CA2802072A1 - Treatment of coagulopathy with hyperfibrinolysis - Google Patents
Treatment of coagulopathy with hyperfibrinolysis Download PDFInfo
- Publication number
- CA2802072A1 CA2802072A1 CA2802072A CA2802072A CA2802072A1 CA 2802072 A1 CA2802072 A1 CA 2802072A1 CA 2802072 A CA2802072 A CA 2802072A CA 2802072 A CA2802072 A CA 2802072A CA 2802072 A1 CA2802072 A1 CA 2802072A1
- Authority
- CA
- Canada
- Prior art keywords
- seq
- thrombomodulin
- phe
- amino acid
- analogue
- 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.)
- Abandoned
Links
- 206010053567 Coagulopathies Diseases 0.000 title claims abstract description 53
- 238000011282 treatment Methods 0.000 title claims abstract description 50
- 208000015294 blood coagulation disease Diseases 0.000 title claims abstract description 44
- 108010079274 Thrombomodulin Proteins 0.000 claims abstract description 434
- 102000012607 Thrombomodulin Human genes 0.000 claims abstract description 434
- 238000000034 method Methods 0.000 claims abstract description 38
- 208000009292 Hemophilia A Diseases 0.000 claims abstract description 28
- 208000031220 Hemophilia Diseases 0.000 claims abstract description 26
- 230000001567 anti-fibrinolytic effect Effects 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 385
- 150000001413 amino acids Chemical group 0.000 claims description 306
- 235000001014 amino acid Nutrition 0.000 claims description 236
- 229940024606 amino acid Drugs 0.000 claims description 164
- 230000000694 effects Effects 0.000 claims description 139
- 230000004048 modification Effects 0.000 claims description 117
- 238000012986 modification Methods 0.000 claims description 117
- 108090000190 Thrombin Proteins 0.000 claims description 114
- 229960004072 thrombin Drugs 0.000 claims description 111
- 108090000201 Carboxypeptidase B2 Proteins 0.000 claims description 109
- 230000009089 cytolysis Effects 0.000 claims description 109
- 230000004913 activation Effects 0.000 claims description 105
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 95
- 239000012634 fragment Substances 0.000 claims description 82
- 238000006467 substitution reaction Methods 0.000 claims description 63
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical group CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 62
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical group CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 60
- 101100118545 Holotrichia diomphalia EGF-like gene Proteins 0.000 claims description 49
- 238000012217 deletion Methods 0.000 claims description 48
- 230000037430 deletion Effects 0.000 claims description 48
- 210000004369 blood Anatomy 0.000 claims description 46
- 239000008280 blood Substances 0.000 claims description 46
- 229960000301 factor viii Drugs 0.000 claims description 46
- 208000032843 Hemorrhage Diseases 0.000 claims description 39
- 108010054218 Factor VIII Proteins 0.000 claims description 38
- 102000001690 Factor VIII Human genes 0.000 claims description 38
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 38
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 38
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 38
- 208000034158 bleeding Diseases 0.000 claims description 37
- 230000000740 bleeding effect Effects 0.000 claims description 37
- 230000002829 reductive effect Effects 0.000 claims description 37
- 235000004279 alanine Nutrition 0.000 claims description 26
- 201000003542 Factor VIII deficiency Diseases 0.000 claims description 25
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 23
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 21
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 17
- -1 His Chemical group 0.000 claims description 17
- 238000005345 coagulation Methods 0.000 claims description 15
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 14
- 230000015271 coagulation Effects 0.000 claims description 14
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical group C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 13
- 210000004072 lung Anatomy 0.000 claims description 13
- 102000015081 Blood Coagulation Factors Human genes 0.000 claims description 12
- 108010039209 Blood Coagulation Factors Proteins 0.000 claims description 12
- 239000003114 blood coagulation factor Substances 0.000 claims description 12
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 238000009256 replacement therapy Methods 0.000 claims description 11
- 101000763314 Homo sapiens Thrombomodulin Proteins 0.000 claims description 10
