充质肿瘤。已识别了不同类型的肉瘤,这些肉瘤包括:脂肪肉瘤(liposarcomas)(包括粘液样脂肪肉瘤(myxoid liposarcomas)和多形性脂肪肉瘤(pleiomorphic liposarcomas))、平滑肌肉瘤(leiomyosarcomas)、横纹肌肉瘤(rhabdomyosarcomas)、恶性周围神经鞘肿瘤(malignant peripheral nerve sheathtumors)(也称为恶性神经鞘瘤(malignant schwannomas)、神经纤维肉瘤(neurofibrosarcomas)或神经源性肉瘤(neurogenic sarcomas))、尤因肿瘤(Ewing'stumors)(包括骨的尤因肉瘤、骨外(即非骨)尤因肉瘤和原始神经外胚层肿瘤(primitiveneuroectodermal tumor[PNET]))、滑膜肉瘤(synovial sarcoma)、血管肉瘤(angiosarcomas)、血管肉瘤(hemangiosarcomas)、淋巴管肉瘤(lymphangiosarcomas)、卡波西肉瘤(Kaposi's sarcoma)、血管内皮瘤(hemangioendothelioma)、纤维肉瘤(fibrosarcoma)、硬纤维瘤(desmoid tumor)(也称为侵袭性纤维瘤病(aggressivefibromatosis))、隆突性皮肤纤维肉瘤(dermatofibrosarcoma protuberans(DFSP))、恶性纤维组织细胞瘤(malignant fibrous histiocytoma(MFH))、血管外皮细胞瘤(hemangiopericytoma)、恶性间充质瘤(malignant mesenchymoma)、肺泡软组织肉瘤(alveolar soft-part sarcoma)、上皮样肉瘤(epithelioid sarcoma)、透明细胞肉瘤(clear cell sarcoma)、结缔组织增生性小细胞瘤(desmoplastic small cell tumor)、胃肠道间质瘤(gastrointestinal stromal tumor(GIST))(也称为GI间质肉瘤)、骨肉瘤(osteosarcoma)(也称为骨源性肉瘤(osteogenic sarcoma))——骨骼和骨骼外、以及软骨肉瘤(chondrosarcoma)。
在一些实施方案中,要治疗的癌症可以是难治性癌症。本文所用的“难治性癌症”是指耐受所开出的标准治疗的癌症。这些癌症可以最初对治疗有反应(然后复发),或者可以对治疗完全没有反应。普通的标准治疗将取决于癌症类型和个体的进展程度而不同。它可以是化疗、或手术、或放疗、或其组合。本领域普通技术人员了解此类标准治疗。因此,按照本公开针对难治性癌症进行治疗的个体可以已经接受过另一种针对其癌症的治疗。备选地,如果癌症可能是难治性的(例如,根据对癌细胞的分析或个体病史),那么个体可以还没有接受过另一种治疗。难治性癌症的实例包括但不限于白血病、黑色素瘤、肾细胞癌、结肠癌、肝癌、胰腺癌、非霍奇金淋巴瘤和肺癌。
任何表达本文所述嵌合受体的免疫细胞都可以作为药物组合物在可药用载体或赋形剂中施用。
与本公开的组合物和/或细胞结合使用的短语“可药用”是指,该组合物的分子实体和其他成分在生理上可耐受并且在对哺乳动物(例如人)施用时通常不产生不良反应。优选地,本文所使用的术语“可药用”是指经联邦或州政府的监管机构批准,或在美国药典或其他公认药典中列出,用于哺乳动物,尤其是人类。“可接受”是指载体与组合物的活性成分(例如核酸、载体、细胞或治疗性抗体)相容,并且不会对施用该组合物的个体产生负面影响。在本发明的方法中使用的任何药物组合物和/或细胞可以以冻干形成物或水溶液形式包含可药用载体、赋形剂或稳定剂。
可药用载体(包括缓冲剂)为本领域公知,且可包含:磷酸、柠檬酸及其他有机酸;抗氧化剂(包括抗坏血酸及蛋氨酸);防腐剂;低分子量多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;氨基酸;疏水性聚合物;单糖;双糖;和其他糖类;金属配合物;和/或非离子型表面活性剂。参见例如Remington:The Science and Practice of Pharmacy 20th Ed.(2000)Lippincott Williams and Wilkins,Ed.K.E.Hoover。
治疗用药盒
在本发明的范围内还包括用于本发明的活性剂/组合物的药盒。此类药盒可包括一个或多个容器,该容器包含含有至少一种单萜或倍半萜和可药用载体的第一药物组合物,以及含有至少一种治疗剂和可药用载体的第二药物组合物。在另一实施方案中,药盒可包括一个或多个容器,该容器包含含有至少一种单萜或倍半萜、至少一种治疗剂和可药用载体的药物组合物。
在一些实施方案中,药盒可以包含用于本文所述的任何方法的说明书。所包括的说明书可以包含对个体施用第一和第二药物组合物以在个体中达到预期活性的描述。该药盒还可以包含基于鉴定个体是否需要治疗来选择适合治疗的个体的描述。在一些实施方案中,该说明书包含对需要治疗的个体施用药物组合物的描述。
与本文所述药物组合物的使用有关的说明书通常包含关于预期治疗的剂量、给药时间表和给药途径的信息。容器可以是单位剂量、大包装(例如多剂量包装)或亚单位剂量。在本公开的药盒中提供的说明通常是标签或包装说明书上的书面说明。标签或包装说明书表明药物组合物用于在个体中治疗、延迟发病和/或减轻疾病或障碍。
本文提供的药盒采用合适的包装。合适的包装包括但不限于小瓶、瓶子、罐子、软包装等。还考虑与特定装置(例如吸入器、鼻腔给药装置或输液装置)组合使用的包装。药盒可具有无菌接口(例如,容器可以是静脉输液袋或具有可通过皮下注射针刺穿的塞子的小瓶)。容器也可以具有无菌接口。
药盒可选地可以提供附加成分,如缓冲液和解释性信息。通常,该药盒包含容器和在容器上或与容器结合的标签或包装说明书。在一些实施方案中,本公开提供包含上述药盒的内容物的制成品。
紫苏醇衍生物包括紫苏醇酯、紫苏醛(perillic aldehyde)、二氢紫苏酸(dihydroperillic acid)和紫苏酸。紫苏醇的衍生物还可以包括它的氧化衍生物和亲核/亲电加成衍生物。美国专利公开号20090031455。美国专利号6,133,324和3,957,856。
本发明还提供用单萜(或倍半萜)和至少一种治疗剂治疗诸如癌症或其它神经系统障碍的疾病的方法。单萜(或倍半萜)可以单独施用,或与治疗剂联合施用。单萜或倍半萜还可以与治疗剂共同施用。单萜或倍半萜还可以与治疗剂联合施用。该治疗剂可以并行或顺序施用。单萜(或倍半萜)可以在施用治疗剂之前、期间或之后施用。
单萜(或倍半萜)可以用作溶剂或渗透增强剂来将治疗剂递送到病灶部位。例如,单萜(或倍半萜)可以用作溶剂或渗透增强剂来将化疗剂递送到肿瘤细胞。单萜或倍半萜还可以用作溶剂用于疫苗,其可以通过任何适合的途径递送。
本发明的组合物和方法可以用于治疗神经系统癌症,如恶性神经胶质瘤(例如星形细胞瘤、间变性星形细胞瘤、多形性胶质母细胞瘤)、视网膜母细胞瘤、毛细胞型星形细胞瘤(pilocytic astrocytomas)(I级)、脑膜瘤(meningiomas)、脑转移瘤、成神经细胞瘤、垂体腺瘤、颅底脑膜瘤(skull base meningiomas)和颅底癌症(skull base cancer)。本文中使用的术语“神经系统肿瘤”是指个体具有神经系统细胞恶性增殖的病症。
可通过本发明的组合物和方法治疗的癌症包括但不限于,肺癌、耳鼻喉癌、白血病、结肠癌、黑素瘤、胰腺癌、乳腺癌、前列腺癌、乳房癌、血液癌、卵巢癌、基底细胞癌、胆管癌;膀胱癌;骨癌;乳房癌;宫颈癌;绒毛膜癌;结肠和直肠癌;结缔组织癌;消化系统癌;子宫内膜癌;食管癌;眼癌;头颈癌;胃癌;上皮内肿瘤;肾癌;喉癌;白血病,包括急性髓性白血病、急性淋巴细胞性白血病、慢性髓性白血病、慢性淋巴细胞性白血病;肝癌;淋巴瘤,包括霍奇金和非霍奇金淋巴瘤;骨髓瘤;纤维瘤、成神经细胞瘤;口腔癌(例如唇、舌、口和咽);卵巢癌;胰腺癌;前列腺癌;视网膜母细胞瘤;横纹肌肉瘤;直肠癌;肾癌;呼吸系统癌症;肉瘤;皮肤癌;胃癌;睾丸癌;甲状腺癌;子宫癌;泌尿系统癌症,以及其它癌和肉瘤。美国专利号7,601,355。
本发明还提供治疗CNS病症的方法和组合物,该CNS病症包括但不限于原发性退行性神经病症(如阿尔茨海默病、帕金森病)、心理障碍、精神病和抑郁症。
本发明的组合物可以与放疗联合使用。
本发明的单萜或倍半萜可以与至少一种治疗剂联合使用,该治疗剂包括但不限于化疗剂、免疫治疗剂和抗体(例如单克隆抗体)。可与纯化的单萜或倍半萜联合使用的抗癌剂可以对癌细胞或个体具有一项或多项以下作用:细胞死亡;细胞增殖减少;细胞数量减少;细胞生长抑制;细胞凋亡;坏死;有丝分裂灾难;细胞周期阻滞;细胞大小减小;细胞分裂减少;细胞存活率降低;细胞代谢减少;细胞损伤或细胞毒性的标志物;细胞损伤或细胞毒性的间接指标,如肿瘤缩小;个体生存率提高;或与非期望的、不需要的或异常的细胞增殖相关的标志物的消失。美国专利公开号20080275057。
本发明还涵盖单萜(或倍半萜)和至少一种治疗剂(包括但不限于化疗剂)的混合物和/或共制剂。
化疗剂包括但不限于DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、长春花生物碱类(vincalkaloids)、紫杉烷类、埃博霉素、酶抑制剂、受体拮抗剂、治疗性抗体、酪氨酸激酶抑制剂、硼放射增敏剂(即万珂(velcade))、和化疗联合治疗。
DNA烷化剂为本领域公知,并用于治疗多种肿瘤。DNA烷化剂的非限制性实例是氮芥类(nitrogen mustards),如二氯甲基二乙胺(Mechlorethamine)、环磷酰胺(Cyclophosphamide)(异环磷酰胺(Ifosfamide)、曲磷胺(Trofosfamide))、苯丁酸氮芥(Chlorambucil)(美法仑(Melphalan)、泼尼苯芥(Prednimustine))、苯达莫司汀(Bendamustine)、尿嘧啶氮芥(Uramustine)和雌氮芥(Estramustine);亚硝基脲类(nitrosoureas),如卡莫司汀(Carmustine(BCNU))、洛莫司汀(Lomustine)(司莫司汀(Semustine))、福莫司汀(Fotemustine)、尼莫司汀(Nimustine)、雷莫司汀(Ranimustine)和链脲霉素(Streptozocin);烷基磺酸类(alkyl sulfonates),如白消安(Busulfan)(甘露舒凡(Mannosulfan)、曲奥舒凡(Treosulfan));氮杂环丙烷类(Aziridines),如卡波醌(Carboquone)、噻替派(ThioTEPA)、三乙撑亚胺苯醌(Triaziquone)、三乙撑蜜胺(Triethylenemelamine);肼(Hydrazines)(甲基苄肼(Procarbazine));三氮烯(Triazenes),如氮烯咪胺(Dacarbazine)和替莫唑胺(Temozolomide);六甲蜜胺(Altretamine)和二溴甘露醇(Mitobronitol)。
