JP5637561B2 - 第Xa因子阻害剤に対する解毒剤およびその使用の方法 - Google Patents
第Xa因子阻害剤に対する解毒剤およびその使用の方法 Download PDFInfo
- Publication number
- JP5637561B2 JP5637561B2 JP2010527220A JP2010527220A JP5637561B2 JP 5637561 B2 JP5637561 B2 JP 5637561B2 JP 2010527220 A JP2010527220 A JP 2010527220A JP 2010527220 A JP2010527220 A JP 2010527220A JP 5637561 B2 JP5637561 B2 JP 5637561B2
- Authority
- JP
- Japan
- Prior art keywords
- fxa
- factor
- protein
- inhibitor
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims description 184
- 229940123583 Factor Xa inhibitor Drugs 0.000 title claims description 55
- 239000000729 antidote Substances 0.000 title description 172
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 183
- 108090000623 proteins and genes Proteins 0.000 claims description 147
- 210000004027 cell Anatomy 0.000 claims description 119
- 239000003112 inhibitor Substances 0.000 claims description 116
- 102000004169 proteins and genes Human genes 0.000 claims description 105
- 235000018102 proteins Nutrition 0.000 claims description 97
- 239000002157 polynucleotide Substances 0.000 claims description 94
- 108091033319 polynucleotide Proteins 0.000 claims description 94
- 102000040430 polynucleotide Human genes 0.000 claims description 94
- 235000001014 amino acid Nutrition 0.000 claims description 88
- 229950011103 betrixaban Drugs 0.000 claims description 75
- XHOLNRLADUSQLD-UHFFFAOYSA-N betrixaban Chemical compound C=1C=C(Cl)C=NC=1NC(=O)C1=CC(OC)=CC=C1NC(=O)C1=CC=C(C(=N)N(C)C)C=C1 XHOLNRLADUSQLD-UHFFFAOYSA-N 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 72
- 230000027455 binding Effects 0.000 claims description 64
- 208000032843 Hemorrhage Diseases 0.000 claims description 63
- 230000000740 bleeding effect Effects 0.000 claims description 62
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 55
- 208000034158 bleeding Diseases 0.000 claims description 55
- 108010074860 Factor Xa Proteins 0.000 claims description 49
- 238000002347 injection Methods 0.000 claims description 39
- 239000007924 injection Substances 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 36
- 125000000539 amino acid group Chemical group 0.000 claims description 33
- -1 otamixerban Chemical compound 0.000 claims description 33
- 210000004369 blood Anatomy 0.000 claims description 29
- 239000008280 blood Substances 0.000 claims description 29
- 238000000338 in vitro Methods 0.000 claims description 29
- 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 claims description 27
- 239000003146 anticoagulant agent Substances 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 27
- 229940127219 anticoagulant drug Drugs 0.000 claims description 26
- 239000003055 low molecular weight heparin Substances 0.000 claims description 25
- 229940127215 low-molecular weight heparin Drugs 0.000 claims description 25
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- 230000010100 anticoagulation Effects 0.000 claims description 21
- 238000002560 therapeutic procedure Methods 0.000 claims description 21
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 20
- 239000002502 liposome Substances 0.000 claims description 20
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 claims description 19
- 229960003886 apixaban Drugs 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 108010014806 prothrombinase complex Proteins 0.000 claims description 19
- 229960001148 rivaroxaban Drugs 0.000 claims description 19
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 claims description 19
- 229960000610 enoxaparin Drugs 0.000 claims description 18
- 239000003937 drug carrier Substances 0.000 claims description 17
- 239000000693 micelle Substances 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 15
- MVPQUSQUURLQKF-MCPDASDXSA-E nonasodium;(2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxylato-4,5-dimethoxy-6-[(2r,3r,4s,5r,6s)-6-methoxy-4,5-disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]oxy-4,5-di Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)O[C@@H]1[C@@H](OS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](OC)[C@H](O[C@@H]4[C@@H]([C@@H](OC)[C@H](OC)[C@@H](COS([O-])(=O)=O)O4)OC)[C@H](O3)C([O-])=O)OC)[C@@H](COS([O-])(=O)=O)O2)OS([O-])(=O)=O)[C@H](C([O-])=O)O1 MVPQUSQUURLQKF-MCPDASDXSA-E 0.000 claims description 13
- 102100037642 Elongation factor G, mitochondrial Human genes 0.000 claims description 12
- 101000880344 Homo sapiens Elongation factor G, mitochondrial Proteins 0.000 claims description 12
- 101100226845 Strongylocentrotus purpuratus EGF2 gene Proteins 0.000 claims description 10
- 235000020958 biotin Nutrition 0.000 claims description 10
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical group O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 10
- UQBOJOOOTLPNST-UHFFFAOYSA-N Dehydroalanine Chemical compound NC(=C)C(O)=O UQBOJOOOTLPNST-UHFFFAOYSA-N 0.000 claims description 9
- 239000011616 biotin Substances 0.000 claims description 9
- 229960002685 biotin Drugs 0.000 claims description 9
- 229960001318 fondaparinux Drugs 0.000 claims description 9
- 238000001356 surgical procedure Methods 0.000 claims description 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 8
- 235000004279 alanine Nutrition 0.000 claims description 8
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 claims description 7
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 claims description 7
- NPBKHEMDWREFJJ-UHFFFAOYSA-N 2-[(7-carbamimidoylnaphthalen-2-yl)methyl-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]sulfamoyl]acetic acid Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)S(=O)(=O)CC(O)=O)C=C1 NPBKHEMDWREFJJ-UHFFFAOYSA-N 0.000 claims description 6
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 claims description 6
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 claims description 6
- 206010018852 Haematoma Diseases 0.000 claims description 6
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- IJNIQYINMSGIPS-UHFFFAOYSA-N darexaban Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC(O)=C1NC(=O)C1=CC=C(N2CCN(C)CCC2)C=C1 IJNIQYINMSGIPS-UHFFFAOYSA-N 0.000 claims description 6
- 229960000622 edoxaban Drugs 0.000 claims description 6
- QQBKAVAGLMGMHI-WIYYLYMNSA-N eribaxaban Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 QQBKAVAGLMGMHI-WIYYLYMNSA-N 0.000 claims description 6
- 208000014674 injury Diseases 0.000 claims description 6
- VYNKVNDKAOGAAQ-RUZDIDTESA-N n-[(1r)-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-1-phenylethyl]-1h-indole-6-carboxamide Chemical compound C1CN(C)CCC1N1CCN(C(=O)[C@H](NC(=O)C=2C=C3NC=CC3=CC=2)C=2C=CC=CC=2)CC1 VYNKVNDKAOGAAQ-RUZDIDTESA-N 0.000 claims description 6
- 239000000863 peptide conjugate Substances 0.000 claims description 6
- LJCBAPRMNYSDOP-LVCYMWGESA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydron;chloride;pentahydrate Chemical compound O.O.O.O.O.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 LJCBAPRMNYSDOP-LVCYMWGESA-N 0.000 claims description 5
- 230000008733 trauma Effects 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 4
- 230000002085 persistent effect Effects 0.000 claims description 4
- 230000000306 recurrent effect Effects 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 229960004969 dalteparin Drugs 0.000 claims description 3
- 208000001780 epistaxis Diseases 0.000 claims description 3
- 208000011309 nasal bleeding Diseases 0.000 claims description 3
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 claims description 2
- 206010065304 Spontaneous haematoma Diseases 0.000 claims description 2
- 229950010535 razaxaban Drugs 0.000 claims description 2
- 230000002776 aggregation Effects 0.000 claims 1
- 238000004220 aggregation Methods 0.000 claims 1
- 210000000664 rectum Anatomy 0.000 claims 1
- 210000001635 urinary tract Anatomy 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 140
- 229920001184 polypeptide Polymers 0.000 description 116
- 241000282414 Homo sapiens Species 0.000 description 98
- 229940024606 amino acid Drugs 0.000 description 75
- 210000002381 plasma Anatomy 0.000 description 75
- 150000001413 amino acids Chemical class 0.000 description 71
- 230000000694 effects Effects 0.000 description 65
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 48
- 108090000317 Chymotrypsin Proteins 0.000 description 40
- 229960002376 chymotrypsin Drugs 0.000 description 40
- 230000035602 clotting Effects 0.000 description 38
- 238000003556 assay Methods 0.000 description 35
- 230000014509 gene expression Effects 0.000 description 34
- 230000004048 modification Effects 0.000 description 33
- 238000012986 modification Methods 0.000 description 33
- 125000003729 nucleotide group Chemical group 0.000 description 33
- 230000002947 procoagulating effect Effects 0.000 description 33
- 230000002829 reductive effect Effects 0.000 description 32
- 239000013598 vector Substances 0.000 description 32
- 108020004414 DNA Proteins 0.000 description 31
- 108090000190 Thrombin Proteins 0.000 description 30
- 229960004072 thrombin Drugs 0.000 description 30
- 108010018682 PRT064445 Proteins 0.000 description 29
- 108020004459 Small interfering RNA Proteins 0.000 description 29
- 239000012634 fragment Substances 0.000 description 29
- 150000007523 nucleic acids Chemical class 0.000 description 29
- 239000002773 nucleotide Substances 0.000 description 29
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 27
- 206010053567 Coagulopathies Diseases 0.000 description 26
- 238000004519 manufacturing process Methods 0.000 description 24
- 102000039446 nucleic acids Human genes 0.000 description 24
- 108020004707 nucleic acids Proteins 0.000 description 24
- 230000003197 catalytic effect Effects 0.000 description 23
- 230000029087 digestion Effects 0.000 description 23
- 238000001727 in vivo Methods 0.000 description 23
- 239000012528 membrane Substances 0.000 description 21
- 210000004379 membrane Anatomy 0.000 description 21
- 230000014508 negative regulation of coagulation Effects 0.000 description 21
- 108091007433 antigens Proteins 0.000 description 20
- 102000036639 antigens Human genes 0.000 description 20
- 230000003993 interaction Effects 0.000 description 20
- 239000000523 sample Substances 0.000 description 20
- 239000000427 antigen Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 19
- 108010013773 recombinant FVIIa Proteins 0.000 description 19
- 108060003951 Immunoglobulin Proteins 0.000 description 18
- 229940075522 antidotes Drugs 0.000 description 18
- 102000018358 immunoglobulin Human genes 0.000 description 18
- 230000002950 deficient Effects 0.000 description 17
- 210000004602 germ cell Anatomy 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 17
- 150000003904 phospholipids Chemical class 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 230000002441 reversible effect Effects 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 15
- 102000012479 Serine Proteases Human genes 0.000 description 15
- 108010022999 Serine Proteases Proteins 0.000 description 15
- 108010000499 Thromboplastin Proteins 0.000 description 15
- 102000002262 Thromboplastin Human genes 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 238000012217 deletion Methods 0.000 description 15
- 230000037430 deletion Effects 0.000 description 15
- 239000003981 vehicle Substances 0.000 description 15
- 108010094028 Prothrombin Proteins 0.000 description 14
- 102100027378 Prothrombin Human genes 0.000 description 14
- 230000035772 mutation Effects 0.000 description 14
- 229940039716 prothrombin Drugs 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000001990 intravenous administration Methods 0.000 description 13
