JP2005533003A5 - - Google Patents

Info

Publication number

JP2005533003A5

JP2005533003A5 JP2003575954A JP2003575954A JP2005533003A5 JP 2005533003 A5 JP2005533003 A5 JP 2005533003A5 JP 2003575954 A JP2003575954 A JP 2003575954A JP 2003575954 A JP2003575954 A JP 2003575954A JP 2005533003 A5 JP2005533003 A5 JP 2005533003A5

Authority

JP

Japan

Prior art keywords

copper

patient

use according

diabetes

diabetic

Prior art date

2003-03-10

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.)

Granted

Links

• Espacenet
• Global Dossier
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• 239000010949 copper Substances 0.000 claims description 514
• 229910052802 copper Inorganic materials 0.000 claims description 503
• RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 494
• 206010012601 diabetes mellitus Diseases 0.000 claims description 280
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 131
• 239000002738 chelating agent Substances 0.000 claims description 125
• 210000001519 tissue Anatomy 0.000 claims description 89
• 239000003814 drug Substances 0.000 claims description 88
• 239000003795 chemical substances by application Substances 0.000 claims description 85
• 229940079593 drug Drugs 0.000 claims description 79
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 73
• VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical group NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 70
• 201000010099 disease Diseases 0.000 claims description 67
• 208000035475 disorder Diseases 0.000 claims description 62
• 210000000130 stem cell Anatomy 0.000 claims description 56
• 208000031229 Cardiomyopathies Diseases 0.000 claims description 54
• 238000012544 monitoring process Methods 0.000 claims description 53
• 230000002792 vascular Effects 0.000 claims description 53
• 229960001124 trientine Drugs 0.000 claims description 51
• 210000001367 artery Anatomy 0.000 claims description 50
• 230000017423 tissue regeneration Effects 0.000 claims description 49
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 45
• 239000011701 zinc Substances 0.000 claims description 45
• 150000003751 zinc Chemical class 0.000 claims description 44
• 229910052725 zinc Inorganic materials 0.000 claims description 44
• VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 43
• 208000029078 coronary artery disease Diseases 0.000 claims description 43
• 229960001639 penicillamine Drugs 0.000 claims description 43
• 238000011282 treatment Methods 0.000 claims description 43
• 210000002216 heart Anatomy 0.000 claims description 40
• 229910052742 iron Inorganic materials 0.000 claims description 39
• 206010048858 Ischaemic cardiomyopathy Diseases 0.000 claims description 37
• 206010019280 Heart failures Diseases 0.000 claims description 32
• 210000004204 blood vessel Anatomy 0.000 claims description 29
• 201000001320 Atherosclerosis Diseases 0.000 claims description 28
• 206010020772 Hypertension Diseases 0.000 claims description 28
• 210000004351 coronary vessel Anatomy 0.000 claims description 28
• 230000004153 glucose metabolism Effects 0.000 claims description 28
• 230000036755 cellular response Effects 0.000 claims description 27
• 230000002159 abnormal effect Effects 0.000 claims description 26
• -1 Desferoxamine Chemical compound 0.000 claims description 25
• MDAXKAUIABOHTD-UHFFFAOYSA-N 1,4,8,11-tetraazacyclotetradecane Chemical compound C1CNCCNCCCNCCNC1 MDAXKAUIABOHTD-UHFFFAOYSA-N 0.000 claims description 21
• 210000000709 aorta Anatomy 0.000 claims description 21
• 210000001715 carotid artery Anatomy 0.000 claims description 21
• 210000001105 femoral artery Anatomy 0.000 claims description 21
• 230000000451 tissue damage Effects 0.000 claims description 21
• 231100000827 tissue damage Toxicity 0.000 claims description 21
• 210000003090 iliac artery Anatomy 0.000 claims description 20
• 230000003902 lesion Effects 0.000 claims description 20
• 210000003137 popliteal artery Anatomy 0.000 claims description 20
• 210000002254 renal artery Anatomy 0.000 claims description 20
• 230000000747 cardiac effect Effects 0.000 claims description 19
• 210000003734 kidney Anatomy 0.000 claims description 18
• 210000004165 myocardium Anatomy 0.000 claims description 18
• 210000005036 nerve Anatomy 0.000 claims description 18
• 229910052751 metal Inorganic materials 0.000 claims description 17
• 239000002184 metal Substances 0.000 claims description 17
• UWMHHZFHBCYGCV-UHFFFAOYSA-N 2,3,2-tetramine Chemical compound NCCNCCCNCCN UWMHHZFHBCYGCV-UHFFFAOYSA-N 0.000 claims description 16
• 208000002972 Hepatolenticular Degeneration Diseases 0.000 claims description 16
• 208000018839 Wilson disease Diseases 0.000 claims description 16