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical group C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 10
- 102100037642 Elongation factor G, mitochondrial Human genes 0.000 claims description 9
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Chemical group CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 9
- 230000003247 decreasing effect Effects 0.000 claims description 9
- 238000001990 intravenous administration Methods 0.000 claims description 9
- 208000009429 hemophilia B Diseases 0.000 claims description 8
- 229960000310 isoleucine Drugs 0.000 claims description 8
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Chemical group CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 8
- 239000004471 Glycine Substances 0.000 claims description 7
- 101000880344 Homo sapiens Elongation factor G, mitochondrial Proteins 0.000 claims description 7
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical group CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 7
- 102000057593 human F8 Human genes 0.000 claims description 7
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 7
- 239000004474 valine Chemical group 0.000 claims description 7
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 6
- 101000938391 Homo sapiens Transmembrane protein Proteins 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 230000037396 body weight Effects 0.000 claims description 6
- 229950001570 octocog alfa Drugs 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000001356 surgical procedure Methods 0.000 claims description 6
- 108010089996 B-domain-deleted factor VIII Proteins 0.000 claims description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical group OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 5
- 230000001747 exhibiting effect Effects 0.000 claims description 5
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims description 5
- 238000007917 intracranial administration Methods 0.000 claims description 5
- 229950003483 moroctocog alfa Drugs 0.000 claims description 5
- 108010025139 recombinant factor VIII SQ Proteins 0.000 claims description 5
- 238000012216 screening Methods 0.000 claims description 5
- 210000004872 soft tissue Anatomy 0.000 claims description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- 238000010171 animal model Methods 0.000 claims description 4
- 230000007812 deficiency Effects 0.000 claims description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 4
- 238000000099 in vitro assay Methods 0.000 claims description 4
- 230000006318 protein oxidation Effects 0.000 claims description 4
- 210000000574 retroperitoneal space Anatomy 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims 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 claims description 3
- 208000028782 Hereditary disease Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 208000005376 factor X deficiency Diseases 0.000 claims description 3
- 208000031169 hemorrhagic disease Diseases 0.000 claims description 3
- 210000003205 muscle Anatomy 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 210000002345 respiratory system Anatomy 0.000 claims description 3
- 208000019048 congenital factor V deficiency Diseases 0.000 claims description 2
- 201000007382 factor V deficiency Diseases 0.000 claims description 2
- 208000035474 group of disease Diseases 0.000 claims description 2
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 102100035023 Carboxypeptidase B2 Human genes 0.000 claims 4
- 101100226846 Strongylocentrotus purpuratus EGF3 gene Proteins 0.000 claims 2
- 230000009145 protein modification Effects 0.000 abstract 1
- 108700003414 solulin Proteins 0.000 description 145
- 210000002381 plasma Anatomy 0.000 description 113
- 102000003847 Carboxypeptidase B2 Human genes 0.000 description 105
- 230000035772 mutation Effects 0.000 description 66
- 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 59
- 101800003838 Epidermal growth factor Proteins 0.000 description 58
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 58
- 229940116977 epidermal growth factor Drugs 0.000 description 58
- 229960000856 protein c Drugs 0.000 description 51
- 102000017975 Protein C Human genes 0.000 description 50
- 101800004937 Protein C Proteins 0.000 description 46
- 101800001700 Saposin-D Proteins 0.000 description 46
- 238000003556 assay Methods 0.000 description 42
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 32
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 32
- 238000002474 experimental method Methods 0.000 description 32
- 102100026735 Coagulation factor VIII Human genes 0.000 description 31