拓扑异构酶I抑制剂的非限制性实例包括喜树碱衍生物,包括如Pommier Y.(2006)Nat.Rev.Cancer 6(10):789-802和美国专利公开号200510250854中描述的CPT-11(伊立替康)、SN-38、APC、NPC、喜树碱(Campothecin)、拓扑替康、依喜替康甲磺酸盐(exatecan mesylate)、9-硝基喜树碱、9-氨基喜树碱、勒托替康(lurtotecan)、鲁比替康(rubitecan)、silatecan、吉马替康(gimatecan)、二氟替康(diflomotecan)、依喜替康(extatecan)、BN-80927、DX-8951f和MAG-CPT;原小檗碱类生物碱(Protoberberinealkaloids)及其衍生物,包括如Li等(2000)Biochemistry 39(24):7107-7116和Gatto等(1996)Cancer Res.15(12):2795-2800中描述的小檗红碱(berberrubine)和甲氧檗因(coralyne);邻菲咯啉(Phenanthroline)衍生物,包括如Makhey等(2003)Bioorg.Med.Chem.11(8):1809-1820中描述的苯并[i]菲啶(Benzo[i]phenanthridine)、两面针碱(Nitidine)和花椒宁碱(fagaronine);如Xu(1998)Biochemistry 37(10):3558-3566中描述的Terbenzimidazole及其衍生物;和蒽环衍生物,包括如Foglesong等(1992)Cancer Chemother.Pharmacol.30(2):123-]25、Crow等(1994)J.Med.Chem.37(19):31913194及Crespi等(1986)Biochem.Biophys.Res.Commun.136(2):521-8中描述的阿霉素(Doxorubicin)、柔红霉素(Daunorubicin)和米托蒽醌(Mitoxantrone)。拓扑异构酶II抑制剂包括但不限于,依托泊苷(Etoposide)和替尼泊苷(Teniposide)。拓扑异构酶I和II双重抑制剂包括但不限于,如Denny和Baguley(2003)Curr.Top.Med.Chem.3(3):339-353中描述的,沙因托品(Saintopin)和其它萘并萘二酮(Naphthecenediones)、DACA和其它吖啶-4-羧酰胺、茚托利辛(Intoplicine)和其他苯并吡啶并吲哚(Benzopyridoindoles)、TAS-I03和其它7H-茚并[2,1-c]喹啉-7-酮、吡唑并吖啶(Pyrazoloacridine)、XR 11576和其他苯并吩嗪(Benzophenazines)、XR 5944和其他二聚化合物、7-氧代-7H-二苯并[f,ij]异喹啉和7-氧代-7H-苯并[e]萘嵌间二氮杂苯(Perimidines)和蒽基-氨基酸缀合物。一些活性剂抑制拓扑异构酶II并具有DNA嵌入活性,例如但不限于蒽环类化合物(阿柔比星(Aclarubicin)、柔红霉素、阿霉素、表柔比星(Epirubicin)、伊达比星(Idarubicin)、氨柔比星(Amrubicin)、吡柔比星(Pirarubicin)、戊柔比星(Valrubicin)、佐柔比星(Zorubicin))和蒽二酮(米托蒽醌和匹杉琼(Pixantrone))。
内质网应激诱导剂的实例包括但不限于二甲基-塞来昔布(DMC)、奈非那韦(nelfinavir)、塞来昔布和硼放射增敏剂(即万珂(硼替佐米))。
铂基化合物是DNA烷化剂的亚类。此类活性剂的非限制性实例包括卡铂(Carboplatin)、顺铂(Cisplatin)、奈达铂(Nedaplatin)、奥沙利铂(Oxaliplatin)、四硝酸三铂(Triplatin tetranitrate)、赛特铂(Satraplatin)、阿罗铂(Aroplatin)、洛铂(Lobaplatin)和JM-216。(参见McKeage等(1997)J.Clin.Oncol.201:1232-1237,一般而言,参见CHEMOTHERAPY FOR GYNECOLOGICAL NEOPLASM,CURRENT THERAPY AND NOVELAPPROACHES,in the Series Basic and Clinical Oncology,Angioli等编辑,2004)。
抗代谢物剂的非限制性实例包括基于叶酸的活性剂,即二氢叶酸还原酶抑制剂,如氨蝶呤(Aminopterin)、甲氨蝶呤(Methotrexate)和培美曲塞(Pemetrexed);胸苷酸合酶抑制剂(thymidylate synthase inhibitors),如雷替曲塞(Raltitrexed)、培美曲塞(Pemetrexed);基于嘌呤的活性剂,即腺苷脱氨酶抑制剂,如喷司他丁(Pentostatin),巯基嘌呤(thiopurine),如硫鸟嘌呤(Thioguanine)和巯嘌呤(Mercaptopurine),卤化/核糖核苷酸还原酶抑制剂,如克拉屈滨(Cladribine)、氯法拉滨(Clofarabine)、氟达拉滨(Fludarabine),或鸟嘌呤/鸟苷(guanine/guanosine):巯基嘌呤,如硫鸟嘌呤;或基于嘧啶的活性剂,即胞嘧啶/胞苷:去甲基化活性剂(hypomethylating agent),如阿扎胞苷(Azacitidine)和地西他滨(Decitabine),DNA聚合酶抑制剂,如阿糖胞苷(Cytarabine),核糖核苷酸还原酶抑制剂,如吉西他滨(Gemcitabine),或胸腺嘧啶/胸苷:胸苷酸合酶抑制剂,如氟尿嘧啶(5-FU)。5-FU的等同物包括其前药、类似物及其衍生物,例如在Papamicheal(1999)The Oncologist 4:478-487中描述的,5’-脱氧-5-氟尿苷(去氧氟尿苷(doxifluroidine))、1-四氢呋喃基-5-氟尿嘧啶(呋氟脲嘧啶(ftorafur))、卡培他滨(Capecitabine)(希罗达(Xeloda))、S-I(MBMS-247616,包含替加氟(tegafur)和两种调节物,5-氯-2,4-二羟基吡啶和氧嗪酸钾(potassium oxonate))、雷替曲噻(ralititrexed)(拓优得(tomudex))、诺拉曲特(nolatrexed)(诺拉曲塞(Thymitaq),AG337)、LY231514和ZD9331。
长春花生物碱类化合物(vincalkaloids)的实例包括但不限于长春花碱(Vinblastine)、长春新碱(Vincristine)、长春氟宁(Vinflunine)、长春地辛(Vindesine)和长春瑞滨(Vinorelbine)。
紫杉烷类化合物(taxanes)的实例包括但不限于多西他赛(docetaxel)、莱龙泰素(Larotaxel)、奥他赛(Ortataxel)、紫杉醇(Paclitaxel)和替司他赛(Tesetaxel)。埃博霉素(epothilone)的实例是伊沙匹隆(iabepilone)。
酶抑制剂的实例包括但不限于法尼基转移酶抑制剂(替吡法尼(tipifamib);CDK抑制剂(阿伏昔地(Alvocidib)、塞利西利(Seliciclib));蛋白酶体抑制剂(硼替佐米);磷酸二酯酶抑制剂(阿那格雷(Anagrelide);咯利普兰(rolipram));IMP脱氢酶抑制剂(噻唑呋林(Tiazofurine));和脂氧合酶抑制剂(马索罗酚(Masoprocol))。受体拮抗剂的实例包括但不限于ERA(阿曲生坦(Atrasentan));类视黄醇X受体(蓓萨罗丁(Bexarotene));和性类固醇(睾内酯(Testolactone))。
治疗性抗体的实例包括但不限于抗HER1/EGFR(西妥昔单抗(Cetuximab)、帕尼单抗(Panitumumab));抗HER2/neu(erbB2)受体(曲妥珠单抗(Trastuzumab));抗EpCAM(卡妥索单抗(Catumaxomab)、依决洛单抗(Edrecolomab));抗VEGF-A(贝伐单抗(Bevacizumab));抗CD20(利妥昔单抗(Rituximab)、托西莫单抗(Tositumomab)、替伊莫单抗(Ibritumomab));抗CD52(阿仑单抗(Alemtuzumab));和抗CD33(吉姆单抗(Gemtuzumab))。美国专利号5,776,427和7,601,355。
酪氨酸激酶抑制剂的实例包括但不限于针对如下的抑制剂:ErbB:HER1/EGFR(埃罗替尼(Erlotinib)、吉非替尼(Gefitinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、舒尼替尼(Sunitinib)、来那替尼(Neratinib));HER2/neu(拉帕替尼、来那替尼(Neratinib));III类RTK:C-kit(阿西替尼(Axitinib)、舒尼替尼、索拉非尼(Sorafenib)),FLT3(来他替尼(Lestaurtinib)),PDGFR(阿西替尼、舒尼替尼、索拉非尼);和VEGFR(凡德他尼、司马沙尼(Semaxanib)、西地尼布(Cediranib)、阿西替尼、索拉非尼);bcr-abl(伊马替尼(Imatinib)、尼罗替尼(Nilotinib)、达沙替尼(Dasatinib));Src(博舒替尼(Bosutinib))和Janus激酶2(来他替尼)。
西妥昔单抗是抗EGFR抗体的实例。它是靶向表皮生长因子受体(EGFR)的人/鼠嵌合单克隆抗体。在此将生物等效抗体鉴定为修饰的抗体和那些结合EGFR抗原的相同表位并产生基本上等同的生物学反应的那些抗体,该生物学反应如阻止EGFR的配体结合、阻止EGFR受体的活化和阻断EGFR途径的下游信号传导(导致细胞生长中断)。
“拉帕替尼”是EGFR和erbB-2双重抑制剂。已经在许多临床试验中研究了拉帕替尼作为抗癌单一疗法,以及与曲妥珠单抗、卡培他滨、来曲唑、紫杉醇和FOLFlRl(伊立替康、5-氟尿嘧啶和甲酰四氢叶酸)联合。目前正针对转移性乳房癌、头颈癌、肺癌、胃癌、肾癌和膀胱癌的口服治疗进行III期试验。拉帕替尼的化学等同物是小分子或化合物,该小分子或化合物是酪氨酸激酶抑制剂(TKI)或者备选地是HER-1抑制剂或HER-2抑制剂。已经发现几种TKI具有有效的抗癌活性,并已经获批准或在临床试验中。这样的实例包括但不限于Zactima(ZD6474)、易瑞沙(吉非替尼)和特罗凯(埃罗替尼)、甲磺酸伊马替尼(STI571;格列卫)、埃罗替尼(OSI-1774;特罗凯)、卡奈替尼(CI 1033)、司马沙尼(semaxinib)(SU5416)、瓦他拉尼碱(PTK787/ZK222584)、索拉非尼(BAY43-9006)、索坦(SUI1248)和来氟米特(SUl0l)。拉帕替尼的生物等同物是肽、抗体或其抗体衍生物,其是HER-1抑制剂和/或HER-2抑制剂。这种实例包括但不限于人源化抗体曲妥珠单抗和赫塞汀。