• MNNBCKASUFBXCO-YFKPBYRVSA-N N-acetyl-D-penicillamine Chemical compound CC(=O)N[C@@H](C(O)=O)C(C)(C)S MNNBCKASUFBXCO-YFKPBYRVSA-N 0.000 claims description 15
• SSRIAMRLMUFTNV-UHFFFAOYSA-N 2,6-pyridinedicarbothioic acid Chemical compound SC(=O)C1=CC=CC(C(S)=O)=N1 SSRIAMRLMUFTNV-UHFFFAOYSA-N 0.000 claims description 14
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 14
• 239000002253 acid Substances 0.000 claims description 14
• 230000007423 decrease Effects 0.000 claims description 14
• IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 claims description 14
• FGGPAWQCCGEWTJ-UHFFFAOYSA-M sodium;2,3-bis(sulfanyl)propane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CC(S)CS FGGPAWQCCGEWTJ-UHFFFAOYSA-M 0.000 claims description 14
• 150000002739 metals Chemical class 0.000 claims description 13
• 230000002829 reductive effect Effects 0.000 claims description 13
• 150000003839 salts Chemical class 0.000 claims description 13
• 210000001508 eye Anatomy 0.000 claims description 12
• 230000002107 myocardial effect Effects 0.000 claims description 12
• YQUVCSBJEUQKSH-UHFFFAOYSA-N 3,4-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims description 10
• 230000001434 glomerular Effects 0.000 claims description 10
• 230000002207 retinal effect Effects 0.000 claims description 10
• 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 9
• 201000010053 Alcoholic Cardiomyopathy Diseases 0.000 claims description 9
• 206010007637 Cardiomyopathy alcoholic Diseases 0.000 claims description 9
• 206010070909 Metabolic cardiomyopathy Diseases 0.000 claims description 9
• 208000009525 Myocarditis Diseases 0.000 claims description 9
• ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 9
• 239000004246 zinc acetate Substances 0.000 claims description 9
• 102000012437 Copper-Transporting ATPases Human genes 0.000 claims description 8
• 210000003169 central nervous system Anatomy 0.000 claims description 8
• OKHMDSCYUWAQPT-UHFFFAOYSA-N n'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine;tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.NCCNCCNCCN OKHMDSCYUWAQPT-UHFFFAOYSA-N 0.000 claims description 8
• 210000001428 peripheral nervous system Anatomy 0.000 claims description 8
• CXVCSRUYMINUSF-UHFFFAOYSA-N tetrathiomolybdate(2-) Chemical compound [S-][Mo]([S-])(=S)=S CXVCSRUYMINUSF-UHFFFAOYSA-N 0.000 claims description 8
• AGMNQPKGRCRYQP-UHFFFAOYSA-N 2-[2-[2-[bis(carboxymethyl)amino]ethylamino]ethyl-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CCNCCN(CC(O)=O)CC(O)=O AGMNQPKGRCRYQP-UHFFFAOYSA-N 0.000 claims description 7
• WYMDDFRYORANCC-UHFFFAOYSA-N 2-[[3-[bis(carboxymethyl)amino]-2-hydroxypropyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)CN(CC(O)=O)CC(O)=O WYMDDFRYORANCC-UHFFFAOYSA-N 0.000 claims description 7
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 7
• DSRJIHMZAQEUJV-UHFFFAOYSA-N Cuprizon Chemical compound C1CCCCC1=NNC(=O)C(=O)NN=C1CCCCC1 DSRJIHMZAQEUJV-UHFFFAOYSA-N 0.000 claims description 7
• YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 7
• QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 7
• VSWDORGPIHIGNW-UHFFFAOYSA-N Pyrrolidine dithiocarbamic acid Chemical compound SC(=S)N1CCCC1 VSWDORGPIHIGNW-UHFFFAOYSA-N 0.000 claims description 7
• QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims description 7
• LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 7
• UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 claims description 7
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 7
• GIEAQDPIWWODTH-UHFFFAOYSA-N [Na].[Na].[Na].[Ca] Chemical compound [Na].[Na].[Na].[Ca] GIEAQDPIWWODTH-UHFFFAOYSA-N 0.000 claims description 7
• 229940116901 diethyldithiocarbamate Drugs 0.000 claims description 7
• WQABCVAJNWAXTE-UHFFFAOYSA-N dimercaprol Chemical compound OCC(S)CS WQABCVAJNWAXTE-UHFFFAOYSA-N 0.000 claims description 7
• AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 claims description 7
• 230000001976 improved effect Effects 0.000 claims description 7
• DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 7
• 229960003987 melatonin Drugs 0.000 claims description 7
• PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 claims description 7
• WDLWFIMADVGTED-UHFFFAOYSA-N n'-[2-(2-aminoethylamino)ethyl]propane-1,3-diamine;tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.NCCCNCCNCCN WDLWFIMADVGTED-UHFFFAOYSA-N 0.000 claims description 7
• VGICAQBLDJAGSJ-UHFFFAOYSA-N n'-[2-[2-(2-aminoethylamino)ethylamino]ethyl]ethane-1,2-diamine;pentahydrochloride Chemical compound Cl.Cl.Cl.Cl.Cl.NCCNCCNCCNCCN VGICAQBLDJAGSJ-UHFFFAOYSA-N 0.000 claims description 7
• 229960003330 pentetic acid Drugs 0.000 claims description 7
• LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 claims description 7