- 108090000623 proteins and genes Proteins 0.000 description 30
- 229960000187 tissue plasminogen activator Drugs 0.000 description 29
- 241000282472 Canis lupus familiaris Species 0.000 description 28
- 230000002950 deficient Effects 0.000 description 25
- 235000018102 proteins Nutrition 0.000 description 25
- 102000004169 proteins and genes Human genes 0.000 description 25
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 230000035602 clotting Effects 0.000 description 18
- 230000001419 dependent effect Effects 0.000 description 18
- 230000020764 fibrinolysis Effects 0.000 description 18
- 229940039716 prothrombin Drugs 0.000 description 17
- 239000000523 sample Substances 0.000 description 17
- 108010094028 Prothrombin Proteins 0.000 description 16
- 102100027378 Prothrombin Human genes 0.000 description 16
- IIYZWOIELWZHJV-NRFANRHFSA-N 2-[(4s)-4-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]-5-(4-ethylpiperidin-1-yl)-5-oxopentyl]guanidine Chemical compound C1CC(CC)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C(N(C)C)C=CC=C12 IIYZWOIELWZHJV-NRFANRHFSA-N 0.000 description 15
- 208000014674 injury Diseases 0.000 description 15
- 102220592986 Plasma alpha-L-fucosidase_F376A_mutation Human genes 0.000 description 14
- 230000003647 oxidation Effects 0.000 description 14
- 238000007254 oxidation reaction Methods 0.000 description 14
- 239000000758 substrate Substances 0.000 description 14
- 241000282465 Canis Species 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000007792 addition Methods 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 230000000019 pro-fibrinolytic effect Effects 0.000 description 12
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 11
- 239000001110 calcium chloride Substances 0.000 description 11
- 229910001628 calcium chloride Inorganic materials 0.000 description 11
- 235000011148 calcium chloride Nutrition 0.000 description 11
- 238000003780 insertion Methods 0.000 description 10
- 230000037431 insertion Effects 0.000 description 10
- 230000036470 plasma concentration Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 230000008733 trauma Effects 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 102220327177 rs201654184 Human genes 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000013598 vector Substances 0.000 description 8
- 241000588724 Escherichia coli Species 0.000 description 7
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 7
- 230000023555 blood coagulation Effects 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 102220549120 Dihydropyrimidinase-related protein 2_L415G_mutation Human genes 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 102220532420 Nucleolar protein 58_D400A_mutation Human genes 0.000 description 6
- 108091005804 Peptidases Proteins 0.000 description 6
- 102000035195 Peptidases Human genes 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 102000007625 Hirudins Human genes 0.000 description 5
- 108010007267 Hirudins Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 102220356859 c.1166T>A Human genes 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000007547 defect Effects 0.000 description 5
- 238000006206 glycosylation reaction Methods 0.000 description 5
- 229940006607 hirudin Drugs 0.000 description 5
- 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 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 102220117203 rs886041020 Human genes 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 229940121981 Carboxypeptidase inhibitor Drugs 0.000 description 4
- 101710127041 Carboxypeptidase inhibitor Proteins 0.000 description 4
- 102100022641 Coagulation factor IX Human genes 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 108010076282 Factor IX Proteins 0.000 description 4
- 108010049003 Fibrinogen Proteins 0.000 description 4
- 102000008946 Fibrinogen Human genes 0.000 description 4
- 108010088842 Fibrinolysin Proteins 0.000 description 4
- 101710140999 Metallocarboxypeptidase inhibitor Proteins 0.000 description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 4
- 108010001953 Protein C Inhibitor Proteins 0.000 description 4
- 235000002595 Solanum tuberosum Nutrition 0.000 description 4
- 244000061456 Solanum tuberosum Species 0.000 description 4
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229960004222 factor ix Drugs 0.000 description 4
- 229940012952 fibrinogen Drugs 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 102000051206 human THBD Human genes 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 229940012957 plasmin Drugs 0.000 description 4