PTK/ZK是靶向所有VEGF受体(VEGFR)、血小板衍生生长因子(PDGF)受体、c-KIT和c-Fms的具有广泛特异性的“小”分子酪氨酸激酶抑制剂。Drevs(2003)Idrugs 6(8):787-794。PTK/ZK是通过抑制结合VEGF的所有已知受体的活性来阻断血管生成和淋巴管生成的靶向药物,所述受体包括VEGFR-1(Flt-1)、VEGFR-2(KDR/Flk-1)和VEGFR-3(Flt-4)。PTK/ZK的化学名称是1-[4-氯苯胺]-4-[4-吡啶基甲基]酞嗪琥珀酸盐或1-酞嗪胺,N-(4-氯苯基)-4-(4-吡啶基甲基)-丁二酸酯(1:1)。PTK/TK的同义词和类似物称为瓦他拉尼(Vatalanib)、CGP79787D、PTK787/ZK 222584、CGP-79787、DE-00268、PTK-787、PTK787A、VEGFR-TK抑制剂、ZK 222584和ZK。
可以与单萜或倍半萜联合使用的化疗剂还可以包括安吖啶(amsacrine)、曲贝替定(Trabectedin)、类视黄醇(retinoids)(阿利维A酸(Alitretinoin)、维甲酸(Tretinoin))、三氧化二砷(Arsenic trioxide)、天冬酰胺消耗物(asparagine deplete)(天冬酰胺酶/培门冬酶(Asparaginase/Pegaspargase))、塞来昔布(Celecoxib)、地美可辛(Demecolcine)、伊利司莫(Elesclomol)、依沙芦星(Elsamitrucin)、乙环氧啶(Etoglucid)、氯尼达明(Lonidamine)、硫蒽酮(Lucanthone)、丙脒腙(Mitoguazone)、米托坦(Mitotane)、奥利默森(Oblimersen)、替西罗莫司(Temsirolimus)和伏立诺他(Vorinostat)。
可与本发明的组合物和方法一起使用的其他治疗剂包括例如CAR-T细胞、CAR-巨噬细胞或CAR-NK细胞。
本发明的组合物和方法可用来增加细胞旁通透性,例如内皮细胞或上皮细胞的细胞旁通透性。本发明的组合物和方法可用来增加血脑屏障通透性。施用对血脑屏障通透性的影响可持续5分钟至10小时;其他范围包括至少约15分钟、30分钟、1小时、2小时、3小时、5小时、10小时、24小时、48小时或72小时。
本发明的组合物和方法可用来降低或抑制血管生成。本发明的组合物和方法可以减少或抑制促血管生成细胞因子,包括但不限于血管内皮生长因子(VEGF),和白介素8(IL8)的产生。
单萜或倍半萜可以与血管生成抑制剂联合使用。血管生成抑制剂的实例包括但不限于血管抑素、血管酶(angiozyme)、抗凝血酶III、AG3340、VEGF抑制剂(例如抗VEGF抗体)、巴马司他(batimastat)、贝伐单抗(阿瓦斯丁)、BMS-275291、CAI、2C3、HuMV833血管能抑素(Canstatin)、卡托普利(Captopril)、羧胺三唑(carboxyamidotriazole)、软骨源抑制剂(CDI)、CC-5013、6-O-(氯乙酰基-羰基)-烟霉醇(fumagillol)、COL-3、康普立停(combretastatin)、康普立停A4磷酸盐、达肝素(Dalteparin)、EMD 121974(西仑吉肽(Cilengitide))、内皮抑素(endostatin)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)(易瑞沙(Iressa))、染料木素(genistein)、氢溴酸常山酮(halofuginone hydrobromide)、Id1、Id3、IM862、伊马替尼甲磺酸盐、IMC-IC11诱导蛋白10、干扰素α、白细胞介素12、熏草菌素A(lavendustin A)、LY317615或AE-941、马立马司他(marimastat)、mspin、乙酸甲羟孕酮(medroxpregesterone acetate)、Meth-1、Meth-2、2-甲氧雌甾二醇(2-ME)、新伐司他(neovastat)、骨桥蛋白裂解产物(oteopontin cleaved product)、PEX、色素上皮生长因子(PEGF)、血小板因子4、催乳素片段、多育曲菌素(proliferin)相关蛋白(PRP)、PTK787/ZK222584、ZD6474、重组人血小板因子4(rPF4)、休眠蛋白(restin)、角鲨胺(squalamine)、SU5416、SU6668、SU11248苏拉明(suramin)、紫杉醇(Taxol)、替康兰(Tecogalan)、沙利度胺(thalidomide)、血小板应答蛋白(thrombospondin)、TNP-470、肌钙蛋白-1(troponin-l)、血管抑制因子(vasostatin)、VEG1、VEGF-Trap和ZD6474。
血管生成抑制剂的非限制性实例还包括酪氨酸激酶抑制剂,如酪氨酸激酶受体Flt-1(VEGFRl)和Flk-1/KDR(VEGFR2)抑制剂、表皮衍生生长因子抑制剂、成纤维细胞衍生生长因子抑制剂、或血小板衍生生长因子抑制剂、MMP(基质金属蛋白酶)抑制剂、整合蛋白阻断剂、戊聚糖多硫酸酯、血管紧张素II拮抗剂、环加氧酶抑制剂(包括非甾体抗炎药(NSAID),如阿斯匹林和布洛芬,以及选择性环加氧酶-2抑制剂,如塞来昔布和罗非昔布),和甾类抗炎药(如皮质类固醇、盐皮质激素、地塞米松、强的松、强的松龙、甲基强的松龙(methylpred)、倍他米松)。
调节或抑制血管生成并且也可以与单萜或倍半萜联合使用的其他治疗剂包括调节或抑制凝血和纤维蛋白溶解系统的活性剂。此类调节或抑制凝血和纤维蛋白溶解途径的活性剂的实例包括但不限于肝素、低分子量肝素和羧肽酶U抑制剂(也称为活性凝血酶可活化纤维蛋白溶解抑制剂[TAFIa]的抑制剂)。美国专利公开号20090328239。美国专利号7,638,549。
免疫调节剂包括但不限于细胞因子,如白介素、淋巴因子、单核因子、干扰素和趋化因子。
其他可以与单萜(或倍半萜)一起使用的渗透增强剂包括但不限于:甘油的脂肪酸酯,如癸酸甘油酯、辛酸甘油酯、月桂酸甘油酯、油酸甘油酯;异山梨醇、蔗糖、聚乙二醇的脂肪酸酯;己酰乳酸(caproyllactylic acid);月桂醇聚醚-2;月桂醇聚醚-2乙酸酯;月桂醇聚醚-2苯甲酸酯;月桂醇聚醚-3羧酸;月桂醇聚醚-4;月桂醇聚醚-5羧酸;油醇聚醚-2;甘油焦谷氨酸油酸酯;甘油油酸酯;N-月桂酰肌氨酸;N-十四酰肌氨酸;N-辛基-2-吡咯烷酮;月桂氨基丙酸;聚丙二醇-4-月桂醇聚醚-2;聚丙二醇-4-月桂醇聚醚-5-二甲基月桂酰胺;月桂酰胺二乙醇(DEA)、十二烷基焦谷氨酸酯(LP)、甘油单月桂酸酯(GML)、甘油单辛酸酯、甘油单癸酸酯、甘油单油酸酯(GMO)、和失水山梨醇单月桂酸酯。多元醇或乙醇可以作为渗透增强剂或共溶剂。其他渗透增强剂参见美国专利号5,785,991;5,843,468;5,882,676;和6,004,578。
共溶剂为本领域公知,包括但不限于甘油、聚乙二醇(PEG)、乙二醇、乙醇、甲醇、丙醇、异丙醇、丁醇等。
本发明的组合物可以通过本领域已知的任何方法施用,包括但不限于动脉内、鼻内、口服、经眼、腹腔内、吸入、静脉内、心内注射(IC)、侧脑室内(ICV)、脑池内注射或输注、皮下、植入、阴道内、舌下、尿道(例如尿道栓)、皮下、肌内、静脉内、经皮、直肠、舌下、粘膜、眼内、脊髓、鞘内、关节内、动脉内、蛛网膜下、支气管和淋巴管施用。局部制剂可以是凝胶、膏剂、乳膏剂、气雾剂等形式;鼻内制剂可以喷雾剂或滴剂形式递送;经皮制剂可以通过透皮贴剂或离子透入法施用;吸入制剂可以利用喷雾器或类似装置施用。组合物还可以采用片剂、丸剂、胶囊剂、半固体、粉末、缓释制剂、溶液、悬液、酏剂、气雾剂或任何其他合适的组合物的形式。
为了制备这种药物组合物,可以按照常规药物配合技术,将一种或多种单萜(或倍半萜)和/或至少一种治疗剂与可药用载体、助剂和/或赋形剂混合。可用于本发明的组合物的可药用载体涵盖任何标准药物载体,如磷酸缓冲盐溶液、水和乳剂,如油/水或水/油乳剂,以及多种类型的润湿剂。该组合物可以另外含有固体药物赋形剂,如淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠、脱脂奶粉等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇和多种油类,该油类包括石油、动物、植物或合成来源的那些油类,例如,花生油、大豆油、矿物油、芝麻油等。液体载体,特别是注射溶液用液体载体,包括水、盐水、葡萄糖水和二醇类。载体、稳定剂和助剂的实例参见Remington's Pharmaceutical Sciences,E.W.Martin编辑(MackPublishing Company,第18版,1990)。组合物还可以包含稳定剂和防腐剂。
本文中使用的术语“治疗有效量”是足以治疗特定病症或疾病的量,或者备选地,足以获得治疗病症或疾病的药理学反应的量。确定最有效的施用方式和剂量的方法可以随着用于治疗的组合物、治疗的目的、治疗的靶细胞和治疗的个体而变。通常可以滴定治疗剂量以优化安全性和有效性。单次或多次施用可以根据治疗医生选择的剂量水平和方式来进行。本领域技术人员可以容易地确定施用活性剂的合适剂量制剂和方法。例如,组合物以约0.01mg/kg至约200mg/kg、约0.1mg/kg至约100mg/kg、或约0.5mg/kg至约50mg/kg施用。当在本文中描述的化合物与另一活性剂或疗法共同施用时,有效量可以小于该活性剂单独使用时的有效量。
本公开还提供如上所述的用于鼻内施用的组合物。同样地,组合物可以进一步包含渗透增强剂。Southall等Developments in Nasal Drug Delivery,2000。本发明的组合物可以以液体形式如溶液、乳剂、悬液、滴剂,或以固体形式如粉末、凝胶或膏剂,鼻内施用。递送鼻内药物的装置为本领域公知。可以利用包括但不限于以下的装置进行鼻腔药物递送:鼻内吸入器、鼻内喷雾装置、雾化器、鼻腔喷雾瓶、单位剂量容器、泵、点滴器、挤压瓶、喷雾器、定量吸入器(MDI)、压力定量吸入器、吹药器和双向装置。可以计量鼻腔递送装置以向鼻腔施用精确有效剂量的量。鼻腔递送装置可用于单一单位递送或多单位递送。在具体实例中,来自Kurve Technology(Bethell,Washington)的ViaNase Electronic Atomizer可用于本发明(http://www.kurvetech.com)。本发明的化合物还可以通过管、导管、注射器、packtail、药棉、鼻塞或通过粘膜下输液来递送。美国专利公开号20090326275、20090291894、20090281522和20090317377。
本发明的组合物可以利用标准方法配制成气雾剂。单萜(或倍半萜)和/或至少一种治疗剂可以与溶剂一起配制或不与溶剂一起配制,以及与载体一起配制或不与载体一起配制。制剂可以是溶液,或可以是含有一种或多种表面活性剂的水性乳剂。例如,可以由带有适合推进剂如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、碳氢化合物、压缩空气、氮气、二氧化碳或其它合适气体的加压容器来制备气雾喷雾。可以通过提供阀门来确定剂量单位以递送计量的量。泵送喷雾分配器可以分配计量的剂量或具有特定的粒径或液滴尺寸的剂量。本文中使用的术语“气雾剂”是指处于气体中的细小固体颗粒或液体溶液滴的悬剂。具体而言,气雾剂包括单萜(或倍半萜)小滴的气载悬剂,其可以在任何适合的装置如MDI、喷雾器或弥雾机中生成。气雾剂还包括悬浮在空气或其他载气中的本发明组合物的干粉组合物。Gonda(1990)Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313。Raeburn等,(1992)Pharmacol.Toxicol.Methods 27:143-159。