• ACTRVOBWPAIOHC-XIXRPRMCSA-N succimer Chemical compound OC(=O)[C@@H](S)[C@@H](S)C(O)=O ACTRVOBWPAIOHC-XIXRPRMCSA-N 0.000 claims description 7
• 229960002178 thiamazole Drugs 0.000 claims description 7
• 229960001177 trimetazidine Drugs 0.000 claims description 7
• OBBKVQRWBGOVCF-UHFFFAOYSA-N 1,4,8,11-tetrazabicyclo[6.6.2]hexadecane Chemical compound C1CCNCCN2CCCNCCN1CC2 OBBKVQRWBGOVCF-UHFFFAOYSA-N 0.000 claims description 6
• QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 claims description 6
• JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 6
• JVHROZDXPAUZFK-UHFFFAOYSA-N TETA Chemical compound OC(=O)CN1CCCN(CC(O)=O)CCN(CC(O)=O)CCCN(CC(O)=O)CC1 JVHROZDXPAUZFK-UHFFFAOYSA-N 0.000 claims description 6
• 229960005228 clioquinol Drugs 0.000 claims description 6
• 238000007911 parenteral administration Methods 0.000 claims description 6
• ACTRVOBWPAIOHC-UHFFFAOYSA-N succimer Chemical compound OC(=O)C(S)C(S)C(O)=O ACTRVOBWPAIOHC-UHFFFAOYSA-N 0.000 claims description 6
• FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 claims description 6
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
• 230000002490 cerebral effect Effects 0.000 claims description 5
• 208000007848 Alcoholism Diseases 0.000 claims description 3
• WYHIICXRPHEJKI-UHFFFAOYSA-N Trientine hydrochloride Chemical group Cl.Cl.NCCNCCNCCN WYHIICXRPHEJKI-UHFFFAOYSA-N 0.000 claims description 3
• 201000007930 alcohol dependence Diseases 0.000 claims description 3
• ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 claims description 3
• 229960002408 trientine hydrochloride Drugs 0.000 claims description 3
• 239000011592 zinc chloride Substances 0.000 claims description 3
• 235000005074 zinc chloride Nutrition 0.000 claims description 3
• NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 3
• 229960001763 zinc sulfate Drugs 0.000 claims description 3
• 229910000368 zinc sulfate Inorganic materials 0.000 claims description 3
• WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 claims description 2
• 239000011670 zinc gluconate Substances 0.000 claims description 2
• 229960000306 zinc gluconate Drugs 0.000 claims description 2
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
• 210000000944 nerve tissue Anatomy 0.000 claims 2
• 210000005084 renal tissue Anatomy 0.000 claims 2
• PKMTWMDBJHRDBM-ODZAUARKSA-N (z)-but-2-enedioic acid;zinc Chemical compound [Zn].OC(=O)\C=C/C(O)=O PKMTWMDBJHRDBM-ODZAUARKSA-N 0.000 claims 1
• 210000000653 nervous system Anatomy 0.000 claims 1
• AGGKEGLBGGJEBZ-UHFFFAOYSA-N tetramethylenedisulfotetramine Chemical compound C1N(S2(=O)=O)CN3S(=O)(=O)N1CN2C3 AGGKEGLBGGJEBZ-UHFFFAOYSA-N 0.000 claims 1
• WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 claims 1
• 229960001939 zinc chloride Drugs 0.000 claims 1
• 239000011746 zinc citrate Substances 0.000 claims 1
• 235000006076 zinc citrate Nutrition 0.000 claims 1
• 229940068475 zinc citrate Drugs 0.000 claims 1
• 235000011478 zinc gluconate Nutrition 0.000 claims 1
• GYBLQYIEAGSJPW-UHFFFAOYSA-L zinc;2-oxopentanedioate Chemical compound [Zn+2].[O-]C(=O)CCC(=O)C([O-])=O GYBLQYIEAGSJPW-UHFFFAOYSA-L 0.000 claims 1
• AGFGXVAAIXIOFZ-UHFFFAOYSA-L zinc;butanedioate Chemical compound [Zn+2].[O-]C(=O)CCC([O-])=O AGFGXVAAIXIOFZ-UHFFFAOYSA-L 0.000 claims 1
• 238000000034 method Methods 0.000 description 242
• 208000001072 type 2 diabetes mellitus Diseases 0.000 description 93
• 241001465754 Metazoa Species 0.000 description 69
• 208000002705 Glucose Intolerance Diseases 0.000 description 68
• 238000002560 therapeutic procedure Methods 0.000 description 67
• 201000009104 prediabetes syndrome Diseases 0.000 description 65
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 62
• 150000001875 compounds Chemical class 0.000 description 53
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• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 34
• 241000124008 Mammalia Species 0.000 description 34
• 239000008103 glucose Substances 0.000 description 34
• 239000000203 mixture Substances 0.000 description 32
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• 150000003624 transition metals Chemical class 0.000 description 32
• 102000004877 Insulin Human genes 0.000 description 31
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• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 31
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• RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 26
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• 108010049003 Fibrinogen Proteins 0.000 description 13
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• 230000006378 damage Effects 0.000 description 13
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