- 230000002028 premature Effects 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 102220117204 rs886041019 Human genes 0.000 description 4
- 238000002741 site-directed mutagenesis Methods 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 102000010911 Enzyme Precursors Human genes 0.000 description 3
- 108010062466 Enzyme Precursors Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101500025568 Homo sapiens Saposin-D Proteins 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000013566 Plasminogen Human genes 0.000 description 3
- 108010051456 Plasminogen Proteins 0.000 description 3
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 3
- 229940122388 Thrombin inhibitor Drugs 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000001949 anaesthesia Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 238000002825 functional assay Methods 0.000 description 3
- 229940100689 human protein c Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000000503 lectinlike effect Effects 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 210000000282 nail Anatomy 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 239000003868 thrombin inhibitor Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 102000005367 Carboxypeptidases Human genes 0.000 description 2
- 108010006303 Carboxypeptidases Proteins 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010058861 Fibrin Fibrinogen Degradation Products Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 206010018852 Haematoma Diseases 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- ZFOMKMMPBOQKMC-KXUCPTDWSA-N L-pyrrolysine Chemical compound C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H]([NH3+])C([O-])=O ZFOMKMMPBOQKMC-KXUCPTDWSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102220603193 Zinc finger protein 423_E426A_mutation Human genes 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000012867 alanine scanning Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000000078 claw Anatomy 0.000 description 2
- 230000009852 coagulant defect Effects 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000000208 fibrin degradation product Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000006623 intrinsic pathway Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 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 2
- 238000012423 maintenance Methods 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 2
- 230000018341 negative regulation of fibrinolysis Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229940055619 selenocysteine Drugs 0.000 description 2
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 2
- 235000016491 selenocysteine Nutrition 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 229960003766 thrombin (human) Drugs 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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 1
- NTUPOKHATNSWCY-PMPSAXMXSA-N (2s)-2-[[(2s)-1-[(2r)-2-amino-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=CC=C1 NTUPOKHATNSWCY-PMPSAXMXSA-N 0.000 description 1
- HRBPBWKDJGGGCX-AWEZNQCLSA-N (2s)-5-(diaminomethylideneazaniumyl)-2-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]pentanoate Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N[C@@H](CCCN=C(N)N)C(O)=O HRBPBWKDJGGGCX-AWEZNQCLSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- CGFFKDRVHZIQHL-UHFFFAOYSA-N 1-but-3-en-2-yl-3-(methylcarbamothioylamino)thiourea Chemical compound CNC(=S)NNC(=S)NC(C)C=C CGFFKDRVHZIQHL-UHFFFAOYSA-N 0.000 description 1
- CFBILACNYSPRPM-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]acetic acid Chemical compound OCC(N)(CO)CO.OCC(CO)(CO)NCC(O)=O CFBILACNYSPRPM-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- 108010093583 ART123 Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241001552669 Adonis annua Species 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000019300 CLIPPERS Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 238000011537 Coomassie blue staining Methods 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000012545 EGF-like domains Human genes 0.000 description 1
- 108050002150 EGF-like domains Proteins 0.000 description 1
- HBGOLJKPSFNJSD-UHFFFAOYSA-N Etamsylate Chemical compound CC[NH2+]CC.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 HBGOLJKPSFNJSD-UHFFFAOYSA-N 0.000 description 1
- 206010015769 Extradural haematoma Diseases 0.000 description 1
- 108010074105 Factor Va Proteins 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins 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