本发明的组合物可以以例如微球形式的粉末通过鼻腔吹药器递送到鼻腔。本发明的组合物可以吸附至固体表面例如载体。所述粉末或微球可以以干燥的、空气可分散的(air-dispensable)形式施用。所述粉末或微球可以储存在吹药器的容器中。或者,所述粉末或微球可以装填成胶囊剂例如明胶胶囊,或其它适合于鼻腔施用的单剂量单元。
药物组合物可以通过在鼻腔中直接放置该组合物来递送到鼻腔,例如以凝胶、膏剂、鼻腔乳剂、洗剂、乳膏剂、鼻塞、点滴器或生物粘附条的形式。在某些实施方案中,例如为了增强吸收,可能希望延长药物组合物在鼻腔中的停留时间。因此,药物组合物可以可选地与生物粘性聚合物、树胶(例如黄原胶)、壳聚糖(例如高纯度阳离子型多糖)、果胶(或可以像凝胶一样稠化或当施加到鼻粘膜时乳化的任何碳水化合物)、微球(例如淀粉、白蛋白、右旋糖酐、环糊精)、明胶、脂质体、卡波姆(carbamer)、聚乙烯醇、藻酸盐、阿拉伯胶、壳聚糖和/或纤维素(例如甲基或丙基;羟基或羧基;羧甲基或羟丙基)一起配制。
组合物可以通过口腔吸入进入呼吸道(即肺)施用。
用于可吸入活性剂的典型递送系统包括雾化吸入器、干粉吸入器(DPI)和定量吸入器(MDI)。
喷雾器装置产生高速空气流,使液体形式的治疗剂以雾的形式喷出。该治疗剂配制成液体形式,如合适大小的颗粒的溶液或悬浮液。在一个实施方案中,该颗粒是微粉化的。术语“微粉化”定义为具有约90%或更多的直径小于约10微米的颗粒。适合的喷雾器装置是商业上提供的,例如,由PARI GmbH(Starnberg,德国)提供。其它喷雾器装置包括Respimat(Boehringer Ingelheim),以及在例如美国专利号7,568,480和6,123,068及WO97/12687中公开的那些。单萜(或倍半萜)可以配制成水溶液或液体悬液以用在喷雾器装置中。
DPI装置通常以自由流动的粉末形式施用治疗剂,该粉末可以分散在患者吸气期间的气流中。使用外部能量来源的DPI装置也可以用于本发明。为了得到自由流动的粉末,治疗剂可以与适合的赋形剂(例如乳糖)一起配制。例如,通过将颗粒大小为约1微米至100微米的干燥乳糖与单萜(或倍半萜)的微粉化颗粒混合再干混,可以制得干粉制剂。备选地,单萜可以不与赋形剂一起配制。将制剂装入干粉分配器,或装入与干粉递送装置一起使用的吸入盒或胶囊中。商业上提供的DPI装置的实例包括Diskhaler(GlaxoSmithKline,Research Triangle Park,N.C.)(参见例如美国专利号5,035,237);Diskus(GlaxoSmithKline)(参见例如美国专利号6,378,519);Turbuhaler(AstraZeneca,Wilmington,Del.)(参见例如美国专利号4,524,769);和Rotahaler(GlaxoSmithKline)(参见例如美国专利号4,353,365)。适合的DPI装置的其他实例在美国专利号5,415,162、5,239,993和5,715,810以及其中的参考文献中描述。
MDI装置通常利用压缩的推进剂气体释放出定量的治疗剂。用于MDI施用的制剂包括在液化推进剂中的活性成分的溶液或悬浮液。推进剂的实例包括氢氟烷烃(HFA),如1,1,1,2-四氟乙烷(HFA134a)和1,1,1,2,3,3,3-七氟-正丙烷(HFA 227),氯氟烃,如CCl3F。用于MDI施用的HFA制剂的其他组分包括共溶剂,如乙醇、戊烷、水;和表面活性剂,如失水山梨糖醇三油酸酯、油酸、卵磷脂和甘油。(参见例如美国专利号5,225,183、EP 0717987和WO92/22286)。将制剂装入气溶胶筒,该气溶胶筒构成MDI装置的一部分。美国专利号6,006,745和6,143,227中提供了特别开发与HFA推进剂一起使用的MDI装置的实例。制备适合制剂和适合于吸入给药的装置的方法的实例参见美国专利号6,268,533、5,983,956和6,221,398,以及WO 99/53901、WO 00/61108、WO 99/55319和WO 00/30614。
为了通过吸入递送,单萜(或倍半萜)和/或至少一种治疗剂可以包封在脂质体或微胶囊中。脂质体是由双层脂质膜和含水内部组成的囊泡。该脂质膜可以由磷脂构成,该磷脂的实例包括磷脂酰胆碱,如卵磷脂和溶血卵磷脂;酸性磷脂,例如磷脂酰丝氨酸和磷脂酰甘油;鞘磷脂,如磷脂酰乙醇胺和神经鞘磷脂。备选地,可以添加胆固醇。微胶囊是包有包衣材料的颗粒。例如,该包衣材料可以包含成膜聚合物、疏水增塑剂、表面活化剂或/和润滑剂含氮聚合物的混合物。美国专利号6,313,176和7,563,768。
由于它们容易渗透真皮的能力,单萜也可以单独或与至少一种治疗剂联合通过局部应用来使用。作为经皮递送活性剂,单萜也可以与麻醉药或止痛药联合用于止痛药的经皮递送。
本发明还提供如上所述的用于经眼施用的组合物。同样地,该组合物可以进一步包含渗透增强剂。对于经眼施用,本文描述的组合物可以配制成溶液、乳剂、悬液等。多种适用于将化合物施用于眼的载体为本领域已知。具体的非限制性实例在美国专利号6,261,547;6,197,934;6,056,950;5,800,807;5,776,445;5,698,219;5,521,222;5,403,841;5,077,033;4,882150和4,738,851中描述。
本发明的组合物可以短期或长期施用。本发明的组合物可以施用于哺乳动物,优选人。哺乳动物包括但不限于鼠、大鼠、兔、猿、牛、绵羊、猪、狗、猫、家畜、运动动物(sportanimals)、宠物、马和灵长类动物。
用于鼻内施用的装置可以是鼻内喷雾装置、雾化器、喷雾器、定量吸入器(MDI)、压力定量吸入器、吹药器、鼻内吸入器、鼻腔喷雾瓶、单位剂量容器、泵、点滴器、挤压瓶或双向装置。
活性剂可以并行或顺次施用。
本发明还提供在体外、离体、或体内抑制细胞生长的方法,其中使细胞如癌细胞与有效量的在本文中描述的纯化单萜(或倍半萜)接触。本发明的组合物和方法可用来抑制对化疗剂有抗性的细胞的生长。例如,本发明的组合物和方法可用来抑制抗替莫唑胺的细胞的生长。
病理细胞或组织如高度增殖的细胞或组织可以通过使该细胞或组织与有效量的本发明的组合物接触来处理。该细胞如癌细胞可以是原发性癌细胞,或可以是能从组织库例如美国典型培养物保藏中心(ATCC)获得的培养细胞。该病理细胞可以是全身性癌症、神经胶质瘤、脑膜瘤、垂体腺瘤、或来自全身性癌症的CNS转移、肺癌、前列腺癌、乳房癌、血液癌症或卵巢癌的细胞。该细胞可以来自于脊椎动物,优选哺乳动物,更优选人。美国专利公开号2004/0087651。Balassiano等(2002)Intern.J.Mol.Med.10:785-788。Thorne等(2004)Neuroscience 127:481-496。Fernandes等(2005)Oncology Reports 13:943-947。DaFonseca等(2008)Surgical Neurology 70:259267。Da Fonseca等(2008)Arch.Immunol.Ther.Exp.56:267-276。Hashizume等(2008)Neuroncology 10:112-120。
癌症干细胞(CSC)或肿瘤起始细胞是具有干细胞特性例如自我更新的未成熟细胞。然而,自我更新在CSC中加剧。Reya等,Stem cells,cancer,and cancer stemcells.Nature.2001,414(6859):105-11。另外,神经胶质瘤CSC对化疗和放疗有抗性。Bao等,Glioma stem cells promote radioresistance by preferential activation ofthe DNA damage response.Nature.2006,444(7120):756-60。Rich等,Chemotherapy andcancer stem cells.Cell Stem Cell.2007;1(4):353-5。本发明的组合物和方法可用来抑制癌症干细胞的生长,该癌症干细胞包括但不限于胶质母细胞瘤癌症干细胞。
提供以下实施例仅为了举例说明目的,并非限制本发明。
实施例1NEO100介导人CAR T细胞递送至脑和肿瘤
人CAR T细胞的制备
人CAR T细胞(CD19和Lym-1)由Epstein博士(USC)提供。嵌合抗原受体(CAR)是合成分子,包含3个不同的模块:基于抗体的胞外识别位点;将分子锚定在细胞膜中的跨膜模块;传递激活信号的嵌合胞内信号传导结构域。Jensen等,Designing chimeric antigenreceptors to effectively and safely target tumors.Curr.Opin.Immunol.2015,33,9-15。靶向CD19的CAR T细胞在治疗复发或难治性(R/R)急性成淋巴细胞白血病(ALL)方面取得了显著的疗效。Ruella等,双重CD19和CD123靶向阻止CD19定向免疫治疗后的抗原丢失性复发(Dual CD19 and CD123 targeting prevents antigen-loss relapses afterCD19-directed immunotherapies.)J.Clin.Invest.2016,126,(10),3814-3826。Maude等,CD19靶向嵌合抗原受体T细胞治疗急性成淋巴细胞白血病(CD19-targeted chimericantigen receptor T-cell therapy for acute lymphoblastic leukemia.)Blood 2015,125,(26),4017-23。Grupp等,具有CD19靶向嵌合抗原受体的工程化T细胞(CTL019)治疗的复发性/难治性ALL儿童中的持久缓解(Durable Remissions in Children withRelapsed/Refractory ALL Treated with T Cells Engineered with a CD19-TargetedChimeric Antigen Receptor(CTL019).)Blood 2015,126,(23),681-681。用从Raji淋巴瘤细胞分离的细胞核免疫小鼠,产生了小鼠IgG2a单克隆抗体Lym-1。Epstein等,与人B淋巴细胞和衍生肿瘤具有反应性的两种新单克隆抗体Lym-1和Lym-2具有免疫诊断和免疫治疗潜力(Two new monoclonal antibodies,Lym-1and Lym-2,reactive with human B-lymphocytes and derived tumors,with immunodiagnostic and immunotherapeuticpotential).Cancer Res.1987,47,(3),830-40。Lym-1与几种HLA-DR亚型上的不连续构象表位结合,对恶性B细胞的结合亲和力高于正常B细胞。Rose等,在多态性HLA-DR分子上的关键性Lym-1结合残基(Critical Lym-1binding residues on polymorphic HLA-DRmolecules).Mol Immunol 1999,36,(11-12),789-97。如图1所示,Lym-1 CAR和CD19(FMC63)CAR构建体的示意图。