- 150000003384 small molecules Chemical class 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000002671 adjuvant Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 230000000295 complement effect Effects 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 12
- 241000894007 species Species 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 108010014173 Factor X Proteins 0.000 description 11
- 241000282412 Homo Species 0.000 description 11
- 241000124008 Mammalia Species 0.000 description 11
- 238000003776 cleavage reaction Methods 0.000 description 11
- 230000015271 coagulation Effects 0.000 description 11
- 238000005345 coagulation Methods 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 229940088598 enzyme Drugs 0.000 description 11
- 210000004408 hybridoma Anatomy 0.000 description 11
- 239000013612 plasmid Substances 0.000 description 11
- 230000007017 scission Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 108010054265 Factor VIIa Proteins 0.000 description 10
- 230000002429 anti-coagulating effect Effects 0.000 description 10
- 230000001580 bacterial effect Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 229940012414 factor viia Drugs 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 238000012546 transfer Methods 0.000 description 10
- 208000007536 Thrombosis Diseases 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 9
- 229960003856 argatroban Drugs 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 239000002299 complementary DNA Substances 0.000 description 9
- 238000012937 correction Methods 0.000 description 9
- 230000023597 hemostasis Effects 0.000 description 9
- 150000002632 lipids Chemical class 0.000 description 9
- 238000002493 microarray Methods 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 230000009261 transgenic effect Effects 0.000 description 9
- 241000196324 Embryophyta Species 0.000 description 8
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 102000035195 Peptidases Human genes 0.000 description 8
- 108091005804 Peptidases Proteins 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 239000004365 Protease Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 230000021615 conjugation Effects 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 239000013604 expression vector Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000001476 gene delivery Methods 0.000 description 8
- 210000004962 mammalian cell Anatomy 0.000 description 8
- 239000011159 matrix material Substances 0.000 description 8
- 230000036470 plasma concentration Effects 0.000 description 8
- 210000001236 prokaryotic cell Anatomy 0.000 description 8
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 241000282693 Cercopithecidae Species 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 7
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 7
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 7
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 7
- 108090000631 Trypsin Proteins 0.000 description 7
- 102000004142 Trypsin Human genes 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 230000001588 bifunctional effect Effects 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 210000003527 eukaryotic cell Anatomy 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000007850 fluorescent dye Substances 0.000 description 7
- 238000000099 in vitro assay Methods 0.000 description 7
- 230000000670 limiting effect Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000012588 trypsin Substances 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- 241000393496 Electra Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 241000238631 Hexapoda Species 0.000 description 6
- 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 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 241001494479 Pecora Species 0.000 description 6
- 230000000692 anti-sense effect Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000009396 hybridization Methods 0.000 description 6
- 229960000485 methotrexate Drugs 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 230000001177 retroviral effect Effects 0.000 description 6
- 239000004055 small Interfering RNA Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000013603 viral vector Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102000007469 Actins Human genes 0.000 description 5
- 108010085238 Actins Proteins 0.000 description 5
- 229920000936 Agarose Polymers 0.000 description 5
- 108090000935 Antithrombin III Proteins 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- 102000014914 Carrier Proteins Human genes 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 5
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 108020004511 Recombinant DNA Proteins 0.000 description 5
- 108091027967 Small hairpin RNA Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 230000023555 blood coagulation Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 108090001015 cancer procoagulant Proteins 0.000 description 5
- 239000003431 cross linking reagent Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 229940087051 fragmin Drugs 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 5
- 230000002163 immunogen Effects 0.000 description 5
- 238000003780 insertion Methods 0.000 description 5
- 230000037431 insertion Effects 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 230000003472 neutralizing effect Effects 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 239000000816 peptidomimetic Substances 0.000 description 5
- 210000004623 platelet-rich plasma Anatomy 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 241000701161 unidentified adenovirus Species 0.000 description 5
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 5
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 4
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 4
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 4
- 108090001008 Avidin Proteins 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- 108010078791 Carrier Proteins Proteins 0.000 description 4
- 241000699800 Cricetinae Species 0.000 description 4
- 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 4
- 102400001368 Epidermal growth factor Human genes 0.000 description 4
- 101800003838 Epidermal growth factor Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 101001024703 Homo sapiens Nck-associated protein 5 Proteins 0.000 description 4
- 108010090444 Innovin Proteins 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 102100036946 Nck-associated protein 5 Human genes 0.000 description 4
- 102000003827 Plasma Kallikrein Human genes 0.000 description 4
- 108090000113 Plasma Kallikrein Proteins 0.000 description 4
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 4
- 108090000787 Subtilisin Proteins 0.000 description 4
- 108700019146 Transgenes Proteins 0.000 description 4
- 238000005576 amination reaction Methods 0.000 description 4
- 210000004102 animal cell Anatomy 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000003302 anti-idiotype Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 150000001718 carbodiimides Chemical class 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000001784 detoxification Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229940116977 epidermal growth factor Drugs 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 230000005847 immunogenicity Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 239000003868 thrombin inhibitor Substances 0.000 description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000011830 transgenic mouse model Methods 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 3
- PMHUSCHKTSTQEP-UHFFFAOYSA-N (4-carbamimidoylphenyl)methanesulfonyl fluoride Chemical compound NC(=N)C1=CC=C(CS(F)(=O)=O)C=C1 PMHUSCHKTSTQEP-UHFFFAOYSA-N 0.000 description 3
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 3
- 241000710929 Alphavirus Species 0.000 description 3
- 102100022977 Antithrombin-III Human genes 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 241000700198 Cavia Species 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 241000254173 Coleoptera Species 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 150000008574 D-amino acids Chemical class 0.000 description 3
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 3
- 241000702421 Dependoparvovirus Species 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 108010048049 Factor IXa Proteins 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 206010055847 Haemorrhage urinary tract Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 244000061176 Nicotiana tabacum Species 0.000 description 3
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 description 3
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101001045455 Proteus vulgaris Antitoxin HigA Proteins 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 206010038063 Rectal haemorrhage Diseases 0.000 description 3
- 108010039491 Ricin Proteins 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 108091081024 Start codon Proteins 0.000 description 3
- 108010090804 Streptavidin Proteins 0.000 description 3
- 229940122388 Thrombin inhibitor Drugs 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000003024 amidolytic effect Effects 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 3
- 239000004023 fresh frozen plasma Substances 0.000 description 3
- 230000005714 functional activity Effects 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 210000005260 human cell Anatomy 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 230000003278 mimic effect Effects 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000003362 replicative effect Effects 0.000 description 3
- 210000003705 ribosome Anatomy 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 229940124547 specific antidotes Drugs 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 239000002435 venom Substances 0.000 description 3
- 231100000611 venom Toxicity 0.000 description 3
- 210000001048 venom Anatomy 0.000 description 3
- 150000003721 vitamin K derivatives Chemical class 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 2
- PMJWDPGOWBRILU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCC(C=C1)=CC=C1N1C(=O)C=CC1=O PMJWDPGOWBRILU-UHFFFAOYSA-N 0.000 description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 2
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-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
- WUAPFZMCVAUBPE-NJFSPNSNSA-N 188Re Chemical compound [188Re] WUAPFZMCVAUBPE-NJFSPNSNSA-N 0.000 description 2
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 2
- VIIIJFZJKFXOGG-UHFFFAOYSA-N 3-methylchromen-2-one Chemical compound C1=CC=C2OC(=O)C(C)=CC2=C1 VIIIJFZJKFXOGG-UHFFFAOYSA-N 0.000 description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-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
- 239000004382 Amylase Substances 0.000 description 2
- 102000013142 Amylases Human genes 0.000 description 2
- 108010065511 Amylases Proteins 0.000 description 2
- 108020005544 Antisense RNA Proteins 0.000 description 2
- 102000004411 Antithrombin III Human genes 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 101150074155 DHFR gene Proteins 0.000 description 2
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000206602 Eukaryota Species 0.000 description 2
- 108010061932 Factor VIIIa Proteins 0.000 description 2
- 108010074105 Factor Va Proteins 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 108010007267 Hirudins Proteins 0.000 description 2