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001024703 Homo sapiens Nck-associated protein 5 Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 108010090444 Innovin Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010026865 Mass Diseases 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000004221 Multiple Trauma Diseases 0.000 description 1
- 208000023637 Multiple injury Diseases 0.000 description 1
- 101100438619 Mus musculus Cpb2 gene Proteins 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 102100036946 Nck-associated protein 5 Human genes 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 230000004989 O-glycosylation Effects 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- NTUPOKHATNSWCY-JYJNAYRXSA-N Phe-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=CC=C1 NTUPOKHATNSWCY-JYJNAYRXSA-N 0.000 description 1
- 229940122791 Plasmin inhibitor Drugs 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 108010066124 Protein S Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 208000026137 Soft tissue injury Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 208000002667 Subdural Hematoma Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000003790 Thrombin receptors Human genes 0.000 description 1
- 108090000166 Thrombin receptors Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000003441 Transfusion reaction Diseases 0.000 description 1
- 102100028885 Vitamin K-dependent protein S Human genes 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940099983 activase Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 229940088007 benadryl Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000007820 coagulation assay Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000002089 crippling effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960004817 etamsylate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940049370 fibrinolysis inhibitor Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 210000004904 fingernail bed Anatomy 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical class O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000002085 hemarthrosis Diseases 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 229960000900 human factor viii Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 108010060007 hypodermin Proteins 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)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)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000002733 pharmacodynamic assay Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 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 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002806 plasmin inhibitor Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000018338 positive regulation of fibrinolysis Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000009101 premedication Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 208000012802 recumbency Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229940127558 rescue medication Drugs 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/7455—Thrombomodulin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EPPCT/EP2010/003541 | 2010-06-14 | ||
| PCT/EP2010/003541 WO2010142461A2 (en) | 2009-06-12 | 2010-06-14 | Treatment of coagulopathy with hyperfibrinolysis |
| PCT/EP2010/007632 WO2011157283A1 (en) | 2010-06-14 | 2010-12-15 | Treatment of coagulopathy with hyperfibrinolysis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2802072A1 true CA2802072A1 (en) | 2011-12-22 |
Family
ID=43857859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2802072A Abandoned CA2802072A1 (en) | 2010-06-14 | 2010-12-15 | Treatment of coagulopathy with hyperfibrinolysis |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2013531651A (enExample) |
| CN (1) | CN103037893A (enExample) |
| AU (1) | AU2010355558A1 (enExample) |
| BR (1) | BR112012031920A2 (enExample) |
| CA (1) | CA2802072A1 (enExample) |
| WO (1) | WO2011157283A1 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298937B (zh) | 2010-11-17 | 2016-05-25 | 中外制药株式会社 | 具有代替凝血因子viii的功能的功能的多特异性抗原结合分子 |
| TW201625299A (zh) * | 2014-06-20 | 2016-07-16 | Chugai Pharmaceutical Co Ltd | 用於因第ｖｉｉｉ凝血因子及／或活化的第ｖｉｉｉ凝血因子的活性降低或欠缺而發病及／或進展的疾病之預防及／或治療之醫藥組成物 |
| MX2018012648A (es) | 2016-04-28 | 2019-01-30 | Chugai Pharmaceutical Co Ltd | Preparaciones que contienen anticuerpos. |
| ES3000618T3 (en) | 2016-09-06 | 2025-03-03 | Chugai Pharmaceutical Co Ltd | Methods of using a bispecific antibody that recognizes coagulation factor ix and/or activated coagulation factor ix and coagulation factor x and/or activated coagulation factor x |