用悬浮在0.9%生理盐水工作液中的200万个CD19和Lym-1人CAR T细胞在有和无心内NEO100的情况下进行IV注射。
NEO100心内穿刺
用于心内注射的NEO100工作液的制备:3%NEO100悬浮于0.9%生理盐水中。
超声引导心内穿刺的标准操作方案
简言之,用2%异氟烷气体麻醉动物并固定在平台上进行心内穿刺。在超声成像引导下,将注射器针头插入肋间隙(intercoastal space)迅速通过皮肤和肌肉层穿入左心室。
新鲜动脉血(粉红色与深红色静脉血形成对比)回流到注射器中是成功将针头插入左心室的标志。缓慢注射40μl含3%NEO100的生理盐水,完成心内应用。直接将细胞注入心脏可导致局部微梗阻,如果注射过程中细胞结团,可导致心包积血和死亡。这就是为什么超声引导下用30G针头进行注射对于最大限度地减少这些潜在的不良反应很重要:(1)使针道可视化,以确保针头只进入左心室;(2)在注射后不仅通过ECG,而且通过心壁功能的可视化进行心脏监测。针头的细度保证了在通过心内穿刺注入细胞时,细胞不会结团。
心内注射确认
新鲜动脉血(粉红色与深红色静脉血形成对比)回流到注射器中是成功将针头插入左心室的标志。
在NEO100注射完成后,立即通过预先用生理盐水处理过的尾静脉导管,将40μlPBS中的200万个人CAR T细胞注入。为了避免通过心内应用由直接注射细胞可能产生的上述不良反应,我们建立了两步骤程序用于本研究。
步骤1:缓慢注射40μl含3%NEO100的生理盐水,完成心内应用。此程序允许NEO100发挥BBB破坏的功能。
步骤2:通过尾静脉导管IV注射200万个CAR T细胞。
通过IHC和共聚焦成像评价CAR
T细胞扩散
脑灌注-为了排除安乐死后残留在血管内的残留物,试验动物经左心室灌注10毫升0.9%正常生理盐水溶液,以冲洗出血液。然后,取出脑,包埋在OCT中,并保存在-80℃下进行进一步分析。
共聚焦成像-用冷冻切片机切出8μM新鲜冰冻切片,粘贴在玻片上。共聚焦检查前用DAPI封片介质将盖玻片封固在脑切片上。
IHC染色-采用标准化IHC染色程序来检测人CAR T细胞在脑和所形成的肿瘤(GL261小鼠神经胶质瘤)内的渗透。用抗人CD3抗体(CD3ε(D7A6ETM)兔mAb(#85061)(Cell Signaling,Boston,MA)一抗识别人源CD3阳性细胞(如图2所示)。
C57 BL/6小鼠中同基因小鼠神经胶质瘤动物模型研究
将100,000个GL261小鼠神经胶质瘤细胞颅内注入免疫感受态C57 BL/6小鼠。在肿瘤细胞注射后3周,通过静脉内应用(IV)和心内(IC)联合IV应用,用200万个人CAR T细胞(抗CD19和Lym-1)注射具有脑肿瘤的小鼠。干预后6h处死经处理的小鼠。对于心内应用:在心内注射含3%NEO100的PBS后,IV注射200万个抗CD19或Lym-1 CAR T细胞。对于静脉内应用:将200万个抗CD19或Lym-1 CAR T细胞悬浮于40ul PBS中,通过尾静脉注射。
用0.9%生理盐水灌注脑,取出,并保存在-80℃下进行进一步分析。
结论
在正常C57 BL/6小鼠脑内未发现可检测到的CD3阳性细胞。
与常规静脉内注射(IV)相比,NEO100介导的人CAR T细胞(抗CD19和Lym-1)心内注射可显著地增加向脑内形成的肿瘤的渗透。
3%NEO100介导的心内注射未引起任何严重的不良反应或动物死亡。
通过心内注射NEO100处理的脑的正常部分中,见到比在仅IV注射的样品中多的CD3阳性细胞。
实施例2在带有颅内同基因小鼠神经胶质瘤(GL261)的C57 BL/6小鼠中抗小鼠PD-1抗体介导的治疗效果
将100,000个GL261小鼠神经胶质瘤细胞颅内注射到免疫感受态C57 BL/6小鼠。注射后7天,将小鼠随机分为4个实验组,于同一天开始处理。
·组1.对照:IV和心内注射40μl生理盐水溶液(5)。
·组2.抗体处理的小鼠:按2.5mg/kg的剂量IV 40μl抗小鼠PD1抗体(5)。
·组3.NEO100处理的小鼠:心内注射40μl 5%NEO100(5)。
·组4.NEO100和抗体联合处理的小鼠:心内注射40μl 5%NEO100,然后按2.5mg/kg的剂量IV 40μl抗PD1抗体(6)。
结果如图3所示。我们证明心内注射NEO100(相当于小鼠动脉内注射)可以为抗体打开BBB。然后我们用颅内植入的小鼠GL26神经胶质瘤细胞建立了同基因模型。对小鼠进行生理盐水、单独NEO100、单独静脉内抗PD1、或先颅内NEO100再静脉内抗PD1的处理。所有用静脉内抗PD1与NEO100联合处理的小鼠仍然存活,而除一只接受静脉内抗PD1的小鼠外所有对照均死亡。
紫苏醇可用介入性神经放射学经股动脉(如脑血管造影)施用。
统计分析
动物存活数据用Kaplan-Meier法作图。采用单因素方差分析对差异进行总体检验。采用调整用于多重比较的Tukey方法进行分组比较。采用Logrank(Mantel-Cox)检验比较生存曲线。统计学评价结果p<0.05认为显著。
·对照vs.IC NEO100+IV抗小鼠PD-1:***P<0.0003
·对照vs.IV抗小鼠PD-1:ns,p=0.31
·IV抗小鼠PD-1vs.IC NEO100+IV抗小鼠:**P<0.005
·对照vs.IC NEO100:ns,p=0.397
实施例3
我们证明NEO100可应用于跨过体外BBB模型,并瞬时允许标记抗体瞬时跨过该模型(图4A-4D)。
进行实验以研究是否可以使用紫苏醇(例如,NEO100)进行动脉内递送以瞬时破坏BBB,使之前不可穿透的小分子或大分子透入脑。
施用紫苏醇(例如,NEO100)可包括心内注射(小鼠动脉内注射)和静脉内输注。
制剂包括10%NEO100(27.5ml甘油+27.5ml乙醇+3.0ml NEO100)。
脑灌注-安乐死前,试验动物经左心室灌注0.9%正常生理盐水溶液。取出脑,包埋在OCT中,并保存在-80℃下进行进一步分析。
超声引导的心内穿刺-简言之,用2%的异氟烷气体麻醉动物并固定在平台上进行心内穿刺。在超声成像引导下,将注射器针头穿入肋间隙快速通过皮肤和肌肉层穿入左心室。新鲜动脉血(粉红色与深红色静脉血形成对比)回流到注射器中是成功将针头插入左心室的标志。
埃文斯蓝是一种偶氮染料,对血清白蛋白有很高的亲和力。染色后的白蛋白从循环渗出可以被观察。
经心内注射(左心室)递送NEO100来确定埃文斯蓝、BBB非渗透性小分子(多巴胺)或抗体摄入脑是否增加。图5A显示NEO100和2%埃文斯蓝(EB)混合物的心内注射(IC)。通过心内穿刺测试不同浓度的NEO100(40μ1于0.9%生理盐水中),然后立即静脉内应用2%埃文斯蓝(体积40μ1)。灌注后取出脑。结果表明,NEO100在1:1000稀释度(6.5mM 40μl)下仍能有效地破坏BBB。
图5B显示通过IC(心内注射)或IV注射应用NEO100后EB穿透进入脑。
实验组包括:
·仅IC 2%EB
·IC 20%乙醇+2%EB
·IC 20%乙醇+2%EB+5%NEO100
·IC 20%乙醇+5%NEO100,然后进行2%EB尾静脉注射
·IV 20%乙醇+2%EB+5%NEO100
·IV 20%乙醇+2%EB
图6显示,与正常脑相比,心内注射5%NEO100处理的脑中紧密连接已经显著地被破坏。
帕金森病(PD)的药物治疗主要是基于多巴胺(DA)的对症替代治疗,因为外源性DA和其他儿茶酚胺的BBB渗透性差,故而不能施用。多巴胺是一种水溶性亲水性药物,不能满足可通过BBB穿透进入脑的物质的特征。
图7显示NEO100介导多巴胺通过破坏的血脑屏障递送。
图8显示BBB打开和关闭时间的测量。免疫感受态的C57 BL/6小鼠经心内穿刺(IC)注射5%NEO100(v/v),然后在IC注射后不同时间点如0、5分钟、15分钟、30分钟、1小时、2小时、3小时、4小时静脉内注射2%埃文斯蓝。
实验流程包括:
1.心内注射(IC):5%NEO100。
2.然后在不同时间静脉内注射(IV)2%EB。
3.试验动物在IV注射后1小时安乐死。
图9显示在没有或存在紫苏醇的情况下递送抗小鼠IgG抗体(兔抗小鼠IgG H&L(Texas Red)–Ab6726)。
图10显示在没有或存在紫苏醇的情况下递送抗PD-1抗体(亚美尼亚仓鼠抗小鼠CD279(PD-1)单克隆抗体(J43))。PD-L1与PD-1结合并抑制T细胞杀伤肿瘤细胞。阻断PD-L1或PD-1允许T细胞杀伤肿瘤细胞。
NEO100动脉内施用是安全的。
实施例4NEO100介导的人CAR T细胞(Lym-1 CAR)递送治疗NSG小鼠颅内Raji淋巴瘤异种移植
(a)颅内淋巴瘤异种移植:
将50,000(5×104)个人B细胞淋巴瘤细胞Raji's-Luc/GFP颅内注入NSG小鼠。
(b)肿瘤摄取确认:
肿瘤细胞注射后5天,进行光学成像以确认肿瘤摄取(100%肿瘤摄取)。
(c)开始通过尾静脉导管进行CAR T输注和心内(IC)NEO100:
3组实验组:(1)对照;(2)IV CAR T(5x10e6);(3)IV CAR T(5x10e6)+IC NEO100(0.3%v/v=492μM)
(d)监测携带IC淋巴瘤的NSG小鼠:
在处理过程中,对于小鼠的生理状况,监测小鼠的体重。通过光学成像监测肿瘤生长。
(e)动物存活率(Kaplan Meier曲线)
从存活曲线(图11)可以明显看出,对照小鼠,即注射人B细胞淋巴瘤细胞的小鼠,在注射后15-20天内死亡,而注射Lym-1 CAR T细胞加NEO100的小鼠存活下来(P=0.0029)。
实施例5
将POH放入鼻内吸入器(例如,来自Kurve Technology(Bethell,Washington)的ViaNase Electronic Atomizer)。来自Kurve Technology的鼻内递送系统能够精确地递送预定的药物体积(例如,0.2-6mL)。该装置以与肺喷雾器相同的方式加载和清洁。该装置可以在台架试验中将药物递送到动物和人的嗅区。
利用雄性无胸腺nu/nu小鼠(6-8周龄)进行此项研究。按以下建立啮齿动物皮下/颅内神经胶质瘤模型。腹腔内注射氯胺酮(80mg/kg)和甲苯噻嗪(10mg/kg)麻醉6至8周龄无胸腺nu/nu小鼠。对于颅内神经胶质瘤模型,将小鼠放入头部立体定位架(HarvardApparatus)中,并将局部麻醉剂(0.2cc的0.25%利多卡因)注入右额头皮中。用刀片制造一个小切口,并用钻头在冠状缝水平在右额颅骨中制造一个小开口。将神经胶质瘤细胞(1×105细胞/10μl)例如U-87人神经胶质瘤细胞,装入标刻度的Hamilton注射器中。将针尖精确放置到大鼠的右额叶,使用控制推动将细胞从Hamilton注射器中缓慢地注入。注射完成之后,移开注射器和针头,并缝合伤口。