- 102000007625 Hirudins Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 241000270322 Lepidosauria Species 0.000 description 2
- 238000007476 Maximum Likelihood Methods 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 108010021466 Mutant Proteins Proteins 0.000 description 2
- 102000008300 Mutant Proteins Human genes 0.000 description 2
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- 241000272144 Naja atra Species 0.000 description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 2
- 108091005461 Nucleic proteins Proteins 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 241000282579 Pan Species 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 102000007327 Protamines Human genes 0.000 description 2
- 108010007568 Protamines Proteins 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 2
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 2
- 101710137500 T7 RNA polymerase Proteins 0.000 description 2
- RDFCSSHDJSZMTQ-ZDUSSCGKSA-N Tos-Lys-CH2Cl Chemical compound CC1=CC=C(S(=O)(=O)N[C@@H](CCCCN)C(=O)CCl)C=C1 RDFCSSHDJSZMTQ-ZDUSSCGKSA-N 0.000 description 2
- 108020004566 Transfer RNA Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 235000019418 amylase Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000000628 antibody-producing cell Anatomy 0.000 description 2
- 229960005348 antithrombin iii Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- YXLGWNWVIGXGME-NRFANRHFSA-N benzyl n-[2-[[2-[[(2s)-5-(diaminomethylideneamino)-2-[(4-methyl-2-oxochromen-7-yl)amino]pentanoyl]amino]-2-oxoethyl]amino]-2-oxoethyl]carbamate Chemical compound O=C([C@H](CCCN=C(N)N)NC1=CC=2OC(=O)C=C(C=2C=C1)C)NC(=O)CNC(=O)CNC(=O)OCC1=CC=CC=C1 YXLGWNWVIGXGME-NRFANRHFSA-N 0.000 description 2
- 108010055460 bivalirudin Proteins 0.000 description 2
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- UHBYWPGGCSDKFX-UHFFFAOYSA-N carboxyglutamic acid Chemical compound OC(=O)C(N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-UHFFFAOYSA-N 0.000 description 2
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 2
- 108020001778 catalytic domains Proteins 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000007385 chemical modification Methods 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
- 239000013611 chromosomal DNA Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 238000007820 coagulation assay Methods 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 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
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000012631 diagnostic technique Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical class [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 2
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 2
- 210000001671 embryonic stem cell Anatomy 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000008393 encapsulating agent Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- IINNWAYUJNWZRM-UHFFFAOYSA-L erythrosin B Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 IINNWAYUJNWZRM-UHFFFAOYSA-L 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- 229940006607 hirudin Drugs 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- DLBFLQKQABVKGT-UHFFFAOYSA-L lucifer yellow dye Chemical compound [Li+].[Li+].[O-]S(=O)(=O)C1=CC(C(N(C(=O)NN)C2=O)=O)=C3C2=CC(S([O-])(=O)=O)=CC3=C1N DLBFLQKQABVKGT-UHFFFAOYSA-L 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 210000003061 neural cell Anatomy 0.000 description 2
- 210000001178 neural stem cell Anatomy 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000123 paper Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000003805 procoagulant Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 229940048914 protamine Drugs 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 229940024790 prothrombin complex concentrate Drugs 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 239000003998 snake venom Substances 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 2
- 235000021286 stilbenes Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 239000005460 tetrahydrofolate Substances 0.000 description 2
- WGTODYJZXSJIAG-UHFFFAOYSA-N tetramethylrhodamine chloride Chemical compound [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C(O)=O WGTODYJZXSJIAG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 229940113082 thymine 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
- 238000001890 transfection Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 241001515965 unidentified phage Species 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 239000011712 vitamin K Substances 0.000 description 2
- 229940046010 vitamin k Drugs 0.000 description 2
- 229940019333 vitamin k antagonists Drugs 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- LLXVXPPXELIDGQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)benzoate Chemical compound C=1C=CC(N2C(C=CC2=O)=O)=CC=1C(=O)ON1C(=O)CCC1=O LLXVXPPXELIDGQ-UHFFFAOYSA-N 0.000 description 1
- FXYPGCIGRDZWNR-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[[3-(2,5-dioxopyrrolidin-1-yl)oxy-3-oxopropyl]disulfanyl]propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O FXYPGCIGRDZWNR-UHFFFAOYSA-N 0.000 description 1
- PVGATNRYUYNBHO-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(2,5-dioxopyrrol-1-yl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O PVGATNRYUYNBHO-UHFFFAOYSA-N 0.000 description 1
- BQWBEDSJTMWJAE-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[(2-iodoacetyl)amino]benzoate Chemical compound C1=CC(NC(=O)CI)=CC=C1C(=O)ON1C(=O)CCC1=O BQWBEDSJTMWJAE-UHFFFAOYSA-N 0.000 description 1
- GKSPIZSKQWTXQG-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[1-(pyridin-2-yldisulfanyl)ethyl]benzoate Chemical compound C=1C=C(C(=O)ON2C(CCC2=O)=O)C=CC=1C(C)SSC1=CC=CC=N1 GKSPIZSKQWTXQG-UHFFFAOYSA-N 0.000 description 1
- JSPNNZKWADNWHI-PNANGNLXSA-N (2r)-2-hydroxy-n-[(2s,3r,4e,8e)-3-hydroxy-9-methyl-1-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoctadeca-4,8-dien-2-yl]heptadecanamide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)C(=O)N[C@H]([C@H](O)\C=C\CC\C=C(/C)CCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JSPNNZKWADNWHI-PNANGNLXSA-N 0.000 description 1
- XHTORJWGZKCDGL-GRGSLBFTSA-N (2s)-1-[(2r,3r)-2-amino-3-methylpentanoyl]-n-[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]pyrrolidine-2-carboxamide Chemical compound CC[C@@H](C)[C@@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 XHTORJWGZKCDGL-GRGSLBFTSA-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
- YYLQUHNPNCGKJQ-NHYDCYSISA-N (3R)-3-hydroxy-L-aspartic acid Chemical compound OC(=O)[C@@H](N)[C@@H](O)C(O)=O YYLQUHNPNCGKJQ-NHYDCYSISA-N 0.000 description 1
- NRMHMZJDVNWOTN-OALUTQOASA-N (4s)-5-[[2-[[(4s)-1-chloro-7-(diaminomethylideneamino)-2,3-dioxoheptan-4-yl]amino]-2-oxoethyl]amino]-4-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]-5-oxopentanoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)C(=O)CCl NRMHMZJDVNWOTN-OALUTQOASA-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
- BWKMGYQJPOAASG-UHFFFAOYSA-M 1,2,3,4-tetrahydroisoquinoline-3-carboxylate Chemical compound C1=CC=C2CNC(C(=O)[O-])CC2=C1 BWKMGYQJPOAASG-UHFFFAOYSA-M 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
- VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 1
- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical compound CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 description 1
- AASYSXRGODIQGY-UHFFFAOYSA-N 1-[1-(2,5-dioxopyrrol-1-yl)hexyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(CCCCC)N1C(=O)C=CC1=O AASYSXRGODIQGY-UHFFFAOYSA-N 0.000 description 1
- MPBMJFQAGBVIDC-UHFFFAOYSA-N 1-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C(O)NC(C(O)=O)CC2=C1 MPBMJFQAGBVIDC-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 1
- WALUVDCNGPQPOD-UHFFFAOYSA-M 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCOCC(C[N+](C)(C)CCO)OCCCCCCCCCCCCCC WALUVDCNGPQPOD-UHFFFAOYSA-M 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- JPHGTWWUDOEBRJ-UHFFFAOYSA-N 2-amino-3,4,4a,5-tetrahydro-1h-naphthalene-2-carboxylic acid Chemical compound C1C=CC=C2CC(N)(C(O)=O)CCC21 JPHGTWWUDOEBRJ-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NUIURNJTPRWVAP-UHFFFAOYSA-N 3,3'-Dimethylbenzidine Chemical compound C1=C(N)C(C)=CC(C=2C=C(C)C(N)=CC=2)=C1 NUIURNJTPRWVAP-UHFFFAOYSA-N 0.000 description 1
- HJBUBXIDMQBSQW-UHFFFAOYSA-N 4-(4-diazoniophenyl)benzenediazonium Chemical compound C1=CC([N+]#N)=CC=C1C1=CC=C([N+]#N)C=C1 HJBUBXIDMQBSQW-UHFFFAOYSA-N 0.000 description 1
- ZMRMMAOBSFSXLN-UHFFFAOYSA-N 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanehydrazide Chemical compound C1=CC(CCCC(=O)NN)=CC=C1N1C(=O)C=CC1=O ZMRMMAOBSFSXLN-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical compound OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 1
- LIFHMKCDDVTICL-UHFFFAOYSA-N 6-(chloromethyl)phenanthridine Chemical compound C1=CC=C2C(CCl)=NC3=CC=CC=C3C2=C1 LIFHMKCDDVTICL-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 101150034533 ATIC gene Proteins 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102400000069 Activation peptide Human genes 0.000 description 1
- 101800001401 Activation peptide Proteins 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- UMHJEEQLYBKSAN-UHFFFAOYSA-N Adipaldehyde Chemical compound O=CCCCCC=O UMHJEEQLYBKSAN-UHFFFAOYSA-N 0.000 description 1
- 108010000239 Aequorin Proteins 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 244000105975 Antidesma platyphyllum Species 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 101710081722 Antitrypsin Proteins 0.000 description 1
- 241000203069 Archaea Species 0.000 description 1
- 241000228254 Aspergillus restrictus Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 108091032955 Bacterial small RNA Proteins 0.000 description 1
- 102100026031 Beta-glucuronidase Human genes 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 108010028614 BnSO(2)-D-Arg-Gly-Arg-ketothiazole Proteins 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 241000219193 Brassicaceae Species 0.000 description 1
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical compound CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102100033620 Calponin-1 Human genes 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 108020004998 Chloroplast DNA Proteins 0.000 description 1
- 108020005133 Chloroplast RNA Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 235000000638 D-biotin Nutrition 0.000 description 1
- 239000011665 D-biotin Substances 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000004594 DNA Polymerase I Human genes 0.000 description 1
- 108010017826 DNA Polymerase I Proteins 0.000 description 1
- 238000000018 DNA microarray Methods 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- XULFJDKZVHTRLG-JDVCJPALSA-N DOSPA trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)CCNC(=O)C(CCCNCCCN)NCCCN)OCCCCCCCC\C=C/CCCCCCCC XULFJDKZVHTRLG-JDVCJPALSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- JYGLAHSAISAEAL-UHFFFAOYSA-N Diphenadione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 JYGLAHSAISAEAL-UHFFFAOYSA-N 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 108010071241 Factor XIIa Proteins 0.000 description 1
- 108010080805 Factor XIa Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 1
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 1
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 1
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 1
- 102000053187 Glucuronidase Human genes 0.000 description 1
- 108010060309 Glucuronidase Proteins 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