| CN107083357B (zh) * | 2017-06-16 | 2021-04-02 | 四川农业大学 | 一种诱导培养骨髓间充质干细胞的方法 |
| JP2019031486A (ja) * | 2017-08-04 | 2019-02-28 | 公立大学法人福島県立医科大学 | 新規ポリペプチド及びその用途 |
| CN107677834B (zh) * | 2017-09-25 | 2019-07-09 | 辽宁迈迪生物科技股份有限公司 | TAFIa含量的检测方法、用于检测TAFIa含量的试剂盒及二者的应用 |
| SG11202003833TA (en) | 2017-11-01 | 2020-05-28 | Chugai Pharmaceutical Co Ltd | Antibody variant and isoform with lowered biological activity |
| CN111961137B (zh) * | 2020-08-27 | 2023-09-05 | 南开大学 | 仿生内皮细胞功能的融合蛋白及其应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3856335T2 (de) | 1987-01-08 | 2000-01-27 | Asahi Kasei Kogyo K.K., Osaka | Peptid zur beschleunigung der wirkung des proteins-c mit thrombin |
| US5256770A (en) | 1990-04-09 | 1993-10-26 | Schering Ag | Oxidation resistant thrombomodulin analogs |
| EP0544826B1 (en) | 1990-08-15 | 2002-01-02 | Paion GmbH | Superior thrombomodulin analogs for pharmaceutical use |
| PT641215E (pt) | 1992-02-05 | 2004-09-30 | Paion Gmbh | Analogos de trombomodulina resistentes a proteases |
| WO1993025675A1 (en) * | 1992-06-10 | 1993-12-23 | Schering Aktiengesellschaft | Mutants of the epidermal growth factor domains of human thrombomodulin |
| US6808927B2 (en) | 2001-04-04 | 2004-10-26 | American Diagnostica, Inc. | Method of preparation of stabilized thrombin-activatable fibrinolysis inhibitor (TAFI) and methods of use thereof |
| CA2671863C (en) * | 2006-12-12 | 2015-07-21 | Eli Lilly And Company | Method of treating acute renal failure with thrombomodulin variants |
| EA201270009A1 (ru) * | 2009-06-12 | 2012-07-30 | Пайон Дойчланд Гмбх | Лечение коагулопатии с гиперфибринолизом |
-
2010
- 2010-12-15 WO PCT/EP2010/007632 patent/WO2011157283A1/en not_active Ceased
- 2010-12-15 AU AU2010355558A patent/AU2010355558A1/en not_active Abandoned
- 2010-12-15 CN CN201080068202XA patent/CN103037893A/zh active Pending
- 2010-12-15 CA CA2802072A patent/CA2802072A1/en not_active Abandoned
- 2010-12-15 JP JP2013514555A patent/JP2013531651A/ja active Pending
- 2010-12-15 BR BR112012031920A patent/BR112012031920A2/pt not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BR112012031920A2 (pt) | 2017-05-16 |
| JP2013531651A (ja) | 2013-08-08 |
| CN103037893A (zh) | 2013-04-10 |
| AU2010355558A1 (en) | 2013-01-24 |
| WO2011157283A1 (en) | 2011-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2802072A1 (en) | Treatment of coagulopathy with hyperfibrinolysis | |
| US5374617A (en) | Treatment of bleeding with modified tissue factor in combination with FVIIa | |
| ES2255157T3 (es) | Reactivo de tiempo de protrombina basado en el factor tisular recombinante de conejo. | |
| JP2015110589A (ja) | 安定性が増大した組換え型第ｖｉｉｉ因子 | |
| KR102186924B1 (ko) | 출혈 장애를 치료하기 위한 변형된 세르핀 | |
| JP2010529155A (ja) | 出血性疾患の治療及び予防的処置における血管外投与のためのｖｗｆ安定化ｆｖｉｉｉ製剤及びｆｖｉｉｉなしのｖｗｆ製剤の使用 | |
| AU2017289214A1 (en) | Complement inhibitors and uses thereof | |
| DK2747776T3 (en) | : RELATIONSHIPS TO USE IN INCREASING COAGULATION | |
| JPH09221432A (ja) | フォンビルブラント因子を含む医薬調製物 | |
| JP2005511038A (ja) | 第ｖｉｉｉ因子ｃ２ドメインのバリアント | |
| ES2742898T3 (es) | Composiciones de protrombina humana y factor X activado para mejorar la hemostasia en el tratamiento de trastornos hemorrágicos | |
| US20140256640A1 (en) | Treatment of coagulopathy with hyperfibrinolysis | |
| US20150005238A1 (en) | Treatment of coagulopathy with hyperfibrinolysis | |
| EA037991B1 (ru) | Прогемостатические белки для лечения кровотечений | |
| JP6629744B2 (ja) | 第Ｘａ因子の半減期を延ばす組成物および方法 | |
| CN114828870A (zh) | 用于调节因子viii功能的组合物和方法 | |
| WO2023246680A1 (en) | Activators of coagulation factor x and formulations thereof for treating bleeding disorders | |
| WO2010078469A2 (en) | Sand fly salivary proteins as novel factor xa inhibitors and methods of use | |
| Hilbert et al. | A new candidate mutation, G1629R, in a patient with type 2A von Willebrand's disease: basic mechanisms and clinical implications | |
| Lillicrap | von Willebrand disease | |
| JP2006528965A (ja) | 血友病の治療のための第ＶＩＩＩ因子および第ＩＸａ因子を含む組成物 | |
| Woods et al. | Coagulation factor concentrates for inherited bleeding disorders | |
| WO2017064213A1 (en) | Method and compounds for treatment and prophylaxis of bleeding episodes | |
| BR112016013591B1 (pt) | Serpina modificada, célula recombinante que expressa a serpina, composição farmacêutica compreendendo a serpina e uso da serpina modificada para o tratamento ou prevenção de hemorragia ou para promoção de hemostasia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |
Effective date: 20161215 |