手术植入之后两周,将小鼠分成4组(6只小鼠/组),分别用以下药物处理:单用盐水滴(对照)、来自Sigma的粗POH(0.03%,50ul/滴,每个鼻孔一滴)、POH(纯化到纯度大于98.5%;0.03%,50ul/滴,每个鼻孔一滴)和TMZ(5mg/kg,口服强饲法)。TMZ作为阳性对照。
采集脑,测定肿瘤大小。通过跟踪小鼠直到它们显现出神经功能缺损,绘制存活曲线。我们的经验是,未处理的小鼠存活到植入之后约4周,用TMZ处理的小鼠存活至多8周。
我们还使用免疫感受态的同基因大鼠模型,其中将RG2大鼠神经胶质瘤细胞(1×105细胞/10ul)植入到Fisher 344大鼠的右额叶中。将大鼠分为与上面相同的4组。因为RG2细胞可以自由迁移并从而侵入到大鼠实质中,我们还利用该大鼠RG2模型检查POH的抗侵袭特性。
实施例6
最近在巴西进行的临床研究中,在复发性恶性神经胶质瘤患者中鼻内递送紫苏醇导致了疾病的消退或稳定化,其中140位经治疗患者中的50%达到6个月的无进展期,且几位患者获得了多至3年的病情缓解。此外,治疗的副作用几乎不存在。Da Fonseca等Correlation of tumor topography and peritumoral edema of recurrent malignantgliomas with therapeutic response to intranasal administration of perillylalcohol.Invest New Drugs 2009,Jan 13。
我们将纯化的POH(具有大于98.5%的纯度)鼻内递送到患有恶性神经胶质瘤的患者。为了研究POH是否可以直接递送到脑肿瘤细胞,通过向患者递送11C标记的POH和随后的正电子发射断层扫描(PET)成像来研究纯化POH的分布。然后患者进行使用递增剂量的吸入POH的有限治疗试验。采用三个组对患者进行剂量递增,每组接受0.05%(w/v)、1%(w/v)、1.5%(w/v)、2%(w/v)、2.5%(w/v)的鼻内纯化POH(具有大于98.5%的纯度)。目前在巴西使用的是2%(w/v)。递送将通过ViaNase鼻内吸入器进行,并且每天施用三次。
PET成像分析。鼻内吸入5-10mCi的11C-POH制剂后,利用Siemens BiographTruePoint HD PET/CT扫描仪,扫描十位患有病理证实的恶性神经胶质瘤的患者。静态成像将在吸入后30分钟开始,在覆盖颅的单层位置(single bed position)中,采用10分钟采集。随后的系列采集以30分钟间隔,持续2小时,以评估脑和肿瘤组织中的进行性累积。取决于患者的依从性以及残余和累积活性的水平,我们将尝试成像超过2小时。在所有患者上,对共记录的PET/CT图像与对比增强MRI研究进行比较,以评估活性累积与增强模式的相关性。
本发明的范围不受限于上文中具体给出和描述的内容。本领域技术人员将认识到,所描述的材料、构造、结构和尺寸的实例存在合适的替换物。发明详述中引用并讨论了多个参考文献,包括专利和多个出版物。提供这些参考文献的引用和讨论仅仅为了澄清本发明的描述,并非承认任何参考文献都是本文中所述的本发明的现有技术。所有在本说明书中引用和讨论的参考文献均以其整体引入作为参考。本领域普通技术人员将明白,在本文中描述的内容的变形、修改及其他实施方式可发生而不背离本发明的精神和范围。虽然已经展示和描述了本发明的某些实施方案,但对本领域技术人员而言显而易见的是,可在不背离本发明的精神和范围的情况下进行变化和修改。提供上述说明和附图中陈述的主题仅仅为了举例说明而不是作为限制。
Claims (23)
1.对哺乳动物的中枢神经系统施用治疗剂的方法,该方法包括在该治疗剂之前或并行施用单萜。
2.权利要求1的方法,其中中枢神经系统是脑。
3.权利要求1的方法,其中单萜是紫苏醇。
4.权利要求3的方法,其中紫苏醇动脉内施用。
5.权利要求3的方法,其中紫苏醇按约0.050mg/kg至约500mg/kg体重范围内的剂量施用。
6.权利要求1的方法,其中哺乳动物是人。
7.权利要求1的方法,其中单萜在施用该治疗剂之前约0.2分钟至约60分钟施用。
8.权利要求7的方法,其中单萜在施用该治疗剂之前约1分钟至约15分钟施用。
9.权利要求1的方法,其中单萜和治疗剂分开施用。
10.权利要求1的方法,其中单萜和治疗剂并行施用。
11.权利要求10的方法,其中单萜和治疗剂在药物组合物中一起施用。
12.权利要求1的方法,其中治疗剂是化疗剂。
13.权利要求12的方法,其中化疗剂选自DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、酶抑制剂、受体拮抗剂、治疗性抗体及其组合。
14.权利要求12的方法,其中化疗剂是二甲基-塞来昔布(DMC)、伊立替康(CPT-11)、替莫唑胺或咯利普兰。
15.权利要求1的方法,其中治疗剂是抗体或抗体片段。
16.权利要求1的方法,其中治疗剂是表达嵌合抗原受体的免疫细胞。
17.权利要求16的方法,其中免疫细胞是T细胞。
18.权利要求16的方法,其中治疗剂是CAR-T细胞。
19.权利要求1的方法,其中单萜通过吸入、鼻内、口服、静脉内、皮下或肌内施用。
20.权利要求1的方法,其中哺乳动物患有癌症。
21.权利要求20的方法,其中癌症是神经系统肿瘤。
22.权利要求21的方法,其中肿瘤是胶质母细胞瘤。
23.权利要求1的方法,其进一步包括用辐射治疗该哺乳动物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862627933P | 2018-02-08 | 2018-02-08 | |
US62/627,933 | 2018-02-08 | ||
US201862716190P | 2018-08-08 | 2018-08-08 | |
US62/716,190 | 2018-08-08 | ||
PCT/US2019/017076 WO2019157195A1 (en) | 2018-02-08 | 2019-02-07 | Methods of permeabilizing the blood brain barrier |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111936125A true CN111936125A (zh) | 2020-11-13 |
Family
ID=67549074
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980023885.8A Pending CN111936125A (zh) | 2018-02-08 | 2019-02-07 | 穿透血脑屏障的方法 |
Country Status (9)
Country | Link |
---|---|
US (3) | US20210228498A1 (zh) |
EP (1) | EP3749291B1 (zh) |
JP (2) | JP7325425B2 (zh) |
KR (1) | KR20200118084A (zh) |
CN (1) | CN111936125A (zh) |
BR (1) | BR112020016074A2 (zh) |
CA (2) | CA3225993A1 (zh) |
DK (1) | DK3749291T3 (zh) |
WO (1) | WO2019157195A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021252432A1 (en) * | 2020-06-08 | 2021-12-16 | Neonc Technologies, Inc. | Compositions and methods for delivering polynucleotides |
WO2022082093A1 (en) * | 2020-10-16 | 2022-04-21 | Neonc Technologies, Inc. | Combination of poh and remdesivir for treatment of cns infections |
US20220287986A1 (en) * | 2021-03-10 | 2022-09-15 | Weijun Wang | Intraarterial (IA) Application of Low Dose of Ethyl Alcohol Enables Blood-Brain Barrier (BBB) Impermeable Therapeutics Brain Entry |
CN114773356B (zh) * | 2022-05-16 | 2023-01-31 | 天津济坤医药科技有限公司 | 一种倍半萜衍生物、其药物组合物及其制备方法和用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020137799A1 (en) * | 2000-11-08 | 2002-09-26 | Gould Michael N. | Monoterpenes and sesquiterpenes as chemotherapeutic and radiation sensitizers and immunomodulators |
CN102892289A (zh) * | 2010-03-03 | 2013-01-23 | 尼昂克技术公司 | 包含单萜的药物组合物 |
CN103946202A (zh) * | 2011-11-21 | 2014-07-23 | 尼昂克技术公司 | 包含富含氘的紫苏醇、异紫苏醇及其衍生物的药物组合物 |
WO2015054333A1 (en) * | 2013-10-08 | 2015-04-16 | Neonc Technologies, Inc. | Methods of treating cancer using compositions comprising perillyl alcohol derivative |
Family Cites Families (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1508602A (en) | 1974-04-01 | 1978-04-26 | Bush Boake Allen Ltd | Production of esters of perillyl alcohol |
BR8007911A (pt) | 1979-12-06 | 1981-06-16 | Glaxo Group Ltd | Inalador aperfeicoado |
EP0069715B1 (en) | 1981-07-08 | 1986-11-05 | Aktiebolaget Draco | Powder inhalator |
CA1272917A (en) | 1985-07-30 | 1990-08-21 | Paul Kenneth Rand | Devices for administering medicaments to patients |