- 244000068988 Glycine max Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- VPZXBVLAVMBEQI-VKHMYHEASA-N Glycyl-alanine Chemical compound OC(=O)[C@H](C)NC(=O)CN VPZXBVLAVMBEQI-VKHMYHEASA-N 0.000 description 1
- 206010019027 Haemothorax Diseases 0.000 description 1
- 101710153310 Hemoglobin subunit beta-3 Proteins 0.000 description 1
- 102100038617 Hemoglobin subunit gamma-2 Human genes 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101000933465 Homo sapiens Beta-glucuronidase Proteins 0.000 description 1
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 1
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108091092195 Intron 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
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 244000207740 Lemna minor Species 0.000 description 1
- 235000006439 Lemna minor Nutrition 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 description 1
- 108010079364 N-glycylalanine Proteins 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 1
- LUZWXMGSPXIQHB-UHFFFAOYSA-N OC(=O)CC(C1=CC=C(C=C1)[N+]([O-])=O)C1=C(O)C2=C(OC1=O)C=CC=C2 Chemical compound OC(=O)CC(C1=CC=C(C=C1)[N+]([O-])=O)C1=C(O)C2=C(OC1=O)C=CC=C2 LUZWXMGSPXIQHB-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-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
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 101000882917 Penaeus paulensis Hemolymph clottable protein Proteins 0.000 description 1
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 1
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 231100000742 Plant toxin Toxicity 0.000 description 1
- 235000001855 Portulaca oleracea Nutrition 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 101900161471 Pseudomonas aeruginosa Exotoxin A Proteins 0.000 description 1
- 102000009572 RNA Polymerase II Human genes 0.000 description 1
- 108010009460 RNA Polymerase II Proteins 0.000 description 1
- 102000014450 RNA Polymerase III Human genes 0.000 description 1
- 108010078067 RNA Polymerase III Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 101100409194 Rattus norvegicus Ppargc1b gene Proteins 0.000 description 1
- 108010073443 Ribi adjuvant Proteins 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 108090000829 Ribosome Inactivating Proteins Proteins 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241001138501 Salmonella enterica Species 0.000 description 1
- 240000003946 Saponaria officinalis Species 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 241000235346 Schizosaccharomyces Species 0.000 description 1
- 241000710961 Semliki Forest virus Species 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 102100035088 Sodium/calcium exchanger 1 Human genes 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 241000194026 Streptococcus gordonii Species 0.000 description 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101150052863 THY1 gene Proteins 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 108010034949 Thyroglobulin Proteins 0.000 description 1
- 102000009843 Thyroglobulin Human genes 0.000 description 1
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 241001492404 Woodchuck hepatitis virus Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 241000235013 Yarrowia Species 0.000 description 1
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 1
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 description 1
- CWRILEGKIAOYKP-SSDOTTSWSA-M [(2r)-3-acetyloxy-2-hydroxypropyl] 2-aminoethyl phosphate Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCCN CWRILEGKIAOYKP-SSDOTTSWSA-M 0.000 description 1
- HIHOWBSBBDRPDW-PTHRTHQKSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate Chemical compound C1C=C2C[C@@H](OC(=O)NCCN(C)C)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 HIHOWBSBBDRPDW-PTHRTHQKSA-N 0.000 description 1
- LWQSEIYNXOYDAQ-UHFFFAOYSA-N [Mg].[Si].[Si].[Si] Chemical compound [Mg].[Si].[Si].[Si] LWQSEIYNXOYDAQ-UHFFFAOYSA-N 0.000 description 1
- 229960002054 acenocoumarol Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- VUBTYKDZOQNADH-UHFFFAOYSA-N acetyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)=O VUBTYKDZOQNADH-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 239000002776 alpha toxin Substances 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940064734 aminobenzoate Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229940003354 angiomax Drugs 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001858 anti-Xa Effects 0.000 description 1
- 230000001475 anti-trypsic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940104697 arixtra Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 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 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 108700021042 biotin binding protein Proteins 0.000 description 1
- 102000043871 biotin binding protein Human genes 0.000 description 1
- 150000001615 biotins Chemical class 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- JCXGWMGPZLAOME-AKLPVKDBSA-N bismuth-212 Chemical compound [212Bi] JCXGWMGPZLAOME-AKLPVKDBSA-N 0.000 description 1
- JCXGWMGPZLAOME-RNFDNDRNSA-N bismuth-213 Chemical compound [213Bi] JCXGWMGPZLAOME-RNFDNDRNSA-N 0.000 description 1
- 229960001500 bivalirudin Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- HCOMFAYPHBFMKU-UHFFFAOYSA-N butanedihydrazide Chemical class NNC(=O)CCC(=O)NN HCOMFAYPHBFMKU-UHFFFAOYSA-N 0.000 description 1
- FCCCRBDJBTVFSJ-UHFFFAOYSA-N butanehydrazide Chemical compound CCCC(=O)NN FCCCRBDJBTVFSJ-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000002458 cell surface marker Substances 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 229930183167 cerebroside Natural products 0.000 description 1
- RIZIAUKTHDLMQX-UHFFFAOYSA-N cerebroside D Natural products CCCCCCCCCCCCCCCCC(O)C(=O)NC(C(O)C=CCCC=C(C)CCCCCCCCC)COC1OC(CO)C(O)C(O)C1O RIZIAUKTHDLMQX-UHFFFAOYSA-N 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960001307 clorindione Drugs 0.000 description 1
- NJDUWAXIURWWLN-UHFFFAOYSA-N clorindione Chemical compound C1=CC(Cl)=CC=C1C1C(=O)C2=CC=CC=C2C1=O NJDUWAXIURWWLN-UHFFFAOYSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229940072645 coumadin Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 238000002574 cystoscopy Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960003828 danaparoid Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- KBODESQIOVVMAI-UHFFFAOYSA-N decyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCC KBODESQIOVVMAI-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 1
- 229940093541 dicetylphosphate Drugs 0.000 description 1
- 229960001912 dicoumarol Drugs 0.000 description 1
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 1
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZLFRJHOBQVVTOJ-UHFFFAOYSA-N dimethyl hexanediimidate Chemical compound COC(=N)CCCCC(=N)OC ZLFRJHOBQVVTOJ-UHFFFAOYSA-N 0.000 description 1
- FRTGEIHSCHXMTI-UHFFFAOYSA-N dimethyl octanediimidate Chemical compound COC(=N)CCCCCCC(=N)OC FRTGEIHSCHXMTI-UHFFFAOYSA-N 0.000 description 1
- 229960000267 diphenadione Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 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
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- ZWIBGKZDAWNIFC-UHFFFAOYSA-N disuccinimidyl suberate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O ZWIBGKZDAWNIFC-UHFFFAOYSA-N 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000000835 electrochemical detection Methods 0.000 description 1
- 238000009297 electrocoagulation Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000002297 emergency surgery Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229940011411 erythrosine Drugs 0.000 description 1
- 239000004174 erythrosine Substances 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- JCLHQFUTFHUXNN-UHFFFAOYSA-N ethyl biscoumacetate Chemical compound C1=CC=C2OC(=O)C(C(C=3C(OC4=CC=CC=C4C=3O)=O)C(=O)OCC)=C(O)C2=C1 JCLHQFUTFHUXNN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000009424 haa Nutrition 0.000 description 1
- 125000005179 haloacetyl group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 229960003569 hematoporphyrin Drugs 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- ODYPFMHOOQOHEF-UHFFFAOYSA-N hexadecanoylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC[N+](C)(C)C ODYPFMHOOQOHEF-UHFFFAOYSA-N 0.000 description 1
- 238000012188 high-throughput screening assay Methods 0.000 description 1
- 102000054751 human RUNX1T1 Human genes 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 238000012872 hydroxylapatite chromatography Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 210000001822 immobilized cell Anatomy 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000006623 intrinsic pathway Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 108010075079 isoleucyl-prolyl-arginine-4-nitroanilide Proteins 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 108010002230 lepirudin Proteins 0.000 description 1
- FIBJDTSHOUXTKV-BRHMIFOHSA-N lepirudin Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)CNC2=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)C(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O FIBJDTSHOUXTKV-BRHMIFOHSA-N 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229940118179 lovenox Drugs 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940118019 malondialdehyde Drugs 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 210000005060 membrane bound organelle Anatomy 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002923 metal particle Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 108091064355 mitochondrial RNA Proteins 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 239000002853 nucleic acid probe Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- WCVRQHFDJLLWFE-UHFFFAOYSA-N pentane-1,2-diol Chemical compound CCCC(O)CO WCVRQHFDJLLWFE-UHFFFAOYSA-N 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960000280 phenindione Drugs 0.000 description 1
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 1
- DQDAYGNAKTZFIW-UHFFFAOYSA-N phenprocoumon Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC)C1=CC=CC=C1 DQDAYGNAKTZFIW-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000003123 plant toxin Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229960003581 pyridoxal Drugs 0.000 description 1
- 235000008164 pyridoxal Nutrition 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000007420 radioactive assay Methods 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940068953 recombinant fviia Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 229940030915 refludan Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000000574 retroperitoneal space Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 108020004418 ribosomal RNA Proteins 0.000 description 1
- 238000002702 ribosome display Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 108010067207 sodium-calcium exchanger 1 Proteins 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 210000001988 somatic stem cell Anatomy 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940056501 technetium 99m Drugs 0.000 description 1
- JEOIUGLPMJAHBL-HWBMXIPRSA-N tert-butyl n-[(2s)-1-[(2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[(4-methyl-2-oxochromen-7-yl)amino]pentanoyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC(=O)[C@H](CCCN=C(N)N)NC1=CC=C(C(C)=CC(=O)O2)C2=C1 JEOIUGLPMJAHBL-HWBMXIPRSA-N 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 229960002175 thyroglobulin Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 230000004865 vascular response Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4826—Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4833—Thrombin (3.4.21.5)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4853—Kallikrein (3.4.21.34 or 3.4.21.35)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6432—Coagulation factor Xa (3.4.21.6)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21006—Coagulation factor Xa (3.4.21.6)
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
Description
本願は、2007年9月28に出願された米国仮特許出願第60/976,343号および2008年8月20日に出願された米国仮特許出願第61/090,574号の利益を、米国特許法§119(e)のもとに主張する。米国仮特許出願第60/976,343号および同第61/090,574号の両方は、その全体が参照として援用される。
本発明の好ましい実施形態では、例えば以下が提供される:
(項目1)
第Xa因子阻害剤と結合し、そしてプロトロンビナーゼ複合体を集合して形成しない第Xa因子タンパク質誘導体の有効量を対象に投与することを含む、前記第Xa因子阻害剤を用いた抗凝固療法を受けている前記対象において出血を防止または減少する方法。
(項目2)
前記第Xa因子阻害剤と結合し、そしてプロトロンビナーゼ複合体を集合して形成しないXaタンパク質誘導体の有効量を対象に投与することを含む、前記対象において体外から投与した第Xa因子阻害剤と選択的に結合してそれを阻害する方法。
(項目3)
前記第Xa因子タンパク質誘導体が、直接または間接的に前記第Xa因子阻害剤と結合する、項目1または項目2に記載の方法。
(項目4)
前記誘導体が、凝固促進活性が減少しているか、または凝固促進活性を有さない、項目3に記載の方法。
(項目5)
前記誘導体が、Gla欠損第Xa因子タンパク質誘導体またはデス−Gla第Xa因子タンパク質である、項目1から4のいずれかに記載の方法。
(項目6)
前記誘導体が修飾された活性部位を有する、項目1から5のいずれかに記載の方法。
(項目7)
前記誘導体が、配列番号3の少なくともアミノ酸残基46〜448またはその均等物を含む、項目1から6のいずれかに記載の方法。
(項目8)
前記誘導体が、配列番号3の少なくともアミノ酸残基46〜139および195〜448またはその均等物を含む、項目1から7のいずれかに記載の方法。
(項目9)
前記誘導体が、fXaの軽鎖を欠き、前記重鎖中に存在するセリンプロテアーゼ触媒ドメインを含有する、項目1から8のいずれかに記載の方法。
(項目10)
前記誘導体が、配列番号5のアミノ酸配列を含むポリペプチドである、項目1から9のいずれかに記載の方法。
(項目11)
前記誘導体が、タンパク質分解活性を欠くが、結合に必要な構造的特徴を維持するように任意選択で化学的にまたは組換えによって修飾された触媒ドメインを含み、前記ドメインが、
a.血漿カリクレイン、トロンビン、およびトリプシンからなる群から選択される哺乳動物プロテアーゼ;または
b.細菌プロテアーゼのサブチリシン
のいずれかに由来する、項目1から10のいずれかに記載の方法。
(項目12)
前記誘導体が、修飾された軽鎖を有する配列番号7のアミノ酸配列またはその均等物を含む、項目1から11のいずれかに記載の方法。
(項目13)
前記誘導体が、リン脂質膜結合が減少するように修飾された軽鎖を含む、項目1から12のいずれかに記載の方法。
(項目14)
前記修飾された軽鎖が、野生型ヒト第Xa因子タンパク質の前記Gla−ドメインと比較して、前記Gla−ドメイン中に少なくとも1つのアミノ酸置換、付加、または欠失を含む、項目1から13のいずれかに記載の方法。
(項目15)
前記誘導体が、未カルボキシル化、低カルボキシル化、および脱カルボキシル化第Xa因子タンパク質からなる群から選択される、項目1から14のいずれかに記載の方法。
(項目16)
前記誘導体が、修飾されている配列番号7の前記重鎖またはその均等物を含む、項目1から15のいずれかに記載の方法。
(項目17)
前記誘導体が、Glu216、Glu218、Arg332、Arg347、Lys351、およびSer379からなる群から選択されるアミノ酸の少なくとも1つのアミノ酸置換によって修飾されている、項目1から16のいずれかに記載の方法。
(項目18)
Ser379がデヒドロ−アラニンまたはアラニンへと修飾されている、項目1から17のいずれかに記載の方法。
(項目19)
前記誘導体が、配列番号10のアミノ酸配列またはその均等物を有するデス−Glaアンヒドロ−fXaである、項目1から18のいずれかに記載の方法。
(項目20)
前記誘導体が、配列番号11のアミノ酸配列またはその均等物を有するデス−Gla fXa−S379Aである、項目1から19のいずれかに記載の方法。
(項目21)
前記誘導体が、ATIII、補因子fV/fVaおよび/またはfVIII/fVIIIaとの相互作用が減少しており、配列番号7のアミノ酸配列またはその均等物を含む、項目1から20のいずれかに記載の方法。
(項目22)
前記誘導体が、配列番号12もしくは13もしくは15のアミノ酸配列または配列番号12もしくは13もしくは15と少なくとも80%の相同性を有するポリペプチドを含む、項目1から21のいずれかに記載の方法。
(項目23)
前記誘導体が、アミノ酸位置Arg306、Glu310、Arg347、Lys351、Lys414、またはArg424で少なくとも1つのアミノ酸置換を有する、項目1から22のいずれかに記載の方法。
(項目24)
前記誘導体が、EGFドメイン中に修飾を有し、前記修飾が、EGF1ドメインの欠失、EGF2ドメインの欠失、ならびに前記EGF1およびEGF2ドメインの両方の欠失からなる群から選択される、項目1から23のいずれかに記載の方法。
(項目25)
前記誘導体が、前記誘導体の循環半減期を延長させることができる部分とコンジュゲートしている、項目1から24のいずれかに記載の方法。
(項目26)
前記部分が、ポリエチレングリコール、アシル基、リポソーム、カプセル封入剤、担体タンパク質、人工リン脂質膜、ナノ粒子、Fcペプチド断片、Fc担体ドメインおよびfXa誘導体を含むキメラタンパク質ならびにその組合せからなる群から選択される、項目25に記載の方法。
(項目27)
前記誘導体の循環半減期を延長させる薬剤を有効量投与することをさらに含む、項目1から26のいずれかに記載の方法。
(項目28)
前記薬剤が、fXaの非活性部位またはα−2−マクログロブリンと結合したfXa誘導体を特異的に認識してそれと結合する抗fXa抗体である、項目27に記載の方法。
(項目29)
前記第Xa因子阻害剤が、フォンダパリヌクス、イドラパリナックス、ビオチン標識イドラパリナックス、エノキサパリン、fragmin、NAP−5、rNAPc2、組織因子経路阻害剤、DX−9065a、YM−60828、YM−150、アピキサバン、リバロキサバン、PD−348292、オタミキサバン、DU−176b、LY517717、GSK913893、ラザキサバン、低分子量ヘパリン、ベトリキサバンまたは製薬上許容されるその塩、およびその組合せからなる群から選択される、項目1から28のいずれかに記載の方法。
(項目30)
前記第Xa因子阻害剤が、ベトリキサバン、リバラオキサバン、アピキサバン、低分子量ヘパリン、およびその組合せから選択される、項目29に記載の方法。
(項目31)
前記対象が、出血、重要臓器内への出血、再手術または新しい治療手順を要する出血、および関連する明白な出血を伴う2.0以上の出血指数からなる群から選択される臨床的な大量出血事象を起こしている、項目1から30のいずれかに記載の方法。
(項目32)
前記対象が、持続性または再発性の鼻出血、治療手順を必要としない直腸または尿路の出血、実質的な注射部位の血腫、非注射部位での自発性血腫、小さな外傷に伴って発生する血腫、実質的な失血、および予定外の輸血を要する出血からなる群から選択される出血事象を起こしている、項目1から31のいずれかに記載の方法。
(項目33)
前記誘導体を手術前に投与する、項目1から32のいずれかに記載の方法。
(項目34)
第Xa因子阻害剤と結合し、プロトロンビナーゼ複合体を集合して形成しない第Xa因子誘導体タンパク質と、製薬上許容される担体とを含む薬剤組成物。
(項目35)
配列番号12のアミノ酸配列または配列番号12と少なくとも80%の相同性を有するポリペプチドを含む、単離したポリペプチド。
(項目36)
配列番号12のアミノ酸配列を含む、単離したポリペプチド。
(項目37)
配列番号13のアミノ酸配列または配列番号13と少なくとも80%の相同性を有するポリペプチドを含む、単離した二本鎖ポリペプチド。
(項目38)
配列番号15のアミノ酸配列または配列番号15と少なくとも80%の相同性を有するポリペプチドを含む、単離したポリペプチド。
(項目39)
項目35から38のいずれか一項に記載のポリペプチドと共有または非共有結合した担体を含む、ペプチドコンジュゲート。
(項目40)
前記担体が、リポソーム、ミセル、製薬上許容されるポリマー、または製薬上許容される担体である、項目39に記載のペプチドコンジュゲート。
(項目41)
担体および項目35から38のいずれか一項に記載のポリペプチドを含む薬剤組成物。
(項目42)
項目35から38のいずれか一項に記載のポリペプチドをコードしているポリヌクレオチド。
(項目43)
項目35から38のいずれか一項に記載のポリペプチドと結合する抗体。
(項目44)
前記抗体が、ポリクローナル抗体、モノクローナル抗体、キメラ抗体またはヒト化抗体である、項目43に記載の抗体。
(項目45)
項目43に記載の抗体の生物活性断片。
(項目46)
検出可能に標識されている、項目43に記載の抗体。
(項目47)
項目43に記載の抗体および担体を含む組成物。
(項目48)
項目45に記載の抗体断片を含む組成物。
(項目49)
項目46に記載の抗体および前記抗体と特異的に結合するポリペプチドを含む、抗体−ペプチド複合体。
(項目50)
前記ポリペプチドが、それに対する抗体が産生されたポリペプチドである、項目49に記載の複合体。
(項目51)
前記抗体が、ポリクローナル抗体、モノクローナル抗体、キメラ抗体またはヒト化抗体である、項目49に記載の複合体。
(項目52)
項目35から38のいずれか一項に記載のポリペプチドをコードしているポリヌクレオチドを、原核または真核宿主細胞中で発現させることを含む、項目35から38のいずれか一項に記載のポリペプチドを調製する方法。
(項目53)
前記ポリペプチドが、配列番号12のアミノ酸配列を含み、前記ポリヌクレオチドが、配列番号16のヌクレオチド配列を含む、項目52に記載の方法。
(項目54)
前記宿主細胞がチャイニーズハムスター卵巣細胞である、項目52に記載の方法。
(項目55)
前記ポリペプチドを単離することをさらに含む、項目52から54のいずれか一項に記載の方法。
(項目56)
項目35から38のいずれか一項に記載のポリペプチドをコードしているポリヌクレオチドを含む、単離した原核または真核宿主細胞。
(項目57)
担体および項目56に記載の原核または真核宿主細胞を含む組成物。
(項目58)
項目41に記載の組成物を対象に有効量投与することを含む、第Xa因子阻害剤を用いた抗凝固療法を受けている前記対象において出血を防止または減少する方法。
(項目59)
項目41に記載の組成物を対象に有効量投与することを含む、第Xa因子阻害剤を用いた抗凝固療法を受けている前記対象において、体外から投与した第Xa因子阻害剤と選択的に結合してそれを阻害する方法。
(項目60)
前記第Xa因子阻害剤が、フォンダパリヌクス、イドラパリナックス、ビオチン標識イドラパリナックス、エノキサパリン、fragmin、NAP−5、rNAPc2、組織因子経路阻害剤、DX−9065a、YM−60828、YM−150、アピキサバン、リバロキサバン、PD−348292、オタミキサバン、DU−176b、LY517717、GSK913893、ラザキサバン、低分子量ヘパリン、ベトリキサバンまたは製薬上許容されるその塩、およびその組合せからなる群から選択される、項目58または59に記載の方法。
(項目61)
前記第Xa因子阻害剤が、ベトリキサバン、リバラオキサバン、アピキサバン、低分子量ヘパリン、およびその組合せから選択される、項目60に記載の方法。
(項目62)
前記誘導体を手術前に投与する、項目60に記載の方法。
本発明の実施では、別段に指定しない限りは、当分野の技術範囲内にある組織培養物、免疫学、分子生物学、微生物学、細胞生物学および組換えDNAの慣用技術を用いる。たとえば、Sambrook and Russell編(2001年)Molecular Cloning: A Laboratory Manual、第3版;シリーズAusubelら編(2007年)Current Protocols in Molecular Biology;シリーズMethods in Enzymology(Academic Press, Inc.、N.Y.);MacPhersonら(1991年)PCR 1: A Practical Approach(IRL Press at Oxford University Press);MacPhersonら(1995年)PCR 2: A Practical Approach;Harlow and Lane編(1999年)Antibodies, A Laboratory Manual;Freshney(2005年)Culture of Animal Cells: A Manual of Basic Technique、第5版;Gait ed.(1984年)Oligonucleotide Synthesis;米国特許第4,683,195号;Hames and Higgins編(1984年)Nucleic Acid Hybridization;Anderson(1999年)Nucleic Acid Hybridization;Hames and Higgins編(1984年)Transcription and Translation;Immobilized Cells and Enzymes(IRL Press(1986年));Perbal(1984年)A Practical Guide to Molecular Cloning;Miller and Calos編(1987年)Gene Transfer Vectors for Mammalian Cells(Cold Spring Harbor Laboratory);Makrides編(2003年)Gene Transfer and Expression in Mammalian Cells;Mayer and Walker編(1987年)Immunochemical Methods in Cell and Molecular Biology(Academic Press、London);Herzenbergら編(1996年)Weir’s Handbook of Experimental Immunology;Manipulating the Mouse Embryo: A Laboratory Manual、第3版(Cold Spring Harbor Laboratory Press(2002年))を参照されたい。
II.本発明の方法
本発明の一態様は、対象に、有効量の第Xa因子タンパク質誘導体を投与することによる、抗凝固療法を受けている対象において出血を防止または減少する方法に関する。一実施形態では、誘導体は修飾された活性部位および/または修飾されたGla−ドメインを有しており、したがって、凝固促進活性が減少しているか、または凝固促進活性を有さない。誘導体は解毒剤として作用し、阻害剤の抗凝固活性を実質的に中和する。一実施形態では、誘導体は、Gla欠損または無Gla−ドメインのどちらかである。対象はは、哺乳動物、またはより詳細にはヒトであり得る。
III.解毒剤
第Xa因子誘導体
本発明の一態様は、凝固fXaの阻害剤の活性を実質的に中和して出血を予防または停止するための安全かつ有効な解毒剤としての、Gla−ドメイン欠損fXaまたはデス−Gla fXaなどのfXa誘導体の使用である。本発明の解毒剤は、fXa阻害剤、特に活性部位特異的小分子阻害剤の抗凝固効果を反転させるために有効であることが企図される。
本発明のポリペプチド
特定の態様では、本発明は、配列番号12、13または15のアミノ酸配列を含む単離したポリペプチドに関する。また、本発明には、配列番号12、13または15と少なくとも80%の相同性を有するポリペプチドも包含される。
ポリペプチドコンジュゲート
本発明のポリペプチドおよびポリペプチド複合体は、意図する使用に応じて変動し得る、様々な配合物中で使用することができる。たとえば、1つまたは複数を、特定の目的に応じてその性質が変動し得る様々な他の分子と、共有または非共有結合(複合体形成)することができる。たとえば、本発明のペプチドは、それだけには限定されないが、天然および合成ポリマー、タンパク質、多糖類、ポリペプチド(アミノ酸)、ポリビニルアルコール、ポリビニルピロリドン、ならびに脂質を含めた、巨大分子担体と共有または非共有的に複合体形成させることができる。ペプチドは、リポソーム内に導入するために、脂肪酸とコンジュゲートさせることができ、米国特許第5,837,249号を参照されたい。本発明のペプチドは、その様々なものが当分野で知られており、本明細書に記載されている固体担体と、共有または非共有的に複合体形成させることができる。本発明の抗原ペプチドエピトープは、MHC複合体などの抗原提示マトリックスと、共刺激分子を用いてまたは用いずに、会合させることができる。
宿主細胞
また、本発明のポリペプチドのうちの1つまたは複数を含む宿主細胞も提供する。一態様では、ポリペプチドは発現され、細胞表面上(細胞外)に存在する。本発明のポリペプチドを含有する適切な細胞には、それだけには限定されないが、細菌細胞、酵母細胞、昆虫細胞、動物細胞、哺乳動物細胞、ネズミ細胞、ラット細胞、ヒツジ細胞、サル細胞およびヒト細胞を含めた、原核および真核細胞が含まれる。細菌細胞の例には、Escherichia coli、Salmonella entericaおよびStreptococcus gordoniiが含まれる。細胞は、American Type Culture Collection(ATCC、米国メリーランド州Rockville)などの商業販売者から購入するか、または当分野で知られている方法を用いて単離物から培養することができる。適切な真核細胞の例には、それだけには限定されないが、293T HEK細胞、およびハムスター細胞系のCHO、BHK−21;NIH3T3、NS0、C127と呼ばれるネズミ細胞系、サル細胞系のCOS、Vero;ならびにヒト細胞系HeLa、PER.C6(Crucellから販売)U−937およびHep G2が含まれる。昆虫細胞の非限定的な例には、Spodoptera frugiperdaが含まれる。発現に有用な酵母の例には、それだけには限定されないが、Saccharomyces、Schizosaccharomyces、Hansenula、Candida、Torulopsis、Yarrowia、またはPichiaが含まれる。たとえば、米国特許第4,812,405号;第4,818,700号;第4,929,555号;第5,736,383号;第5,955,349号;第5,888,768号および第6,258,559号を参照されたい。
単離したポリヌクレオチドおよび組成物
また、本発明は、上記同定した配列またはその相補体に対する相補的ポリヌクレオチドも提供する。相補性は、中等度または高ストリンジェンシーの条件下における従来のハイブリダイゼーション用いて決定することができる。本明細書で使用する用語、ポリヌクレオチドとは、DNAおよびRNAならびに修飾されたヌクレオチドを意図する。たとえば、本発明は、アンチセンスポリヌクレオチド鎖、たとえば、これらの配列またはその相補体に対するアンチセンスRNAも提供する。
dsRNAおよびsiRNAの合成
dsRNAおよびsiRNAは、Micura(2002年)Agnes Chem. Int. Ed. Emgl.、41巻:2265〜2269頁;Betz(2003年)Promega Notes、85巻:15〜18頁;およびPaddison and Hannon(2002年)Cancer Cell.、2巻:17〜23頁に記載のように、化学的または酵素的にin vitroで合成することができる。化学合成は、Micura(2002年)、上記に記載されているように、どちらも当分野で周知の手動または自動の方法によって行うことができる。また、siRNAは、細胞の内部でshRNAの形態で、Yuら(2002年)Proc. Natl. Acad. Sci. USA、99巻:6047〜6052頁;およびMcManusら(2002年)RNA、8巻:842〜850頁に記載のように内在発現させることもできる。内在発現は、プラスミドに基づいた発現系を用いて、核内低分子RNAプロモーター、たとえば、RNAポリメラーゼIII U6もしくはH1、またはRNAポリメラーゼII U1を使用して、Brummelkampら(2002年)Science、296巻:550〜553頁(2002年);およびNovarinoら(2004年)J. Neurosci.、24巻:5322〜5330頁に記載のように達成されている。
治療用抗体組成物
また、本発明は、本発明の治療方法において有用な、本発明のタンパク質またはポリペプチドと複合体を特異的に形成することができる抗体も提供する。用語「抗体」には、ポリクローナル抗体およびモノクローナル抗体、抗体断片、ならびにその誘導体(上述)が含まれる。抗体には、それだけには限定されないが、マウス、ラット、およびウサギまたはヒト抗体が含まれる。抗体は、細胞培養物中、ファージ中、または、それだけには限定されないが、ウシ、ウサギ、ヤギ、マウス、ラット、ハムスター、モルモット、ヒツジ、イヌ、ネコ、サル、チンパンジー、類人猿などを含めた様々な動物中で産生することができる。また、抗体は、治療ポリペプチドの同定および精製にも有用である。
また、本発明の抗体を修飾してキメラ抗体を作製することもできる。キメラ抗体とは、抗体の重鎖および軽鎖の様々なドメインが、複数種由来のDNAによってコードされている抗体である。たとえば、米国特許第4,816,567号を参照されたい。
用語「抗体誘導体」には、「直鎖状抗体」がさらに含まれる。直鎖状抗体を作製する手順は当分野で知られており、Zapataら(1995年)Protein Eng.、8巻(10号):1057〜1062頁に記載されている。手短に述べると、これらの抗体は、一対の抗原結合領域を形成する一対の直列型のFdセグメント(VH−CH1−VH−CH1)を含む。直鎖状抗体は二重特異性または単一特異性であり得る。
IV.治療
本発明は、抗凝固療法を受けている対象において出血を防止または減少する治療方法に関する。本発明の解毒剤または誘導体は、有害な血行動態副作用または傷害に対する増殖性の血管応答の再燃を引き起こさずに、fXa阻害剤の慣用の抗凝固特性を安全かつ特異的に中和することができる、待機的または緊急の状況で使用する短期間薬であり得ることが企図される。
a)ポリエチレングリコール;
b)アシル基;
c)リポソームおよびカプセル封入剤;
d)担体タンパク質;
e)人工リン脂質膜;
f)免疫グロブリン;および
g)ナノ粒子。
V.薬剤組成物
本発明は、fXa誘導体および製薬上許容される担体を含む組成物をさらに提供する。
VI.キット
本発明は、キットまたはパッケージをさらに提供する。一部の実施形態では、本発明のキットは、(a)血栓症を治療するために定型的に投与するfXa阻害剤を含有する第1の容器、および(b)(a)中に過量のfXa阻害剤が存在する場合、または出血を停止もしくは予防するために正常な止血を回復させる必要がある場合に使用する、本発明の解毒剤を含有する第2の容器を含む。他の実施形態では、キットは、これら(a)および(b)中の2つの薬剤をどのような場合に使用すべきかを説明するラベルをさらに含む。
キモトリプシン消化によるデス−Glaアンヒドロ−fXaの調製
デス−Glaアンヒドロ−fXaを、Morita, T.ら、J. Bio. Chem.、1986年、261巻(9号):4015〜4023頁の手順に従って、デヒドロアラニンが活性部位セリンを置き換えているアンヒドロ−fXaを、キモトリプシンと、0.05Mのトリス−HCl、0.1MのNaCl、pH7.5中、22℃で60分間インキュベートすることによって調製した。典型的な実験設定では、0.5ミリグラム/ミリリットル(mg/mL)のアンヒドロ−fXaを、5単位/ミリリットル(U/mL)のα−キモトリプシン−アガロースビーズと共に、穏やかに攪拌しながらインキュベートした。反応の終了時に、α−キモトリプシン−アガロースビーズを遠心分離または濾過によって除去した。次いで、これを過剰量の阻害剤4−アミジノ−フェニル−メタン−スルホニルフルオライド(APMSF)、トシル−L−リシンクロロメチルケトン(TLCK)、およびトシル−L−フェニルアラニンクロロメチルケトン(TPCK)と共にインキュベートして、残留fXa活性またはビーズから浸出した可能性のあるすべてのキモトリプシン活性を反応停止した。Gla−ドメイン断片および阻害剤を、Amicon超遠心分離濾過装置(YM10膜)によって、または慣用の透析によって、最終産物デス−Glaアンヒドロ−fXaから除去した。必要な場合は、濃縮または緩衝液交換も同時に達成した。Gla−ドメイン含有アンヒドロ−fXaを、Nogamiら、J. Biol. Chem.、1999年、274巻(43号):31000〜7頁によって報告されている手順に従って調製した。α−キモトリプシン−アガロースビーズはSigmaから購入し、特異的活性(U/mL)は、使用した特定のロット番号の製造者のデータに基づく。
乏血小板血漿(PPP)または多血小板血漿(PRP)におけるトロンビン産生アッセイ