US4738851A (en) | 1985-09-27 | 1988-04-19 | University Of Iowa Research Foundation, Inc. | Controlled release ophthalmic gel formulation |
US4882150A (en) | 1988-06-03 | 1989-11-21 | Kaufman Herbert E | Drug delivery system |
US5225183A (en) | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5521222A (en) | 1989-09-28 | 1996-05-28 | Alcon Laboratories, Inc. | Topical ophthalmic pharmaceutical vehicles |
US6313176B1 (en) | 1989-10-17 | 2001-11-06 | Everett J. Ellinwood, Jr. | Dosing method of administering deprenyl via intraoral administration or inhalation administration |
SK280967B6 (sk) | 1990-03-02 | 2000-10-09 | Glaxo Group Limited | Inhalačný prístroj |
US5077033A (en) | 1990-08-07 | 1991-12-31 | Mediventures Inc. | Ophthalmic drug delivery with thermo-irreversible gels of polxoxyalkylene polymer and ionic polysaccharide |
US6006745A (en) | 1990-12-21 | 1999-12-28 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
JP2594486B2 (ja) | 1991-01-15 | 1997-03-26 | アルコン ラボラトリーズ インコーポレイテッド | 局所的眼薬組成物 |
US5874063A (en) | 1991-04-11 | 1999-02-23 | Astra Aktiebolag | Pharmaceutical formulation |
AU2178392A (en) | 1991-06-12 | 1993-01-12 | Minnesota Mining And Manufacturing Company | Albuterol sulfate suspension aerosol formulations |
US5337740A (en) | 1991-08-01 | 1994-08-16 | New England Pharmaceuticals, Inc. | Inhalation devices |
ES2099415T3 (es) | 1991-12-18 | 1997-05-16 | Minnesota Mining & Mfg | Formulaciones de aerosol en suspension. |
US5239993A (en) | 1992-08-26 | 1993-08-31 | Glaxo Inc. | Dosage inhalator providing optimized compound inhalation trajectory |
US5497763A (en) | 1993-05-21 | 1996-03-12 | Aradigm Corporation | Disposable package for intrapulmonary delivery of aerosolized formulations |
US5415162A (en) | 1994-01-18 | 1995-05-16 | Glaxo Inc. | Multi-dose dry powder inhalation device |
IL114193A (en) | 1994-06-20 | 2000-02-29 | Teva Pharma | Ophthalmic pharmaceutical compositions based on sodium alginate |
ES2094688B1 (es) | 1994-08-08 | 1997-08-01 | Cusi Lab | Manoemulsion del tipo de aceite en agua, util como vehiculo oftalmico y procedimiento para su preparacion. |
US5983956A (en) | 1994-10-03 | 1999-11-16 | Astra Aktiebolag | Formulation for inhalation |
SE9501384D0 (sv) | 1995-04-13 | 1995-04-13 | Astra Ab | Process for the preparation of respirable particles |
US5882676A (en) | 1995-05-26 | 1999-03-16 | Alza Corporation | Skin permeation enhancer compositions using acyl lactylates |
US5785991A (en) | 1995-06-07 | 1998-07-28 | Alza Corporation | Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate |
DE19536902A1 (de) | 1995-10-04 | 1997-04-10 | Boehringer Ingelheim Int | Vorrichtung zur Hochdruckerzeugung in einem Fluid in Miniaturausführung |
IT1283911B1 (it) | 1996-02-05 | 1998-05-07 | Farmigea Spa | Soluzioni oftalmiche viscosizzate con polisaccaridi della gomma di tamarindo |
AU4990797A (en) | 1996-10-24 | 1998-05-15 | Alza Corporation | Permeation enhancers for transdermal drug delivery compositions, devices, and methods |
US6040344A (en) | 1996-11-11 | 2000-03-21 | Sepracor Inc. | Formoterol process |
US5800807A (en) | 1997-01-29 | 1998-09-01 | Bausch & Lomb Incorporated | Ophthalmic compositions including glycerin and propylene glycol |
US6143227A (en) | 1997-07-30 | 2000-11-07 | Visteon Global Technologies, Inc. | Method for injection molding an article having film covered flanges |
US6261547B1 (en) | 1998-04-07 | 2001-07-17 | Alcon Manufacturing, Ltd. | Gelling ophthalmic compositions containing xanthan gum |
CN1145478C (zh) | 1998-04-18 | 2004-04-14 | 葛兰素集团有限公司 | 药用气溶胶制剂 |
GB9808802D0 (en) | 1998-04-24 | 1998-06-24 | Glaxo Group Ltd | Pharmaceutical formulations |
US6133324A (en) | 1998-05-07 | 2000-10-17 | The Regents Of The University Of California | Use of perillyl alcohol in organ transplantation |
US6197934B1 (en) | 1998-05-22 | 2001-03-06 | Collagenesis, Inc. | Compound delivery using rapidly dissolving collagen film |
SE9804000D0 (sv) | 1998-11-23 | 1998-11-23 | Astra Ab | New composition of matter |
ATE233084T1 (de) | 1999-04-14 | 2003-03-15 | Glaxo Group Ltd | Pharmazeutische aerosolformulierung |
JP2002097137A (ja) | 2000-07-19 | 2002-04-02 | Junichi Sudo | パーキンソン病の予防および/または治療剤 |
IT1320180B1 (it) | 2000-12-29 | 2003-11-26 | Hunza Di Marazzita Maria Carme | Preparazioni nutrizionali e terapeutiche dotate di attivita'antiossidante ed in grado di controllare gli eccessi ponderali e |
BR0107262B1 (pt) | 2001-12-17 | 2014-04-22 | Da Fonseca Clovis Orlando Pereira | Composição farmacêutica inalatória |
US6994083B2 (en) | 2001-12-21 | 2006-02-07 | Trudell Medical International | Nebulizer apparatus and method |
ITPD20020138A1 (it) | 2002-05-24 | 2003-11-24 | Matteo Bevilacqua | Composizione di sostanze a base terpenica, metodo di preparazione e metodo di dispersione in ambiente della medesima. |
JP4537956B2 (ja) | 2003-03-26 | 2010-09-08 | クリングルファーマ株式会社 | 喘息治療剤 |