本実施例では、ヒトの乏血小板血漿または多血小板血漿試料を、0.32%のクエン酸塩中に抜き取った健康なドナーの血液から調製した。PRPおよびPPPは、抗凝血処理した血液を、それぞれ約100×重力までまたは1000×重力で20分間、室温で遠心することによって調製した。75〜100マイクロリットル(uL)の血漿を、CaCl2およびZ−Gly−Gly−Arg−アミノメチルクマリン(Z−GGR−AMC、トロンビン蛍光原基質)と混合した。組織因子(Innovin、Dade Behring)を加えてトロンビンの産生を開始させた。典型的な実験では、反応混合物は、15ミリモーラー(mM)のCa2+、100マイクロモーラー(μM)のZ−GGR−AMC、および0.1ナノモーラー(nM)の組織因子(TF)(Innovin)を含有していた。トロンビンの形成は、37℃で蛍光定量的プレートリーダー(Molecular Devices)によって連続的にモニターし、相対蛍光単位(RFU)を測定した。存在する場合は、トロンビン産生を開始させる前に、阻害剤および解毒剤を血漿と共に20分間、室温でプレインキュベートした。
凝固延長アッセイ
2つの凝固アッセイ様式を用いて、凝固延長に対する第Xa因子阻害剤および解毒剤の効果を試験した。第1の様式では、96ウェルプレートを用いて複数の試料を同時に測定した。第2のアッセイ様式では、aPTTを慣用の凝固装置(MLA Electra800自動凝固タイマー)で測定した。
デス−Glaアンヒドロ−fXaによる、ベトリキサバンによるfXaの阻害の反転
ベトリキサバンによるfXa活性の阻害およびその阻害効果の反転を測定するために、精製した活性fXa、様々な濃度のベトリキサバンおよび解毒剤デス−Glaアンヒドロ−fXaを、20mMのトリス、150mMのNaCl、5mMのCa2+、および0.1%のウシ血清アルブミン(BSA)に加えた。室温で20分間インキュベートした後、100μMのSpectrozyme−fXa(第Xa因子発色基質、Chromogenix)を混合物に加え、基質の切断速度を5分間、405ナノメートル(nm)でプレートリーダーによって連続的にモニターした。図5では、色素原活性を、どの阻害剤も存在しない場合の活性fXaに対して正規化した。生成物形成の初期速度を、阻害剤および解毒剤の濃度の関数として非線形回帰によって分析して、解毒剤に対するベトリキサバンの親和性を推定した(図8)。
脱カルボキシル化γ−カルボキシグルタミン酸残基を有するfXaの調製
脱カルボキシル化γ−カルボキシグルタミン酸残基を有するfXa誘導体は、fXaタンパク質を、たとえば、Bajajら、J. Biol. Chem.、1982年、257巻(7号):3726〜3731頁によって報告されている手順に基づいて処理することによって、調製することができる。2mLの0.1モーラーの炭酸水素アンモニウム、pH8.0中の、2〜5mgの精製または組換えfXaを凍結乾燥した。生じる散剤を20μM未満の真空下で密封し、110℃で様々な時間加熱して、脱カルボキシル化fXaが得られた。
組換えデス−Gla fXa−S379Aの調製
fXa誘導体は、突然変異誘発および分子生物学の一般手順に従って、適切な宿主生物中でfX(配列番号1、3)またはfXa誘導体(配列番号4、5、9、および11)を発現させるためのfX cDNA(配列番号2)に基づいた、以下の手順のうちの1つを用いた組換えDNA方法によって産生し得る。
CHO細胞中での組換えfXa突然変異体の発現
本実施例では、組換えタンパク質発現構築体および無Gla−ドメインfXa−S379A(キモトリプシンの番号付けでS195A)変異体を直接発現するための細胞系を記載する。組換え解毒剤は、pd−解毒剤を産生するために必要な活性化または化学修飾ステップを必要とせず、本明細書に記述するin vitroアッセイにおいて、血漿由来のタンパク質に対して比較可能な親和性を有する。
in vivoマウスモデル
解毒剤を投与したまたは投与していない、雄のC57Bl/6マウスにおけるベトリキサバンの薬物動態学および薬力学(PK−PD)のプロフィールを試験した。単一のベトリキサバンの経口投与を、対照群に0、15、25、および75mg/kgで投薬した。15mg/kgを解毒剤治療群に使用した。解毒剤(300ug/200μL)またはビヒクル(正常生理食塩水、200μL)の単一の静脈内(IV)注射を、1.5時間時点の5分前に投与した。
解毒剤によるリバロキサバンおよびアピキサバンのin vitro反転
予想どおり、本発明によって企図される解毒剤は、他の活性部位特異的fXa阻害剤と結合してそれを中和することもできた。表15および16は、pd−解毒剤およびr−解毒剤による、ベトリキサバン、リバロキサバンおよびアピキサバンによる阻害のin vitro補正を示す。精製したfXa(3.0nM)、阻害剤(7.5nM)、および様々な濃度の解毒剤を、10分間、22℃で、20mMのトリス、150mMのNaCl、0.1%のBSA、pH7.4を含む緩衝液中でインキュベートした。fXa活性を実施例4と同様にアッセイした。
r−解毒剤によるベトリキサバンのin vitro反転
表17では、ベトリキサバンによる抗凝固の反転に対する組換え解毒剤タンパク質の効果を、ヒト血漿凝固アッセイで試験した。血漿のaPTT延長および阻害効果の反転に対する300nMおよび400nMのベトリキサバンの効果を、MLA Electra800自動凝固タイマーによって測定した。100μLのプールしたクエン酸塩で抗凝血処理したヒト血漿を、300nMまたは400nMのベトリキサバンおよび様々な濃度の解毒剤と混合した。aPTT試薬(Actin FS、Dade Behring)およびCaCl2を製造者の指示に従って加えた。
r−解毒剤による低分子量ヘパリン(「LMWH」)のin vitro反転
図18では、LMWHエノキサパリン(Sanofi−Aventis)の阻害効果を反転させるr−解毒剤の効果を、ヒト血漿の濁度変化によって試験した。エノキサパリン(0〜1.25U/mL)を、22℃で20分間、508nMのr−解毒剤を用いてまたは用いずにインキュベートした。濁度変化は、実施例3に記載の手順に従って測定した。508nMのr−解毒剤は、0.3125〜1.25U/mLのエノキサパリンの阻害効果を実質的に補正した(>75%)。
r−解毒剤によるリバロキサバンのin vitro反転
図20では、小分子第Xa因子阻害剤(リバロキサバン、Bay59−7939)による抗凝固の反転に対する組換え解毒剤タンパク質の効果を、ヒト血漿凝固アッセイで試験した。Perzbornら、J. Thromb. Haemost.、3巻:514〜521頁、2005年によって報告されているように、プロトロンビン時間の測定は、リバロキサバン抗凝固効果を評価する正確な方法である。プールしたヒト血漿のプロトロンビン時間(PT)延長および阻害効果の反転に対する1μMのリバロキサバンの効果を、MLA Electra800自動凝固タイマーによって測定した。100μLのプールしたクエン酸塩で抗凝血処理したヒト血漿を、リバロキサバンおよび様々な濃度の解毒剤と混合した。凝固時間を測定する前に、ウサギ脳トロンボプラスチンC Plus試薬(Dade Behring)を製造者の指示に従って血漿試料に加えた。1.9μMの組換え解毒剤を加えることで、1μMのリバロキサバンによって生じる抗凝固の100%の補正が生じた。
r−解毒剤によるアピキサバンのin vitro反転
表18では、アピキサバンによる抗凝固の反転に対する組換え解毒剤タンパク質の効果を、ヒト血漿凝固アッセイで試験した。Pintoら、J. Med. Chem.、55巻(22号):5339〜5356頁、2007年によって報告されているように、プロトロンビン時間(PT)の測定は、アピキサバンのex vivo抗凝固効果を評価する正確な方法である。プールしたヒト血漿のプロトロンビン時間(PT)延長および阻害効果の反転に対する1μMおよび1.5μMのアピキサバンの効果を、MLA Electra800自動凝固タイマーによって測定した。100μLのプールしたクエン酸塩で抗凝血処理したヒト血漿を、アピキサバンおよび様々な濃度の解毒剤と混合した。凝固時間を測定する前に、ウサギ脳トロンボプラスチンC Plus試薬(Dade Behring)を製造者の指示に従って血漿試料に加えた。1.9μMの組換え解毒剤を加えることで、1.5μMのアピキサバンによって生じる抗凝固の97%の補正が生じた。
デス−Glaアンヒドロ−fXaによるアルガトロバンのin vitro阻害
アルガトロバンによるトロンビン活性の阻害およびその阻害効果の反転を測定するために、精製したヒトトロンビン(5nM)、アルガトロバン(50nM)および様々な濃度の解毒剤デス−GlaアンヒドロfXaを、20mMのトリス、0.15MのNaCl、5mMの塩化カルシウム、0.1%のウシ血清アルブミン、pH7.4を含有する緩衝液に加えた。室温で20分間インキュベートした後、アミド分解基質S2288(200uM)を混合物に加え、p−ニトロアニリド基質の切断速度を405nmの吸光度によってモニターした。結果を図12に表す。
Claims (33)
- 単離した第Xa因子(fXa)誘導体タンパク質であって、
(a)配列番号3のSer379のデヒドロ−アラニンまたはアラニンでの置換を含むfXa重鎖を含み、そして
(b)軽鎖を含み、
該軽鎖は、配列番号3のアミノ酸残基6〜39を含まず、該タンパク質は、(i)配列番号13のアミノ酸配列、(ii)配列番号13に少なくとも90%の同一性を有するアミノ酸配列、(iii)配列番号12のアミノ酸配列、および(iv)配列番号12に少なくとも90%の同一性を有するアミノ酸配列から選択され、
該配列番号13に少なくとも90%の同一性を有するアミノ酸配列は、
(a)第Xa因子阻害剤へ結合し得る、および
(b)集合してプロトロンビナーゼ複合体を形成することがなく、
該配列番号12に少なくとも90%の同一性を有するアミノ酸配列は、
(a)第Xa因子阻害剤へ結合し得る、および
(b)集合してプロトロンビナーゼ複合体を形成することがない、
単離したfXa誘導体タンパク質。 - 前記重鎖が、アミノ酸位置Arg306、Glu310、Arg347、Lys351、Lys414またはArg424での少なくとも1つのアミノ酸置換をさらに含む、請求項1に記載の単離したfXa誘導体タンパク質。
- 前記軽鎖が配列番号3のアミノ酸残基1〜39、6〜39、1〜44または1〜45を欠く、請求項1〜2のいずれか1項に記載の単離したfXa誘導体タンパク質。
- 前記軽鎖がEGF1ドメインおよび/またはEGF2ドメインを含まない、請求項1から3のいずれか1項に記載の単離したfXa誘導体タンパク質。
- 前記誘導体タンパク質が別個の軽鎖および重鎖の二本の鎖からなる、請求項1から4のいずれか1項に記載の単離したfXa誘導体タンパク質。
- 前記軽鎖と重鎖とが連結されている、請求項1〜4のいずれか1項に記載の単離したfXa誘導体タンパク質。
- 前記軽鎖と前記重鎖との間にペプチドリンカーをさらに含む、請求項6に記載の単離したfXa誘導体タンパク質。
- 前記ペプチドリンカーが−RKRRKR−を含む、請求項7に記載の単離したfXa誘導体タンパク質。
- 前記誘導体タンパク質が活性化ペプチドを含まない、請求項1から8のいずれか1項に記載の単離したfXa誘導体タンパク質。
- 配列番号13のアミノ酸配列を含む、単離した二本鎖タンパク質。
- 配列番号12のアミノ酸配列を含む、単離したタンパク質。
- 担体および請求項1から11のいずれか一項に記載のタンパク質を含む薬剤組成物。
- 請求項1から11のいずれか一項に記載のタンパク質と共有結合または非共有結合した担体を含む、ペプチドコンジュゲート。
- 前記担体が、リポソーム、ミセル、製薬上許容されるポリマー、または製薬上許容される担体である、請求項13に記載のペプチドコンジュゲート。
- 請求項1から11のいずれか一項に記載のタンパク質をコードしているポリヌクレオチド。
- 請求項1から11のいずれか一項に記載のタンパク質をコードしているポリヌクレオチドを、原核または真核宿主細胞中で発現させることを含む、請求項1から11のいずれか一項に記載のタンパク質を調製するインビトロでの方法。
- 前記タンパク質が、配列番号13のアミノ酸配列を含む、請求項16に記載の方法。
- 前記宿主細胞がチャイニーズハムスター卵巣細胞である、請求項16または17に記載の方法。
- 前記タンパク質を単離することをさらに含む、請求項16から18のいずれか一項に記載の方法。
- 請求項1から11のいずれか一項に記載のタンパク質をコードしているポリヌクレオチドを含む、単離した原核または真核宿主細胞。
- 担体および請求項20に記載の原核または真核宿主細胞を含む組成物。
- 第Xa因子阻害剤を用いた抗凝固療法を受けている被験体において出血を防止または減少するための、請求項12に記載の組成物。
- 第Xa因子阻害剤を用いた抗凝固療法を受けている被験体において、体外から投与した第Xa因子阻害剤と選択的に結合してそれを阻害するための、請求項12に記載の組成物。
- 前記第Xa因子阻害剤が、フォンダパリヌクス、イドラパリナックス、ビオチン標識イドラパリナックス、エノキサパリン、ダルテパリン、rNAPc2、組織因子経路阻害剤、DX−9065a、YM−60828、YM−150、アピキサバン、リバロキサバン、PD−348292、オタミキサバン、DU−176b、LY517717、ラザキサバン、低分子量ヘパリン、ベトリキサバンまたは製薬上許容されるその塩、およびその組合せからなる群から選択される、請求項22または23に記載の組成物。
- 前記第Xa因子阻害剤が、ベトリキサバン、リバロキサバン、アピキサバン、低分子量ヘパリン、およびその組合せから選択される、請求項24に記載の組成物。
- 前記組成物は手術前に投与されるものであることを特徴とする、請求項24に記載の組成物。
- 第Xa因子阻害剤と結合し、そして集合してプロトロンビナーゼ複合体を形成することがない請求項1に記載の単離された第Xa因子タンパク質誘導体を含む、第Xa因子阻害剤を用いた抗凝固療法を受けている被験体において出血を防止または減少するための組成物。
- 第Xa因子阻害剤と結合し、そして集合してプロトロンビナーゼ複合体を形成すること
がない請求項1に記載の単離された第Xaタンパク質誘導体を含む、被験体において体外から投与した第Xa因子阻害剤と選択的に結合してそれを阻害するための組成物。 - 前記組成物が前記誘導体の循環半減期を延長させる薬剤の有効量と組み合わせて投与されるものであることを特徴とする、請求項27または28に記載の組成物。
- 前記薬剤が、fXaの非活性部位またはα−2−マクログロブリンと結合したfXa誘導体を特異的に認識してそれと結合する抗fXa抗体である、請求項29に記載の組成物。
- 前記第Xa因子阻害剤が、フォンダパリヌクス、イドラパリナックス、ビオチン標識イドラパリナックス、エノキサパリン、ダルテパリン、rNAPc2、組織因子経路阻害剤、DX−9065a、YM−60828、YM−150、アピキサバン、リバロキサバン、PD−348292、オタミキサバン、DU−176b、LY517717、ラザキサバン、低分子量ヘパリン、ベトリキサバンまたは製薬上許容されるその塩、およびその組合せからなる群から選択される、請求項27から30のいずれか一項に記載の組成物。
- 前記被験体が、出血、重要臓器内への出血、再手術または新しい治療手順を要する出血、および関連する明白な出血を伴う2.0以上の出血指数からなる群から選択される臨床的な大量出血事象を起こしている、請求項27から31のいずれか一項に記載の組成物。
- 前記被験体が、持続性または再発性の鼻出血、治療手順を必要としない直腸または尿路の出血、実質的な注射部位の血腫、非注射部位での自発性血腫、小さな外傷に伴って発生する血腫、実質的な失血、および予定外の輸血を要する出血からなる群から選択される出血事象を起こしている、請求項27から32のいずれか一項に記載の組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US97634307P | 2007-09-28 | 2007-09-28 | |
US60/976,343 | 2007-09-28 | ||
US9057408P | 2008-08-20 | 2008-08-20 | |
US61/090,574 | 2008-08-20 | ||
PCT/US2008/078014 WO2009042962A2 (en) | 2007-09-28 | 2008-09-26 | Antidotes for factor xa inhibitors and methods of using the same |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014166333A Division JP6047127B2 (ja) | 2007-09-28 | 2014-08-19 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2010539945A JP2010539945A (ja) | 2010-12-24 |
JP2010539945A5 JP2010539945A5 (ja) | 2014-11-06 |
JP5637561B2 true JP5637561B2 (ja) | 2014-12-10 |
Family
ID=40481812
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010527220A Active JP5637561B2 (ja) | 2007-09-28 | 2008-09-26 | 第Xa因子阻害剤に対する解毒剤およびその使用の方法 |
JP2014166333A Active JP6047127B2 (ja) | 2007-09-28 | 2014-08-19 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2016225290A Active JP6300885B2 (ja) | 2007-09-28 | 2016-11-18 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2018033229A Pending JP2018100290A (ja) | 2007-09-28 | 2018-02-27 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2020042919A Pending JP2020109113A (ja) | 2007-09-28 | 2020-03-12 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2022121451A Pending JP2022153574A (ja) | 2007-09-28 | 2022-07-29 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
Family Applications After (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014166333A Active JP6047127B2 (ja) | 2007-09-28 | 2014-08-19 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2016225290A Active JP6300885B2 (ja) | 2007-09-28 | 2016-11-18 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2018033229A Pending JP2018100290A (ja) | 2007-09-28 | 2018-02-27 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2020042919A Pending JP2020109113A (ja) | 2007-09-28 | 2020-03-12 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
JP2022121451A Pending JP2022153574A (ja) | 2007-09-28 | 2022-07-29 | 第Xa因子阻害剤に対する抗体およびその使用の方法 |
Country Status (27)
Country | Link |
---|---|
US (8) | US8153590B2 (ja) |
EP (4) | EP3078743B1 (ja) |
JP (6) | JP5637561B2 (ja) |
KR (4) | KR20170100071A (ja) |
CN (4) | CN101802188B (ja) |
AU (6) | AU2008304192B9 (ja) |
BR (2) | BRPI0816837B1 (ja) |
CA (1) | CA2697583C (ja) |
CY (2) | CY1118482T1 (ja) |
DK (3) | DK2193196T3 (ja) |
ES (3) | ES2597436T3 (ja) |
FR (1) | FR20C1045I2 (ja) |
HK (1) | HK1210443A1 (ja) |
HR (2) | HRP20161255T1 (ja) |
HU (4) | HUE050063T2 (ja) |
IL (4) | IL203993A (ja) |
LT (3) | LT2193196T (ja) |
MX (1) | MX2010003095A (ja) |
NL (1) | NL301063I2 (ja) |
NO (2) | NO2019040I1 (ja) |
NZ (1) | NZ583944A (ja) |
PL (3) | PL2915564T3 (ja) |
PT (3) | PT2193196T (ja) |
SG (1) | SG185263A1 (ja) |
SI (3) | SI2915564T1 (ja) |
WO (1) | WO2009042962A2 (ja) |
ZA (2) | ZA201002039B (ja) |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7696352B2 (en) * | 2004-06-18 | 2010-04-13 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
BRPI0711296A2 (pt) | 2006-05-05 | 2011-08-23 | Millennium Phamaceutical Inc | inibidores de fator xa |
CN101802188B (zh) * | 2007-09-28 | 2013-08-21 | 普托拉制药有限公司 | 用于因子Xa抑制剂的解毒剂和其使用方法 |
EP2364165B1 (en) | 2008-11-14 | 2018-01-03 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents |
AU2009327338B2 (en) * | 2008-12-19 | 2015-07-02 | Takeda Pharmaceutical Company Limited | TFPI inhibitors and methods of use |
EP2414517B1 (en) * | 2009-03-30 | 2016-09-21 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
WO2011008885A1 (en) * | 2009-07-15 | 2011-01-20 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same |
GB0916576D0 (en) * | 2009-09-22 | 2009-10-28 | Malmsten Nils M | Polypeptides and uses thereof |
EP2316931B1 (de) * | 2009-10-30 | 2016-12-28 | Senova Gesellschaft für Biowissenschaft und Technik mbH | Polymergekoppelte Peptidasen |
WO2011075602A1 (en) | 2009-12-17 | 2011-06-23 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
CA2784921A1 (en) | 2009-12-17 | 2011-07-14 | Millennium Pharmaceuticals, Inc. | Salts and crystalline forms of a factor xa inhibitor |
TWI513466B (zh) * | 2010-01-20 | 2015-12-21 | Boehringer Ingelheim Int | 抗凝血劑解毒劑 |
NZ603028A (en) | 2010-03-19 | 2014-11-28 | Baxter Healthcare Sa | Tfpi inhibitors and methods of use |
TW201240664A (en) * | 2010-09-01 | 2012-10-16 | Portola Pharm Inc | Methods and formulations of treating thrombosis with betrixaban and a P-glycoprotein inhibitor |
TW201221128A (en) | 2010-09-01 | 2012-06-01 | Portola Pharm Inc | Crystalline forms of a factor Xa inhibitor |
WO2012098089A1 (en) | 2011-01-19 | 2012-07-26 | Bayer Pharma Aktiengesellschaft | Binding proteins to inhibitors of coagulation factors |
FR2972114B1 (fr) * | 2011-03-01 | 2013-03-15 | Univ Grenoble 1 | Un nouveau leurre moleculaire procoagulant pour le traitement des hemophiles a ou b avec ou sans inhibiteur |
BR112013025031A2 (pt) | 2011-03-30 | 2017-08-01 | Boehringer Ingelheim Int | antídotos anticoagulantes |
US9371522B2 (en) * | 2011-09-30 | 2016-06-21 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating hemostasis |
AP2014007662A0 (en) * | 2011-11-29 | 2014-05-31 | Perosphere Inc | Anticoagulant reversal agents |
JP2015507929A (ja) | 2012-02-14 | 2015-03-16 | ポートラ ファーマシューティカルズ, インコーポレイテッド | 第Xa因子阻害剤に対する組み換え拮抗剤を製作するためのプロセス |
WO2013123248A1 (en) | 2012-02-16 | 2013-08-22 | Portola Pharmaceuticals, Inc. | MODULATION OF FACTOR Xa INHIBITOR MEDIATED BLOOD LOSS BY PARTIAL AND TRANSIENT ADMINISTRATION OF ANTIDOTE |
NZ724133A (en) | 2012-03-21 | 2020-07-31 | Baxalta Inc | Tfpi inhibitors and methods of use |
ES2612458T3 (es) * | 2012-06-14 | 2017-05-17 | Portola Pharmaceuticals, Inc. | Procedimiento para purificación de derivados de factor Xa recombinante |
US9145552B2 (en) | 2012-07-25 | 2015-09-29 | Catalyst Biosciences, Inc. | Modified factor X polypeptides and uses thereof |
US9200268B2 (en) | 2012-12-27 | 2015-12-01 | Portola Pharmaceuticals, Inc. | Compounds and methods for purification of serine proteases |
FR3000895B1 (fr) * | 2013-01-11 | 2017-02-24 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies Sa | Utilisation d'antidotes d'inhibiteurs de la coagulation indiques dans la prevention ou le traitement de pathologies thromboemboliques |
US20150352194A1 (en) * | 2013-01-24 | 2015-12-10 | Portola Pharmaceuticals, Inc. | Inhibition of tissue factor pathway inhibitor with factor xa derivatives |
MX2015008813A (es) | 2013-01-31 | 2016-03-31 | Pfizer | Composiciones y metodos para contrarrestar la inhibicion del factor xa. |
FR3007410B1 (fr) * | 2013-06-21 | 2016-05-27 | Lab Francais Du Fractionnement | Facteur x depourvu de domaine gla |
MX2016003871A (es) * | 2013-09-24 | 2016-08-04 | Pfizer | Composiciones que comprenden poblaciones heterogeneas de proteinas recombinantes humanas de factor xa de coagulacion. |
EP3063170A4 (en) * | 2013-11-01 | 2017-06-28 | The Children's Hospital of Philadelphia | Compositions and methods for increasing the half-life of factor xa |
CA2949349A1 (en) | 2014-05-26 | 2015-12-03 | Academisch Ziekenhuis Leiden | Prohemostatic proteins for the treatment of bleeding |
WO2016019145A1 (en) * | 2014-07-31 | 2016-02-04 | Haemonetics Corporation | Detection and classification of an anticoagulant using a clotting assay |
US10676731B2 (en) | 2014-08-19 | 2020-06-09 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating factor IX function |
EA036091B1 (ru) * | 2014-08-20 | 2020-09-25 | Портола Фармасьютикалз, Инк. | ВОДНЫЕ СОСТАВЫ АНТИДОТОВ ФАКТОРА Xa (fXa) ДЛЯ ПРЕДУПРЕЖДЕНИЯ ИЛИ УМЕНЬШЕНИЯ КРОВОТЕЧЕНИЯ И ИХ ПРИМЕНЕНИЕ |
CN105030703B (zh) * | 2015-06-23 | 2018-03-23 | 上海旭东海普药业有限公司 | 一种防治疗栓塞性疾病的利伐沙班片及其制备方法 |
US9849125B1 (en) | 2015-11-03 | 2017-12-26 | Banner Lifie Sciences LLC | Anti-overingestion dosage forms |
WO2017147522A1 (en) | 2016-02-24 | 2017-08-31 | Portola Pharmaceuticals, Inc. | Lyophilized formulations for factor xa antidote |
US10640822B2 (en) | 2016-02-29 | 2020-05-05 | Iridia, Inc. | Systems and methods for writing, reading, and controlling data stored in a polymer |
CN109415766A (zh) * | 2016-02-29 | 2019-03-01 | 艾瑞迪亚公司 | 用于信息存储的方法、组合物和装置 |
US10859562B2 (en) | 2016-02-29 | 2020-12-08 | Iridia, Inc. | Methods, compositions, and devices for information storage |
US10438662B2 (en) | 2016-02-29 | 2019-10-08 | Iridia, Inc. | Methods, compositions, and devices for information storage |
TW201802121A (zh) | 2016-05-25 | 2018-01-16 | 諾華公司 | 抗因子XI/XIa抗體之逆轉結合劑及其用途 |
HUE054597T2 (hu) | 2016-06-17 | 2021-09-28 | Alexion Pharma Inc | Az XA faktor származékainak elõkészítése |
WO2018115235A1 (en) | 2016-12-22 | 2018-06-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antidotes to anti-coagulant drugs allowing diagnosis and treatment |
KR102616666B1 (ko) | 2016-12-23 | 2023-12-27 | 노파르티스 아게 | 인자 xi 항체 및 사용 방법 |
US10335375B2 (en) | 2017-05-30 | 2019-07-02 | Patheon Softgels, Inc. | Anti-overingestion abuse deterrent compositions |
EP3672520A4 (en) * | 2017-08-21 | 2021-06-30 | Allele Biotechnology And Pharmaceuticals, Inc. | LIGHT ABSORBING COMPOSITIONS AND METHODS OF USE |
WO2019096874A1 (en) | 2017-11-15 | 2019-05-23 | Novo Nordisk A/S | Factor x binders enhancing fx activation |
US20210371842A1 (en) * | 2018-06-19 | 2021-12-02 | Alexion Pharmaceuticals, Inc. | Antidotes to factor xa inhibitors |
CA3109007A1 (en) * | 2018-08-14 | 2020-02-20 | Jiangsu Hengrui Medicine Co., Ltd. | Injectable pharmaceutical composition and preparation method therefor |
US11655465B1 (en) | 2019-05-02 | 2023-05-23 | Iridia, Inc. | Enzymes and systems for synthesizing DNA |
US20220251534A1 (en) * | 2019-08-08 | 2022-08-11 | Alexion Pharmaceuticals, Inc. | Compositions and methods for preparing factor xa and derivatives |
US11837302B1 (en) | 2020-08-07 | 2023-12-05 | Iridia, Inc. | Systems and methods for writing and reading data stored in a polymer using nano-channels |
CN113484386B (zh) * | 2021-05-21 | 2024-02-13 | 郑州轻工业大学 | 一种金属聚酞菁纳米材料的制备方法及其应用,适配体传感器及其制备方法 |
CN114681597A (zh) * | 2022-03-11 | 2022-07-01 | 兆科药业(合肥)有限公司 | 蝰蛇蛇毒血凝酶在制备用于逆转凝血因子Xa抑制剂的抗凝作用的药物中的应用 |
CN116327627B (zh) * | 2023-03-10 | 2024-06-07 | 四川大学 | 一种四面体框架核酸-光甘草定复合物及其在皮肤美白方面的用途 |
Family Cites Families (96)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH596313A5 (ja) * | 1975-05-30 | 1978-03-15 | Battelle Memorial Institute | |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4754065A (en) | 1984-12-18 | 1988-06-28 | Cetus Corporation | Precursor to nucleic acid probe |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US6492107B1 (en) | 1986-11-20 | 2002-12-10 | Stuart Kauffman | Process for obtaining DNA, RNA, peptides, polypeptides, or protein, by recombinant DNA technique |
EP0590689B2 (fr) | 1985-03-30 | 2006-08-16 | KAUFFMAN, Stuart A. | Procédé d'obtention d'ADN, ARN, peptides, polypeptides ou protéines, par une technique de recombinaison d'ADN |
US5837249A (en) | 1985-04-19 | 1998-11-17 | The Wistar Institute | Method for generating an immunogenic T cell response protective against a virus |
US4818700A (en) | 1985-10-25 | 1989-04-04 | Phillips Petroleum Company | Pichia pastoris argininosuccinate lyase gene and uses thereof |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
US4812405A (en) | 1986-02-18 | 1989-03-14 | Phillips Petroleum Company | Double auxotrophic mutants of Pichia pastoris and methods for preparation |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4704692A (en) | 1986-09-02 | 1987-11-03 | Ladner Robert C | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
EP0279582A3 (en) | 1987-02-17 | 1989-10-18 | Pharming B.V. | Dna sequences to target proteins to the mammary gland for efficient secretion |
US5202231A (en) | 1987-04-01 | 1993-04-13 | Drmanac Radoje T | Method of sequencing of genomes by hybridization of oligonucleotide probes |
US6270961B1 (en) | 1987-04-01 | 2001-08-07 | Hyseq, Inc. | Methods and apparatus for DNA sequencing and DNA identification |
US5229490A (en) | 1987-05-06 | 1993-07-20 | The Rockefeller University | Multiple antigen peptide system |
US4873316A (en) | 1987-06-23 | 1989-10-10 | Biogen, Inc. | Isolation of exogenous recombinant proteins from the milk of transgenic mammals |
US4929555A (en) | 1987-10-19 | 1990-05-29 | Phillips Petroleum Company | Pichia transformation |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5120537A (en) * | 1989-06-14 | 1992-06-09 | Oklahoma Medical Research Foundation | Factor xa based anticoagulant compositions |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5686073A (en) | 1990-05-23 | 1997-11-11 | The University Of Iowa Research Foundation | Polyclonal and monoclonal antibodies against a 43 KDA dystrophin associated protein |
CA2090126C (en) | 1990-08-02 | 2002-10-22 | John W. Schrader | Methods for the production of proteins with a desired function |
US5583107A (en) | 1990-09-04 | 1996-12-10 | Cor Therapeutics, Inc. | Agents affecting thrombosis and hemostasis |
US5597799A (en) | 1990-09-04 | 1997-01-28 | Cor Therapeutics, Inc. | Recombinant agents affecting thrombosis |
US5278144A (en) * | 1990-09-04 | 1994-01-11 | Cor Therapeutics, Inc. | Antithrombosis agents |
WO1992013878A2 (en) | 1991-02-07 | 1992-08-20 | Board Of Trustees Of The University Of Illinois | Conformationally restricted mimetics of beta turns and beta bulges and peptides containing the same |
US6797492B2 (en) | 1991-05-17 | 2004-09-28 | Merck & Co., Inc. | Method for reducing the immunogenicity of antibody variable domains |
EP0519596B1 (en) | 1991-05-17 | 2005-02-23 | Merck & Co. Inc. | A method for reducing the immunogenicity of antibody variable domains |
PL171489B1 (pl) | 1991-09-13 | 1997-05-30 | Chiron Corp | Sposób wytwarzania kompozycji immunogenicznej reagujacej immunologicznie krzyzowo z wieloma izolatami HCV PL |
WO1993009804A1 (en) | 1991-11-18 | 1993-05-27 | The Scripps Research Institute | Serine protease derived-polypeptides and anti-peptide antibodies, systems and therapeutic methods for inhibiting coagulation |
AU3178993A (en) | 1991-11-25 | 1993-06-28 | Enzon, Inc. | Multivalent antigen-binding proteins |
EP0571613B1 (en) | 1991-12-13 | 2003-09-17 | Xoma Corporation | Methods and materials for preparation of modified antibody variable domains and therapeutic uses thereof |
DE4203965A1 (de) | 1992-02-11 | 1993-08-12 | Max Planck Gesellschaft | Antidot fuer hirudin und synthetische thrombininhibitoren |
US6117836A (en) | 1992-03-20 | 2000-09-12 | Cor Therapeutics, Inc. | Glycosylation-mediated inhibition of factor X |
ATE304604T1 (de) | 1993-06-24 | 2005-09-15 | Frank L Graham | Adenovirus vektoren für gentherapie |
US5858659A (en) | 1995-11-29 | 1999-01-12 | Affymetrix, Inc. | Polymorphism detection |
SK283703B6 (sk) | 1993-10-25 | 2003-12-02 | Canji, Inc. | Rekombinantný adenovírusový vektor a jeho použitie |
US5455338A (en) | 1993-11-05 | 1995-10-03 | Zymogenetics, Inc. | DNA encoding novel human kunitz-type inhibitors and methods relating thereto |
US5952172A (en) | 1993-12-10 | 1999-09-14 | California Institute Of Technology | Nucleic acid mediated electron transfer |
US5827690A (en) | 1993-12-20 | 1998-10-27 | Genzyme Transgenics Corporatiion | Transgenic production of antibodies in milk |
US7252989B1 (en) | 1994-04-04 | 2007-08-07 | Board Of Regents, The University Of Texas System | Adenovirus supervector system |
DE4430205A1 (de) | 1994-08-26 | 1996-02-29 | Behringwerke Ag | Zusammensetzungen, die als Gegenmittel für Blut-Antikoagulanzien geeignet sind und deren Verwendung |
US5589571A (en) * | 1994-10-28 | 1996-12-31 | Cor Therapeutics, Inc. | Process for production of inhibited forms of activated blood factors |
AT404357B (de) | 1995-06-13 | 1998-11-25 | Immuno Ag | Prothrombin-derivate |
US5968740A (en) | 1995-07-24 | 1999-10-19 | Affymetrix, Inc. | Method of Identifying a Base in a Nucleic Acid |
US5955349A (en) | 1996-08-26 | 1999-09-21 | Zymogenetics, Inc. | Compositions and methods for producing heterologous polypeptides in Pichia methanolica |
DE19605126A1 (de) | 1996-02-12 | 1997-08-14 | Basf Ag | Thrombinmuteine als Antidot für Thrombininhibitoren |
US5714352A (en) | 1996-03-20 | 1998-02-03 | Xenotech Incorporated | Directed switch-mediated DNA recombination |
US6200955B1 (en) | 1996-06-11 | 2001-03-13 | Commonwealth Biotechnologies, Inc. | Heparin binding peptides |