US20090031455A1 (en) | 2004-10-14 | 2009-01-29 | Plant Research International B.V. | Terpene hydroxylation |
JP2009506076A (ja) | 2005-08-26 | 2009-02-12 | ザ・ボード・オブ・トラスティーズ・オブ・ザ・レランド・スタンフォード・ジュニア・ユニバーシティ | 三叉神経疼痛のための薬物送達のための治療手順 |
US20140142071A1 (en) * | 2005-11-22 | 2014-05-22 | Atheronova Operations, Inc. | Regression of arterial plaque |
JP2007302572A (ja) | 2006-05-09 | 2007-11-22 | Pokka Corp | 脳機能改善剤及びそれを含有する脳機能改善組成物 |
HUE059861T2 (hu) | 2007-04-11 | 2023-01-28 | Canbas Co Ltd | N-Szubsztituált 2,5-dioxo-azolin vegyületek a rák kezelésében való felhasználásra |
US8889622B2 (en) | 2007-07-25 | 2014-11-18 | Washington University | Methods of inhibiting seizure in a subject |
US7745670B2 (en) | 2008-06-27 | 2010-06-29 | Codman & Shurtleff, Inc. | Curcumin-Resveratrol hybrid molecule |
AU2009248914A1 (en) | 2008-05-21 | 2009-11-26 | Neurotez, Inc. | Methods for Treating Neurodegenerative Disorders Related to Neurofibrillary Tangles |
EP3620154A1 (en) * | 2009-02-06 | 2020-03-11 | University Of Southern California | Therapeutic compositions comprising monoterpenes |
GB2478595B (en) | 2010-03-12 | 2018-04-04 | Gw Pharma Ltd | Phytocannabinoids in the treatment of glioma |
BR112013004698B1 (pt) | 2010-08-27 | 2022-03-22 | Neonc Technologies Inc. | Composições farmacêuticas compreendendo derivados de poh |
DK2651864T3 (en) | 2010-12-17 | 2016-09-05 | Neonc Tech Inc | Methods and devices for use of isoperillylalkohol |
WO2015151123A1 (en) | 2014-04-03 | 2015-10-08 | Biosfered S.R.L. | Process for preparing a powdered mixture of borneol and plant proteins to be used as dietary or food supplement, and related dietary or food supplement |
-
2019
- 2019-02-07 CA CA3225993A patent/CA3225993A1/en active Pending
- 2019-02-07 US US16/967,549 patent/US20210228498A1/en not_active Abandoned
- 2019-02-07 CN CN201980023885.8A patent/CN111936125A/zh active Pending
- 2019-02-07 WO PCT/US2019/017076 patent/WO2019157195A1/en unknown
- 2019-02-07 CA CA3101475A patent/CA3101475C/en active Active
- 2019-02-07 BR BR112020016074-1A patent/BR112020016074A2/pt unknown
- 2019-02-07 EP EP19750825.2A patent/EP3749291B1/en active Active
- 2019-02-07 DK DK19750825.2T patent/DK3749291T3/da active
- 2019-02-07 JP JP2020542628A patent/JP7325425B2/ja active Active
- 2019-02-07 KR KR1020207024860A patent/KR20200118084A/ko unknown
-
2023
- 2023-03-27 US US18/190,643 patent/US20230248662A1/en active Pending
- 2023-03-27 US US18/190,416 patent/US20230233481A1/en active Pending
- 2023-08-01 JP JP2023125681A patent/JP2023145654A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020137799A1 (en) * | 2000-11-08 | 2002-09-26 | Gould Michael N. | Monoterpenes and sesquiterpenes as chemotherapeutic and radiation sensitizers and immunomodulators |
CN102892289A (zh) * | 2010-03-03 | 2013-01-23 | 尼昂克技术公司 | 包含单萜的药物组合物 |
CN103946202A (zh) * | 2011-11-21 | 2014-07-23 | 尼昂克技术公司 | 包含富含氘的紫苏醇、异紫苏醇及其衍生物的药物组合物 |
WO2015054333A1 (en) * | 2013-10-08 | 2015-04-16 | Neonc Technologies, Inc. | Methods of treating cancer using compositions comprising perillyl alcohol derivative |
Non-Patent Citations (2)
Title |
---|
CHRISTINE E. BROWN等: "Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy", 《THE NEW ENGLAND JOURNAL OF MEDICINE》 * |
郭鹏辉等: "药食两用植物紫苏及其秸秆的饲料化利用研究进展", 《甘肃畜牧兽医》 * |
Also Published As
Publication number | Publication date |
---|---|
JP2021512907A (ja) | 2021-05-20 |
CA3101475A1 (en) | 2019-08-15 |
DK3749291T3 (da) | 2024-04-08 |
CA3101475C (en) | 2024-02-20 |
US20210228498A1 (en) | 2021-07-29 |
CA3225993A1 (en) | 2019-08-15 |
JP7325425B2 (ja) | 2023-08-14 |
US20230248662A1 (en) | 2023-08-10 |
BR112020016074A2 (pt) | 2020-12-08 |
JP2023145654A (ja) | 2023-10-11 |
KR20200118084A (ko) | 2020-10-14 |
EP3749291A1 (en) | 2020-12-16 |
EP3749291B1 (en) | 2024-01-03 |
EP3749291A4 (en) | 2021-11-24 |
US20230233481A1 (en) | 2023-07-27 |
WO2019157195A1 (en) | 2019-08-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230233481A1 (en) | Methods of permeabilizing the blood brain barrier | |
US10092562B2 (en) | Pharmaceutical compositions comprising POH derivatives | |
JP6674957B2 (ja) | ペリリルアルコール誘導体を含む医薬組成物 | |
US10899691B2 (en) | Pharmaceutical compositions comprising monoterpenes | |
TWI643618B (zh) | 包含紫蘇醇衍生物之化合物於製造治療癌症之藥物的用途 | |
US20210268108A1 (en) | Pharmaceutical compositions comprising poh derivatives | |
CN110769831A (zh) | 包含poh衍生物的药物组合物及使用方法 | |
JP2023545472A (ja) | Cns感染症の治療のためのpohとレムデシビルとの組み合わせ | |
JP2023550033A (ja) | ペリリルアルコールでの再発性神経膠芽腫の治療 | |
CN112469401A (zh) | 包含poh衍生物的药物组合物 | |
WO2022221759A1 (en) | Pharmaceutical compositions comprising poh derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20230824 Address after: California, USA Applicant after: University OF SOUTHERN CALIFORNIA Address before: California, USA Applicant before: NeOnc Technologies, Inc. |
|
TA01 | Transfer of patent application right |