US5736383A (en) | 1996-08-26 | 1998-04-07 | Zymogenetics, Inc. | Preparation of Pichia methanolica auxotrophic mutants |
US6709659B1 (en) | 1996-08-02 | 2004-03-23 | Zymogenetics, Inc. | Antibodies that bind testis-specific insulin homolog polypeptides |
SE9604744D0 (sv) | 1996-12-20 | 1996-12-20 | Pharmacia & Upjohn Ab | A modified coagulation agent |
AT405517B (de) * | 1997-02-27 | 1999-09-27 | Immuno Ag | Faktor x-deletionsmutanten und analoge davon |
AT405516B (de) | 1997-02-27 | 1999-09-27 | Immuno Ag | Faktor x-analoge mit modifizierter proteasespaltstelle |
AU6673898A (en) * | 1997-03-07 | 1998-09-22 | Washington University | Factor x variant |
JPH1149800A (ja) | 1997-06-05 | 1999-02-23 | Fujimori Kogyo Kk | アンヒドロトロンビンの合成方法 |
DK2180007T4 (da) | 1998-04-20 | 2017-11-27 | Roche Glycart Ag | Glycosyleringsteknik for antistoffer til forbedring af antistofafhængig cellecytotoxicitet |
US6322788B1 (en) | 1998-08-20 | 2001-11-27 | Stanley Arthur Kim | Anti-bacterial antibodies and methods of use |
JP2002530081A (ja) | 1998-11-18 | 2002-09-17 | ジェネンテック・インコーポレーテッド | 親抗体より高度な結合親和性を持つ抗体変異体 |
WO2000054787A1 (en) | 1999-03-16 | 2000-09-21 | The Children's Hospital Of Philadelphia | Enhanced gamma-carboxylation of recombinant vitamin k-dependent clotting factors |
US6624141B1 (en) | 1999-03-17 | 2003-09-23 | The Regents Of The University Of Michigan | Protamine fragment compositions and methods of use |
US6258559B1 (en) | 1999-03-22 | 2001-07-10 | Zymogenetics, Inc. | Method for producing proteins in transformed Pichia |
US6939545B2 (en) | 1999-04-28 | 2005-09-06 | Genetics Institute, Llc | Composition and method for treating inflammatory disorders |
US6858599B2 (en) | 1999-06-30 | 2005-02-22 | Mochida Pharmaceutical Co., Ltd. | Tricyclic compound having spiro union |
AT411997B (de) * | 1999-09-14 | 2004-08-26 | Baxter Ag | Faktor ix/faktor ixa aktivierende antikörper und antikörper-derivate |
EP1095933A1 (en) | 1999-10-30 | 2001-05-02 | Aventis Pharma Deutschland GmbH | Novel N-guanidinoalkylamides, their preparation, their use, and pharmaceutical preparations comprising them |
CA2401778C (en) | 2000-02-29 | 2010-12-21 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor xa |
WO2001068605A1 (en) | 2000-03-13 | 2001-09-20 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
MXPA03002049A (es) | 2000-09-08 | 2003-07-24 | Schering Corp | Genes de mamiferos: reactivos y metodos relacionados. |
US7070740B1 (en) | 2000-09-28 | 2006-07-04 | Beckman Coulter, Inc. | Method and apparatus for processing biomolecule arrays |
US20030064414A1 (en) | 2001-03-30 | 2003-04-03 | Benecky Michael J. | Rapid assessment of coagulation activity in whole blood |
WO2002090599A1 (en) | 2001-05-09 | 2002-11-14 | Genetic Id, Inc. | Universal microarray system |
US6989267B2 (en) | 2001-07-02 | 2006-01-24 | Agilent Technologies, Inc. | Methods of making microarrays with substrate surfaces having covalently bound polyelectrolyte films |
DE10155075A1 (de) * | 2001-11-09 | 2003-05-22 | Merck Patent Gmbh | Cyclische Sulfonamide |
US6861236B2 (en) | 2002-05-24 | 2005-03-01 | Applied Nanosystems B.V. | Export and modification of (poly)peptides in the lantibiotic way |
CN1480466A (zh) * | 2002-09-03 | 2004-03-10 | �й������ž�����ҽѧ��ѧԺ����ҽ | 一类溶栓抗凝双功能融合蛋白及应用 |
US20040198660A1 (en) | 2002-11-06 | 2004-10-07 | Petersen Lars Christian | Tissue factor antagonist and protein C polypeptide compositions |
US7247654B2 (en) | 2003-06-04 | 2007-07-24 | Bristol-Myers Squibb Company | 3,4-disubstituted benzamidines and benzylamines, and analogues thereof, useful as serine protease inhibitors |
WO2005088310A2 (en) | 2004-03-05 | 2005-09-22 | The Scripps Research Institute | High throughput glycan microarrays |
JP4441336B2 (ja) | 2004-06-11 | 2010-03-31 | 日本碍子株式会社 | マイクロアレイの製造方法 |
US9223929B2 (en) | 2005-03-14 | 2015-12-29 | The California Institute Of Technology | Method and apparatus for detection, identification and quantification of single-and multi-analytes in affinity-based sensor arrays |
US7119179B1 (en) | 2005-03-21 | 2006-10-10 | Los Alamos National Security, Llc | Preparation of high nitrogen compound and materials therefrom |
US9164108B2 (en) | 2005-03-22 | 2015-10-20 | Sri International | Liposome-based microarray and methods of use thereof |
PT1948608E (pt) | 2005-11-08 | 2012-05-24 | Millennium Pharm Inc | Novos sais farmacêuticos e polimorfos de um inibidor do fator xa |
MX2008006313A (es) * | 2005-11-15 | 2008-11-06 | Philadelphia Children Hospital | Metodos y composiciones para modular la hemostasia. |
US20070111322A1 (en) | 2005-11-15 | 2007-05-17 | Lin-Cheng Yang | Novel method of using inject printing for creating microarrays |
EP1820508A1 (en) | 2006-02-21 | 2007-08-22 | CSL Behring GmbH | Coagulation factor X polypeptides with modified activation properties |
CN101802188B (zh) * | 2007-09-28 | 2013-08-21 | 普托拉制药有限公司 | 用于因子Xa抑制剂的解毒剂和其使用方法 |
EP2364165B1 (en) * | 2008-11-14 | 2018-01-03 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents |
WO2010070137A1 (en) | 2008-12-19 | 2010-06-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Serine protease derivatives and uses in the prevention or the treatment of blood coagulation disorders |
EP2414517B1 (en) * | 2009-03-30 | 2016-09-21 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same |
WO2011008885A1 (en) * | 2009-07-15 | 2011-01-20 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same |
-
2008
- 2008-09-26 CN CN2008801079738A patent/CN101802188B/zh active Active
- 2008-09-26 KR KR1020177023761A patent/KR20170100071A/ko not_active Application Discontinuation
- 2008-09-26 DK DK08834136.7T patent/DK2193196T3/en active
- 2008-09-26 HU HUE16167534A patent/HUE050063T2/hu unknown
- 2008-09-26 LT LTEP08834136.7T patent/LT2193196T/lt unknown
- 2008-09-26 CN CN201310301566.3A patent/CN103446579B/zh active Active
- 2008-09-26 CN CN201110447251.0A patent/CN102559644B/zh active Active
- 2008-09-26 DK DK16167534.3T patent/DK3078743T3/da active
- 2008-09-26 SG SG2012072716A patent/SG185263A1/en unknown
- 2008-09-26 ES ES08834136.7T patent/ES2597436T3/es active Active
- 2008-09-26 CN CN2011104472050A patent/CN102533702A/zh active Pending
- 2008-09-26 JP JP2010527220A patent/JP5637561B2/ja active Active
- 2008-09-26 PL PL14197779T patent/PL2915564T3/pl unknown
- 2008-09-26 WO PCT/US2008/078014 patent/WO2009042962A2/en active Application Filing
- 2008-09-26 KR KR1020167003860A patent/KR102069498B1/ko active IP Right Grant
- 2008-09-26 MX MX2010003095A patent/MX2010003095A/es active IP Right Grant
- 2008-09-26 HU HUE14197779A patent/HUE052423T2/hu unknown
- 2008-09-26 KR KR1020207001549A patent/KR102271404B1/ko active IP Right Grant
- 2008-09-26 EP EP16167534.3A patent/EP3078743B1/en active Active
- 2008-09-26 DK DK14197779.3T patent/DK2915564T3/da active
- 2008-09-26 HU HUE08834136A patent/HUE031647T2/en unknown
- 2008-09-26 KR KR1020107008718A patent/KR101698214B1/ko active IP Right Grant
- 2008-09-26 EP EP20198287.3A patent/EP3824902A1/en active Pending
- 2008-09-26 PT PT88341367T patent/PT2193196T/pt unknown
- 2008-09-26 BR BRPI0816837-7A patent/BRPI0816837B1/pt active IP Right Grant
- 2008-09-26 PT PT161675343T patent/PT3078743T/pt unknown
- 2008-09-26 PL PL08834136T patent/PL2193196T3/pl unknown
- 2008-09-26 EP EP14197779.3A patent/EP2915564B1/en active Active
- 2008-09-26 CA CA2697583A patent/CA2697583C/en active Active
- 2008-09-26 SI SI200832153T patent/SI2915564T1/sl unknown
- 2008-09-26 AU AU2008304192A patent/AU2008304192B9/en active Active
- 2008-09-26 SI SI200831678A patent/SI2193196T1/sl unknown
- 2008-09-26 NZ NZ583944A patent/NZ583944A/en unknown
- 2008-09-26 ES ES16167534T patent/ES2796623T3/es active Active
- 2008-09-26 PL PL16167534T patent/PL3078743T3/pl unknown
- 2008-09-26 LT LTEP16167534.3T patent/LT3078743T/lt unknown
- 2008-09-26 PT PT141977793T patent/PT2915564T/pt unknown
- 2008-09-26 EP EP08834136.7A patent/EP2193196B1/en active Active
- 2008-09-26 ES ES14197779T patent/ES2849426T3/es active Active
- 2008-09-26 BR BR122022001846-7A patent/BR122022001846B1/pt active IP Right Grant
- 2008-09-26 SI SI200832130T patent/SI3078743T1/sl unknown
- 2008-09-26 US US12/239,651 patent/US8153590B2/en active Active
-
2010
- 2010-02-16 IL IL203993A patent/IL203993A/en active IP Right Grant
- 2010-03-23 ZA ZA2010/02039A patent/ZA201002039B/en unknown
-
2012
- 2012-03-07 US US13/414,499 patent/US8455441B2/en active Active
-
2013
- 2013-04-11 AU AU2013205326A patent/AU2013205326A1/en not_active Abandoned
- 2013-05-07 US US13/889,014 patent/US9062298B2/en active Active
- 2013-06-11 US US13/915,525 patent/US8889129B2/en active Active
-
2014
- 2014-07-21 US US14/337,074 patent/US9388401B2/en active Active
- 2014-08-07 AU AU2014210620A patent/AU2014210620B2/en active Active
- 2014-08-19 JP JP2014166333A patent/JP6047127B2/ja active Active
- 2014-09-04 ZA ZA2014/06514A patent/ZA201406514B/en unknown
-
2015
- 2015-11-13 HK HK15111214.0A patent/HK1210443A1/xx unknown
-
2016
- 2016-06-08 US US15/176,461 patent/US10675335B2/en active Active
- 2016-10-03 HR HRP20161255TT patent/HRP20161255T1/hr unknown
- 2016-10-12 CY CY20161101020T patent/CY1118482T1/el unknown
- 2016-11-18 JP JP2016225290A patent/JP6300885B2/ja active Active
-
2017
- 2017-01-12 AU AU2017200212A patent/AU2017200212A1/en not_active Abandoned
- 2017-11-02 IL IL255397A patent/IL255397B/en active IP Right Grant
-
2018
- 2018-02-27 JP JP2018033229A patent/JP2018100290A/ja active Pending
-
2019
- 2019-02-18 IL IL264886A patent/IL264886B/en active IP Right Grant
- 2019-06-13 AU AU2019204123A patent/AU2019204123A1/en not_active Abandoned
- 2019-11-08 NO NO2019040C patent/NO2019040I1/no unknown
-
2020
- 2020-02-26 IL IL272926A patent/IL272926A/en unknown
- 2020-03-12 JP JP2020042919A patent/JP2020109113A/ja active Pending
- 2020-05-07 US US16/869,117 patent/US11839646B2/en active Active
- 2020-07-08 HR HRP20201071TT patent/HRP20201071T1/hr unknown
- 2020-08-04 CY CY20201100715T patent/CY1123504T1/el unknown
- 2020-09-09 NL NL301063C patent/NL301063I2/nl unknown
- 2020-09-23 FR FR20C1045C patent/FR20C1045I2/fr active Active
- 2020-09-23 NO NO2020033C patent/NO2020033I1/no unknown
- 2020-12-22 HU HUS2000057C patent/HUS2000057I1/hu unknown
- 2020-12-22 LT LTPA2020540C patent/LTC3078743I2/lt unknown
-
2021
- 2021-08-17 AU AU2021218033A patent/AU2021218033A1/en active Pending
-
2022
- 2022-07-29 JP JP2022121451A patent/JP2022153574A/ja active Pending
-
2023
- 2023-11-02 US US18/500,675 patent/US20240082367A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6300885B2 (ja) | 第Xa因子阻害剤に対する抗体およびその使用の方法 | |
EP3121271B1 (en) | Antidotes for factor xa inhibitors and methods of using the same | |
EP2453910B1 (en) | Unit dose formulation of antidote for factor xa inhibitors for use in preventing bleeding | |
EP2364165B1 (en) | Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110922 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110922 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120911 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130702 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20131001 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20131008 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20140618 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20140819 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20140922 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20141015 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20141016 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5637561 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |