CN101460188B - 使用促红细胞生成素的局部缺血疾病的治疗 - Google Patents
使用促红细胞生成素的局部缺血疾病的治疗 Download PDFInfo
- Publication number
- CN101460188B CN101460188B CN2007800209636A CN200780020963A CN101460188B CN 101460188 B CN101460188 B CN 101460188B CN 2007800209636 A CN2007800209636 A CN 2007800209636A CN 200780020963 A CN200780020963 A CN 200780020963A CN 101460188 B CN101460188 B CN 101460188B
- Authority
- CN
- China
- Prior art keywords
- peripheral blood
- erythropoietin
- experimenter
- cell
- epo
- 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.)
- Expired - Fee Related
Links
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 116
- 102000003951 Erythropoietin Human genes 0.000 title claims abstract description 51
- 108090000394 Erythropoietin Proteins 0.000 title claims abstract description 51
- 229940105423 erythropoietin Drugs 0.000 title claims abstract description 51
- 208000023589 ischemic disease Diseases 0.000 title claims abstract description 30
- 210000005259 peripheral blood Anatomy 0.000 claims abstract description 47
- 239000011886 peripheral blood Substances 0.000 claims abstract description 47
- 210000005087 mononuclear cell Anatomy 0.000 claims description 51
- 230000000250 revascularization Effects 0.000 claims description 27
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 abstract description 30
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 abstract description 28
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 abstract description 28
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 abstract description 4
- 208000018262 Peripheral vascular disease Diseases 0.000 abstract description 2
- 210000004204 blood vessel Anatomy 0.000 abstract description 2
- 230000008929 regeneration Effects 0.000 abstract 1
- 238000011069 regeneration method Methods 0.000 abstract 1
- 108010092408 Eosinophil Peroxidase Proteins 0.000 description 64
- 102100031939 Erythropoietin Human genes 0.000 description 64
- 210000004027 cell Anatomy 0.000 description 53
- -1 amino acid modified EPO Chemical class 0.000 description 36
- 210000004369 blood Anatomy 0.000 description 27
- 239000008280 blood Substances 0.000 description 27
- 235000001014 amino acid Nutrition 0.000 description 24
- 150000001413 amino acids Chemical class 0.000 description 22
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 230000002093 peripheral effect Effects 0.000 description 13
- 239000004094 surface-active agent Substances 0.000 description 11
- 230000008859 change Effects 0.000 description 10
- 229920001214 Polysorbate 60 Polymers 0.000 description 9
- 230000033115 angiogenesis Effects 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 125000003275 alpha amino acid group Chemical group 0.000 description 6
- 210000001185 bone marrow Anatomy 0.000 description 6
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 6
- 230000000302 ischemic effect Effects 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000001483 mobilizing effect Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 4
- 206010047115 Vasculitis Diseases 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000002583 angiography Methods 0.000 description 4
- 230000008321 arterial blood flow Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 230000003511 endothelial effect Effects 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 3
- 208000033386 Buerger disease Diseases 0.000 description 3
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 206010047139 Vasoconstriction Diseases 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 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 3
- 102000044890 human EPO Human genes 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000001364 upper extremity Anatomy 0.000 description 3
- 230000025033 vasoconstriction Effects 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010002913 Asialoglycoproteins Proteins 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 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
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 208000003782 Raynaud disease Diseases 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000002617 apheresis Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 239000007766 cera flava Substances 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 210000004976 peripheral blood cell Anatomy 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 210000001778 pluripotent stem cell Anatomy 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- DCBSHORRWZKAKO-UHFFFAOYSA-N rac-1-monomyristoylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)CO DCBSHORRWZKAKO-UHFFFAOYSA-N 0.000 description 2
- 125000005629 sialic acid group Chemical group 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IYSAXDXXJFVLSQ-GASJEMHNSA-N (2R,3S,4R,5R)-1,2,3,4,5,6-hexahydroxyhexane-1-sulfonic acid Chemical compound S(=O)(=O)(O)C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO IYSAXDXXJFVLSQ-GASJEMHNSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- REYLLNRLWCBKCM-YFKPBYRVSA-N (2s)-2-acetamido-4-sulfanylbutanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCS REYLLNRLWCBKCM-YFKPBYRVSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- UUABJBNMBCIBFA-UHFFFAOYSA-N 1-hydroxy-2-(2-hydroxyethoxy)ethanesulfonic acid Chemical compound OCCOCC(O)S(O)(=O)=O UUABJBNMBCIBFA-UHFFFAOYSA-N 0.000 description 1
- QAQJMLQRFWZOBN-UHFFFAOYSA-N 2-(3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl)-2-hydroxyethyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)C1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-UHFFFAOYSA-N 0.000 description 1
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 1
- 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
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 239000004261 Ascorbyl stearate Substances 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101100289995 Caenorhabditis elegans mac-1 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 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
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 206010048858 Ischaemic cardiomyopathy Diseases 0.000 description 1
- 206010069384 Ischaemic nephropathy Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010013709 Leukocyte Common Antigens Proteins 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010029719 Nonspecific reaction Diseases 0.000 description 1
- XHCYBIGJUPTJRR-UHFFFAOYSA-N OC(=O)CC(C(O)=O)S(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O.CCCCCCCCCCCC[Na] XHCYBIGJUPTJRR-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 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
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N anhydrous gallic acid Natural products OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940119744 dextran 40 Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000003013 erythroid precursor cell Anatomy 0.000 description 1
- 230000000913 erythropoietic effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical class CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 210000004524 haematopoietic cell Anatomy 0.000 description 1
- 239000003219 hemolytic agent Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 210000003701 histiocyte Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 201000002818 limb ischemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000003003 monocyte-macrophage precursor cell Anatomy 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002669 organ and tissue protective effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000004206 promonocyte Anatomy 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 235000011083 sodium citrates Nutrition 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- MWZFQMUXPSUDJQ-KVVVOXFISA-M sodium;[(z)-octadec-9-enyl] sulfate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCCOS([O-])(=O)=O MWZFQMUXPSUDJQ-KVVVOXFISA-M 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 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
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001931 thermography Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 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
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
- A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
-
- 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
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/10—Growth factors
- C12N2501/14—Erythropoietin [EPO]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Cell Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Developmental Biology & Embryology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Virology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及一种血管再生的方法,包括以下步骤:(a)向受试者施用促红细胞生成素;(b)从受试者收集外周血单核细胞;和(c)向受试者体内的目标位点施用收集的外周血单核细胞。当向受试者施用促红细胞生成素时,外周血单核细胞(尤其是CD34阳性细胞)被动员进入受试者的外周血中。该方法对于治疗诸如外周血管障碍的局部缺血疾病是有用的。
Description
技术领域
本发明涉及血管再生的方法、治疗局部缺血疾病的方法和用于这些方法的组合物。
背景技术
外周血管障碍是一种疾病,其中,外周组织由于外周动脉血流减少变成局部缺血状态,而外周动脉血流减少由例如血管内腔狭窄、血凝块形成、血管阻塞、血管炎、血管收缩或血粘度增加导致。近年来已经发现,当源自骨髓的单核细胞移植到缺血部位时,增强了血管新生,并且源自骨髓的单核细胞的移植被认为是治疗外周血管障碍的潜在的方法。但是,源自骨髓的单核细胞的移植需要从病人收集骨髓,这给病人增加了实质的负担。
为了减轻病人的负担,已经有人尝试使用源自外周血液的单核细胞代替源自骨髓的单核细胞;但是,由于外周血液中存在的单核细胞数目很少,该方法不能成功地提供有效的治疗。
促红细胞生成素(也称为EPO)是一种酸性糖蛋白激素,其促进红系祖细胞的分化和增殖并主要在肾中产生。红细胞(血液中最大量的细胞)在一定时间段内发挥作用,然后主要在脾中被破坏(在人体内的平均寿命期限是约120天)。正常情况下,通过来自骨髓的连续供应,总的外周红细胞计数得以持续地保持恒定。EPO在体内红细胞的这一动态平衡中发挥了重要作用。在临床情况下,EPO用来治疗贫血和用于手术前后的处理。
另外,已有报导,EPO具有促进血管生成的活性,且作为治疗局部缺血疾病的治疗剂是有效的(Besarab A等人,The New England Journal ofMedicine,339(9),584-590,(1998),Heeschen C等人,Blood,102(4),1340-1346,(2003),Bahlmann F H等人,Blood,103(3),921-926,(2004),Smith K J等人,Cardiovascular Research,(59),538-548,(2003),BahlmannF H等人,Kidney International,64,1648-1652,(2003))。也有报导,EPO促进了血管内皮祖细胞进入外周血液的动员(Heeschen C等人,Blood,102(4),1340-1346,(2003),Bahlmann F H等人,Blood,103(3),921-926,(2004))。
但是,还不清楚,由EPO动员进入外周血液的细胞对于诸如外周血管障碍的局部缺血疾病的治疗是否是有效的。
发明概述
本发明者已经发现,通过施用EPO促进了单核细胞进入外周血液的动员,和如此地由EPO动员的单核细胞对于治疗局部缺血疾病是特别有用的。
本发明提供了动员用于治疗局部缺血疾病或用于刺激血管再生的单核细胞进入外周血液的组合物,其中,该组合物包括作为活性成分的促红细胞生成素。优选地,动员的单核细胞从受试者收集,然后施用给同一受试者。
优选在从受试者收集外周血液之前3-12天向受试者施用本发明的组合物。
本发明也提供了用于治疗局部缺血疾病的组合物和用于刺激血管再生的组合物,包括从预先施用了促红细胞生成素的受试者的外周血液分离的作为活性成分的单核细胞。在这样的组合物中,优选在收集外周血液之前3-12天向受试者施用促红细胞生成素。
本发明也提供了动员用于治疗局部缺血疾病或用于刺激血管再生的CD34阳性细胞进入外周血液的组合物,其包括作为活性成分的促红细胞生成素。
另一方面,本发明提供了用于刺激血管再生和用于治疗局部缺血疾病的单核细胞的制备方法,包括从预先施用了促红细胞生成素的受试者的外周血液分离单核细胞。
另一方面,本发明提供了治疗受试者的局部缺血疾病或刺激血管再生的方法,包括以下步骤:
(a)向受试者施用促红细胞生成素;
(b)从受试者收集外周血单核细胞;和
(c)向受试者的目标位点施用收集的外周血单核细胞。
附图简要说明
图1显示了测量促红细胞生成素动员造血干细胞的FACS分析的结果;
图2显示了由施用促红细胞生成素动员的造血干细胞的集落数目的测量结果;和
图3显示了接受促红细胞生成素的病人(病例3)外周血单核细胞移植一个月后的血管造影照片。
本发明的优选实施方式
促红细胞生成素对外周血单核细胞的动员
本发明的一个方面涉及动员用于治疗局部缺血疾病或用于刺激血管再生的单核细胞进入外周血液的组合物,其中,该组合物包括作为活性成分的促红细胞生成素。术语“‘动员(mobilizing)’单核细胞”和“单核细胞‘的动员(mobilization of)’”表示刺激存在于各种器官中的多能干细胞的分化和增殖,和释放包含多能干细胞的单核细胞进入血液中。为了治疗局部缺血疾病或刺激血管再生,可以从受试者的外周血液收集以这种方式动员的单核细胞并施用于受试者。受试者优选为患有局部缺血疾病的病人或需要血管再生治疗的病人。
本发明对于在收集外周血单核细胞之前向受试者施用促红细胞生成素的剂数没有特别的限制,但一般地为1-3剂。在施用3剂的情况中,例如,第一次促红细胞生成素的施用在收集外周血单核细胞之前约2周对受试者全身性地(例如,皮下或静脉注射)给予。大约一周后,第二次促红细胞生成素的施用在供血(取血)后全身性地给予。再一周后,第三次促红细胞生成素的施用局部地给予,然后可以从受试者的外周血液中收集想要的外周单核细胞。在施用2剂的情况中,例如,第一次促红细胞生成素的施用在收集外周血单核细胞之前约一周对受试者全身性地给予,和第二次促红细胞生成素的施用在大约一周后局部地给予,然后可以从外周血液中收集想要的外周单核细胞。在单次施用的情况中,例如,向受试者全身性地施用促红细胞生成素,并可以在大约一周后收集想要的外周单核细胞。
促红细胞生成素的单位剂量一般地含有1000U/人体-100000U/人体,优选3000U/人体-12000U/人体(例如,6000U/人体)。个体受试者的剂量将由主治医师通过考虑例如受试者的年龄、体重和状态及施用途径的因素来确定。因此,在本发明中促红细胞生成素的剂量不限于上述剂量。
一般地促红细胞生成素通过肠胃外途径施用,例如,可以以注射剂(例如,皮下、静脉、肌肉内或腹膜内)施用或通过跨粘膜、经皮、鼻或肺途径施用。它也可以口服施用。
外周血单核细胞是存在于外周血液中的单核细胞。单核细胞(mononuclear cell),也称为单核细胞(monocyte),是主要存在于血液中并且驻留于分化为巨噬细胞型细胞的阶段中的细胞。造血干细胞在骨髓中分化为成单核细胞和幼单核细胞,然后分化为单核细胞,其被释放进入血液。在迁移进入组织时,单核细胞分化成为,例如,巨噬细胞、树突状细胞和组织细胞。
关于使用EPO动员单核细胞进入外周血液,据认为在施用EPO后需要两周时间以动员单核细胞进入外周血液(Bahlmann F H等人,Blood,103(3),921-926,(2004))。但是,根据本发明发现,在施用EPO后大约一周时间,就动员了足够用于治疗局部缺血疾病或刺激血管再生的量的单核细胞进入外周血液。
因此,本发明涉及获得单核细胞的方法或制备用于移植的单核细胞的方法,包括以下步骤:
(a)向受试者施用促红细胞生成素;和
(b)在施用促红细胞生成素大约一周后,从受试者收集外周血单核细胞。
在本发明的上下文中,短语“大约一周”一般为3-12天,优选5-9天(例如,6-8天或7天)。
另一方面,本发明涉及动员用于治疗局部缺血疾病或刺激血管再生的CD34阳性细胞进入外周血液的组合物,包括作为活性成分的促红细胞生成素。
CD34是血液干细胞(blood stem cell)抗原。它在血液干细胞上表达,也在例如血管内皮细胞、血管内皮祖细胞和基质细胞中表达。由于已知诸如血管内皮祖细胞的CD34阳性细胞参与血管生成,为了获得更好的局部缺血疾病的治疗效果或更好的血管再生效果,需要提高CD34阳性细胞在移植的单核细胞群中的比例。根据本发明的方法动员进入外周血液的单核细胞群一般具有足够获得局部缺血疾病的治疗效果或血管再生效应的CD34阳性细胞效价(titer)。在以治疗局部缺血疾病或刺激血管再生为目的的移植中,通过从由本发明的方法获得的单核细胞群分离或浓缩CD34阳性细胞来提高CD34阳性细胞的比例尤其有利。
在本发明中,在单核细胞中CD34阳性细胞的高比例意味着CD34阳性细胞计数占单核细胞的至少1%,优选至少2%,更优选至少3%。在单核细胞中CD34阳性细胞的比例上限可以是,例如,99.99%、99.9%或99%,且理论上为100%。
根据本发明获得的单核细胞中存在的CD34阳性细胞也可以是CD45阳性的。CD45是白细胞共同抗原,并且是造血类型细胞的关键的膜糖蛋白。
可以通过常见的方法从受试者收集外周血单核细胞。例如,单核细胞可以通过直接回收由血液的血浆分离置换(blood apheresis)得到的血源单核细胞,采用捕捉外周血白细胞必要的离心除去大部分的红细胞、粒细胞和血小板,然后通过例如离心来洗涤获得的外周血白细胞而获得。
以这种方式获得的外周血单核细胞可以任选地通过添加、分离或纯化进行进一步的处理。例如,诸如CD34阳性细胞和/或血管内皮祖细胞的想要的细胞可以进一步由收集的外周血单核细胞浓缩或分离以用于施用。可以使用标准技术来制备基本上纯的CD34阳性细胞。例如,外周血单核细胞与抗CD34抗体反应,然后CD34阳性细胞附着在载有抗小鼠IgG抗体的磁性珠上。用片状磁体收集结合在磁性珠上的CD34阳性细胞反应,随后通过酶处理从磁性珠释放CD34阳性细胞。或者,CD34阳性细胞结合在用荧光染料标记的抗CD34抗体上,并使用荧光细胞分选器收集。
局部缺血疾病的治疗和血管再生
可以将根据本发明制备的外周血单核细胞施用给受试者用于治疗局部缺血疾病的目的。因此,本发明另一方面涉及治疗受试者的局部缺血疾病的方法,包括以下步骤:
(a)向受试者施用促红细胞生成素;
(b)从受试者收集外周血单核细胞;和
(c)向受试者的目标位点施用收集的外周血单核细胞。
局部缺血疾病是一种疾病,其中,组织由于各种因素(如血管内腔狭窄、血凝块形成、血管阻塞、血管炎、血管收缩或血液粘度增加)导致的脉管系统中血流减少而陷入局部缺血状态。局部缺血疾病包括外周血管障碍、缺血性心脏病(例如,缺血性心肌病、心肌梗塞、缺血性心力衰竭)、缺血性脑血管病、缺血性肾病、缺血性肺病和与传染病有关的局部缺血疾病。
外周血管障碍是一种疾病,其中,外周组织由于外周动脉血流减少而陷于局部缺血状态,而外周动脉血流减少由例如血管内腔狭窄、血凝块形成、血管阻塞、血管炎、血管收缩或血液粘度增加导致。与外周血管障碍相关的疾病包括诸如闭塞性动脉硬化和血栓闭塞性脉管炎(Buerger’s disease)的慢性动脉阻塞性疾病,及进行性系统性硬化病、系统性红斑狼疮(systemic erythematosus)、雷诺病(Raynaud’s disease)、振动综合症、动脉瘤和血管炎。外周血管障碍是本发明的治疗剂的优选目标疾病,闭塞性动脉硬化和血栓闭塞性脉管炎为尤其优选的目标。
另外,可以将根据本发明制备的外周血单核细胞施用于受试者来刺激血管再生。因此,本发明另一方面涉及刺激受试者的血管再生的方法,包括以下步骤:
(a)向受试者施用促红细胞生成素;
(b)从受试者收集外周血单核细胞;和
(c)向受试者的目标位点施用收集的外周血单核细胞。
如本文中所用,血管再生表示刺激血管生成和/或血管的生长和发育。本发明的方法可用于刺激任何类型的血管,优选为动脉,尤其优选为外周动脉的新生、生长和发育。可以通过本领域的技术人员已知的技术监测血管再生,例如,使用碱性磷酸酶染料测量毛细血管密度。
如本文中所用,目标位点一般指局部缺血发生的位点和需要血管再生的位点。在外周血单核细胞移植到另一位点导致需要血管再生的位点发生血管再生的情况中,目标位点可以指这样的另一位点。局部施用的位点的特定的例子包括下肢骨骼肌、上肢骨骼肌和心脏(心肌)。
施用或移植到目标位点的所收集的单核细胞的数目没有特别限制,但是一般为1.0×107-1.0×1012个细胞,优选1×109-1×1011个细胞。
局部施用是一种能够将细胞有效施用于受影响的区域而不产生明显的系统性影响的方法。局部施用可以通过使用例如普通注射器、针或定位针来进行。
在向目标位点施用收集的单核细胞时,单核细胞可以单独施用或与另一种物质组合施用。与单核细胞共同施用的物质没有特别的限制,但优选为能够提高血管再生活性的物质。
促红细胞生成素
本发明可以采用任一类型的EPO,但优选高纯度的EPO,也优选具有与哺乳动物的EPO、尤其是人类EPO基本上相同的生物活性的EPO。
本发明中使用的EPO可以通过任一种方法来制备,例如,它可以是通过从人源的提取物进行纯化获得的天然的人类EPO(见,例如,审查过的日本专利申请公开平1-38800号),或者它可以是在大肠杆菌、酵母、中国仓鼠卵巢细胞(CHO细胞)、C127细胞、COS细胞、骨髓瘤细胞、BHK细胞或昆虫细胞中通过基因工程技术产生,然后通过各种方法中的任一种提取、分离和纯化的人类EPO。本发明中使用的EPO优选为通过基因工程技术产生的EPO,且优选为使用哺乳动物细胞(尤其是CHO细胞)产生的EPO(见,例如,审查过的日本专利申请公开平1-44317号,Kenneth Jacobs等人,Nature,313,806-810(1985))。
通过基因重组技术获得的EPO可以具有与天然来源的EPO相同的氨基酸序列,或可以具有与天然来源的EPO相同的生物活性而氨基酸序列具有一个或多个氨基酸的缺失、取代或添加。氨基酸的缺失、取代或添加可以通过本领域内已知的方法引入。例如,本领域的技术人员可以通过使用定点诱变在EPO的氨基酸序列上引入合适的突变来制备与EPO功能相当的多肽(Gotoh,T.等人(1995)Gene 152,271-275;Zoller,M.J.和Smith,M.(1983)Methods Enzymol.100,468-500;Kramer,W.等人(1984)Nucleic Acids Res.12,9441-9456;Kramer,W.和Fritz,H.J.(1987)Methods Enzymol.154,350-367;Kunkel,T.A.(1985)Proc.Natl.Acad.Sci.USA.82,488-492;Kunkel(1988)Methods Enzymol.85,2763-2766)。氨基酸突变也可能自然地产生。一般地,氨基酸残基优选使用具有类似的氨基酸侧链性质的另一氨基酸残基取代。氨基酸侧链的性质包括,例如,疏水氨基酸(A、I、L、M、F、P、W、Y、V)、亲水氨基酸(R、D、N、C、E、Q、G、H、K、S、T)、具有脂族侧链的氨基酸(G、A、V、L、I、P)、具有羟基功能侧链的氨基酸(S、T、Y)、具有含硫侧链的氨基酸(C、M)、具有含羧酸或含酰胺侧链的氨基酸(D、N、E、Q)、具有含碱基侧链的氨基酸(R、K、H)和具有芳香侧链的氨基酸(H、F、Y、W)(括号中给出氨基酸的单字母代号)。已知具有由一个或多个氨基酸残基的缺失、添加或取代导致的经修饰氨基酸序列的多肽保留其生物活性(Mark,D.F.等人,Proc.Natl.Acad.Sci.USA(1984)81,5662-5666;Zoller,M.J.& Smith,M.Nucleic AcidsResearch(1982)10,6487-6500;Wang,A.等人,Science 224,1431-1433;Dalbadie-McFarland,G.等人,Proc.Natl.Acad.Sci.USA(1982)79,6409-6413)。
也可以使用EPO与另一种蛋白质的融合蛋白质。例如,融合蛋白质可以通过在框架中将编码EPO的DNA编码另一种蛋白质的DNA连接,将DNA插入表达载体,表达载体随之在宿主中表达而构建。对与本发明的EPO融合的另一种蛋白质没有特别限制。
本发明也可以使用化学修饰的EPO。化学修饰的EPO包括连接到例如聚乙二醇或维生素B12的无机或有机化合物上的EPO。本发明中使用的EPO也可以是EPO衍生物。
如本文中所用,EPO衍生物指在EPO分子中具有氨基酸修饰的EPO,或在EPO分子中具有糖链修饰的EPO。EPO分子中的糖链修饰包括糖链的添加、取代或缺失。本发明中优选的糖链修饰是从EPO分子中除去唾液酸。
所获得的由重组动物细胞产生的EPO或源自尿的EPO一般是包含具有不同糖链结构的各种类型EPO的EPO组合物。连接于EPO组合物中EPO分子上的唾液酸的数目将随EPO分子发生变化,但一般地,11-15个唾液酸连接在各单个EPO分子上。可以通过除去唾液酸制备非唾液酸化(asialylated)的EPO(asialo-EPO)。对非唾液酸化过程中除去的唾液酸的数目没有特别限制;可以除去所有的唾液酸,或者可以除去1、2、3、4、5、6、7、8、9、10、11、12、13或14个唾液酸。优选用于本发明的asialo-EPO含有不超过10个连接在EPO分子上的唾液酸,更优选不超过5个,和尤其优选不超过2个。这里提到的唾液酸的数目指包含在EPO组合物中的EPO分子上的唾液酸的平均数目。每分子的平均唾液酸可以通过本领域的技术人员已知的方法来测量(见,例如,EP0428267)。
已经除去唾液酸的EPO(asialo-EPO)可以通过本领域的技术人员已知的方法产生。例如,可以通过使用诸如唾液酸酶的酶对EPO进行处理来制备。可商购得到的唾液酸酶可用于此目的(见,例如,翻译版本2005-507426号的国家公布;Nobuo Imai等人,Eur.J.Biochem.194,457-462(1990))。
在EPO分子中的氨基酸修饰的例子包括氨基甲酰化、生物素化、脒基化(amidination)、乙酰化和胍基化(guanidination)。氨基甲酰化是本发明优选的氨基酸修饰方式。
对进行修饰的氨基酸残基没有特别的限制,且可以包括赖氨酸、精氨酸、谷氨酸和色氨酸。赖氨酸是本发明优选的修饰氨基酸。
因此,含有氨基甲酰化的赖氨酸的EPO是本发明中氨基酸修饰的EPO的特别优选的实施方式(见,例如,Marcel L.等人,Derivatives ofErythropoietin that are tissue protective but not erythropoietic.Science,2004;305:239;Fiordaliso E.等人,A nonerythropoietic derivative oferythropoietin protects the myocardium from ischemia-reperfusion injury.PNAS,2005;102:2046)。EPO氨基甲酰化的方法包括,例如,通过与氰酸盐离子反应的氨基甲酰化、通过与烷基异氰酸酯反应的烷基氨基甲酰化和通过与芳香基异氰酸酯反应的芳香基氨基甲酰化。
药物制剂
可以根据本领域内已知的技术通过适当地加入,例如,悬浮剂、增溶剂、稳定剂、等渗剂(isotonizer)、防腐剂、吸附抑制剂、表面活性剂、稀释剂、赋形剂、pH调节剂、安抚剂、缓冲剂、含硫还原剂、抗氧化剂等将EPO制成制剂。
悬浮剂包括甲基纤维素、聚山梨酯80、羟乙基纤维素、阿拉伯胶、黄蓍胶粉末、羧甲基纤维素钠和聚氧乙烯山梨聚糖单月桂酸酯。
增溶剂包括聚氧乙烯氢化蓖麻油、聚山梨酯80、烟酰胺、聚氧乙烯山梨聚糖单月桂酸酯、聚乙二醇和蓖麻油脂肪酸的乙基酯。
稳定剂包括右旋糖酐40、甲基纤维素、明胶、亚硫酸钠和焦亚硫酸钠。
也可以加入特定的氨基酸作为稳定剂(见,例如,日本专利申请公开平10-182481)。加入作为稳定剂的氨基酸包括,例如,游离氨基酸及其盐(如钠盐、钾盐和盐酸盐)。可以加入单一的氨基酸或者两种或多种氨基酸的组合。对作为稳定剂添加的氨基酸没有特别的限制,但这方面的优选氨基酸为,例如,亮氨酸、色氨酸、丝氨酸、谷氨酸、精氨酸、组氨酸和赖氨酸。
等渗剂包括D-甘露醇和山梨醇。
防腐剂包括对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、山梨酸、苯酚、甲酚和氯甲酚。
吸附抑制剂包括人血清白蛋白、卵磷脂、右旋糖酐、环氧乙烷-环氧丙烷共聚物、羧丙基纤维素、甲基纤维素、聚氧乙烯氢化蓖麻油和聚乙二醇。
表面活性剂的代表性的例子为非离子表面活性剂,例如,具有6-18的HLB的非离子表面活性剂,例如,诸如山梨聚糖单辛酸酯、山梨聚糖单月桂酸酯和山梨聚糖单棕榈酸酯的山梨聚糖脂肪酸酯,诸如甘油单辛酸酯、甘油单肉豆蔻酸酯和甘油单硬脂酸酯的甘油脂肪酸酯,诸如十甘油单硬脂酸酯、十甘油二硬脂酸酯和十甘油单亚油酸酯的聚甘油脂肪酸酯,诸如聚氧乙烯山梨聚糖单月桂酸酯、聚氧乙烯山梨聚糖单油酸酯、聚氧乙烯山梨聚糖单硬脂酸酯、聚氧乙烯山梨聚糖单棕榈酸酯、聚氧乙烯山梨聚糖三油酸酯和聚氧乙烯山梨聚糖三硬脂酸酯的聚氧乙烯山梨聚糖脂肪酸酯,诸如聚氧乙烯山梨聚糖四硬脂酸酯和聚氧乙烯山梨聚糖四油酸酯的聚氧乙烯山梨聚糖脂肪酸酯,诸如聚氧乙烯甘油单硬脂酸酯的聚氧乙烯甘油脂肪酸酯,诸如聚乙二醇二硬脂酸酯的聚乙二醇脂肪酸酯,诸如聚氧乙烯月桂基醚的聚氧乙烯烷基醚,诸如聚氧乙烯-聚氧丙烯乙二醇、聚氧乙烯-聚氧丙烯丙醚和聚氧乙烯-聚氧丙烯十六烷基醚的聚氧乙烯-聚氧丙烯烷基醚,诸如聚氧乙烯壬基苯基醚的聚氧乙烯烷基苯基醚,聚氧乙烯蓖麻油和聚氧乙烯硬化蓖麻油(聚氧乙烯氢化蓖麻油),诸如聚氧乙烯山梨醇蜂蜡的聚氧乙烯/蜂蜡衍生物,诸如聚氧乙烯羊毛脂的聚氧乙烯/羊毛脂衍生物,和诸如聚氧乙烯硬脂酰胺的聚氧乙烯脂肪酸酰胺。另外的表面活性剂的代表性的例子为阴离子表面活性剂,例如,诸如十六烷基硫酸钠、月桂基硫酸钠和油烯基硫酸钠的具有C10-18烷基的烷基硫酸盐,诸如聚氧乙烯月桂基硫酸钠的具有平均2-4摩尔的环氧乙烷加入和具有C10-18烷基的聚氧乙烯烷基醚硫酸盐,和诸如月桂基磺基丁二酸钠的具有C8-18烷基的烷基磺基丁二酸盐。另外的表面活性剂的代表性的例子为天然的表面活性剂,例如,卵磷脂、甘油磷脂、诸如神经鞘磷脂的鞘磷脂和与C12-18脂肪酸的蔗糖脂肪酸酯。这些表面活性剂中的单个表面活性剂或这些表面活性剂中的两种或多种的组合可以添加到本发明的制剂中。诸如聚山梨酯20、40、60和80的聚氧乙烯山梨聚糖脂肪酸酯是优选的表面活性剂,尤其优选聚山梨酯20和80。诸如泊洛沙姆(例如,Pluronic F-68(注册商标))的聚氧乙烯-聚氧丙烯乙二醇也是优选的。
含硫还原剂包括诸如N-乙酰半胱氨酸、N-乙酰高半胱氨酸、硫代乳酸、硫代二甘醇、硫代乙醇胺、硫代甘油、硫代山梨醇、硫代乙醇酸(thioglycol acid)和其盐、硫代硫酸钠、谷胱甘肽和C1-7硫代链烷酸的含巯基的还原剂。
抗氧化剂包括异抗坏血酸、二丁基羟基甲苯、丁基羟基苯甲醚、α-生育酚、醋酸生育酚、L-抗坏血酸及其盐、L-抗坏血酸棕榈酸酯、L-抗坏血酸硬脂酸酯、亚硫酸氢钠、亚硫酸钠、没食子酸三戊酯和没食子酸丙酯,及诸如乙二胺四乙酸二钠(EDTA)、焦磷酸钠和偏磷酸钠的螯合剂。
可以适当地加入的组分还包括诸如氯化钠、氯化钾、氯化钙、磷酸钠、磷酸钾和碳酸氢钠的无机盐,和诸如柠檬酸钠、柠檬酸钾和醋酸钠的有机盐。
在本申请的说明书中清楚地引用的所有专利和参考文献的内容将完整引入本文作为参考。另外,作为本申请的优先权要求的基础的日本专利申请2006-158998的说明书和附图的内容完整引入本文作为参考。
通过下面的实施例详细描述本发明,但本发明并不受这些实施例的限制。
实施例1
EPO对造血细胞的动员
向小鼠(C57BL/6,鼠龄:9周)皮下施用重组人EPO(Epogin(注册商标)),一天一次,以100μg/kg/天的剂量施用4天。向对照小鼠类似地皮下施用单独的载体。第5天,处死小鼠,收集外周血细胞(0.6-1mL)。加入0.01M的Tris-HCl缓冲液(pH7.5±0.2)中的含有8.3g/L的氯化铵的红细胞溶解缓冲液(SIGMA)作为溶血剂,并在室温下静置5-10分钟,然后用2% BSF+PBS(-)洗涤。以1μg/106细胞的量加入CD16/CD32(Fcγ III/II受体)非特异性的反应抑制抗体(reaction blocking antibody)(BD-Pharmingen,San Diego,CA),并在冰上保持30分钟。FITC-偶联的抗-mSca-1抗体(BD Pharmingen,San Diego,CA)、PE-偶联的抗-mCD34抗体、APC-偶联的抗-mc-Kit抗体(BD Pharmingen,San Diego,CA)和APC-Cy7-偶联的抗-mCD3、CD4、CD8a、CD45R/B220、Ly6G(Gr-1)、CD11b(Mac-1α链)和Ter119抗体的混合物用作谱系标志物(lineage marker)。抗体染色后,通过FACSvantage SE(Becton Dickinson,Mountain View,CA)分析细胞。
图1显示了分析结果。如图1的R3所示,通过施用EPO,c-Kit+Sca-1+Lin-细胞的数目增加大约13倍。c-Kit+Sca-1+Lin-细胞是小鼠中的CFU-S-样细胞的标志物(见,例如,Blood,1992 Dec.15;80(12):3044-50)。以上报告的结果表明通过施用EPO将CFU-S-样细胞动员进入外周血液。
CFU-S集落分析
来自已经皮下施用EPO5天的C57/b6小鼠的外周血细胞用作供体细胞。104-105细胞/100-200μL的供体细胞通过受体C57/b6小鼠的尾静脉进行移植,受体C57/b6小鼠已经使用放射性照射装置(Hitachi Medico)接受了致死剂量的γ-辐射(来自137Cs的950cGy)。在移植后8-12天切除脾,并通过Bouin’s染色分析脾的集落(在脾中形成的集落的数目)。
图2显示了与FACS分析的结果一致的分析结果,观察到了CFU-S-样细胞进入外周血液的动员。
实施例2
通过外周血液单核细胞移植的血管生成治疗
本研究设计为调查是否能够通过施用促红细胞生成素制剂在5个患有严重肢缺血疾病的病人中动员造血干细胞进入外周血液中。还进行了通过外周单核细胞的自身移植进行血管生成治疗的临床研究。临床研究的总体设计采用开放性的研究方案。
在计划的细胞移植之前两周,病人通过皮下注射接受6000U的EPO(第一次施用)。在细胞移植前一周,为了自体供血的目的而取血(约400mL),并皮下注射接受6000U的EPO(第二次施用)。在手术日的早上,注射6000U的EPO(第三次施用),然后通过血液的血浆分离置换法从外周血液中分离大约109的外周单核细胞。在施用EPO之前、在第二次施用之后和正好在血浆分离置换之前收集外周血液样本,并进行血液检测(WBC、CRP、CK)和CD34阳性细胞计数。
在50-100个位点将分离的外周单核细胞注射到病人的局部缺血的一个或多个肢体的肌肉中。在细胞移植前、施用后的一天、一周后、两周后、1月后、2月后和6月后,基于观察和对于下面项目的测量来评价血管生成治疗的效果:
QOL:以视觉模拟评分法(VAS)评价疼痛,0为不痛,10为最强疼痛
血样采集
血液检测
血管造影术
踏板试验:以2.4千米/小时、水平条件测量绝对行走距离或疼痛出现距离
皮肤和溃疡损伤的客观评价:踝肱指数(ABPI)、指(趾)容积描记法、踏板试验(走动能力)、温度记录法、激光多普勒血流灌注成像仪(LDPI)和透皮氧分压(TdPO2)测量
CD34阳性细胞的改变
下面的表1给出了病例、移植细胞计数和CD34阳性细胞计数的总结。在施用促红细胞生成素之前的值标准化为100%,则在第一次施用促红细胞生成素一周之后抽取血液时,外周血液中的CD34阳性细胞的比例显示出82-245%(平均为158%)的增长。在再一周后正好在血浆分离置换之前,增长率为88-175%(平均为139%)。这些结果表明在第一次施用促红细胞生成素后一周,CD34阳性细胞计数(在放血过程中)与两周后(正好在血浆分离置换之前)的细胞计数一样或更大。
CD34阳性细胞占通过血液的血浆分离置换回收的单核细胞的0.02-0.1%(平均为0.06%)。
表1.
病例 | 性别 | 年龄 | 病因 | 移植位点 | 移植细胞总数 | CD34阳性细胞 |
1 | 男 | 77 | 闭塞性动脉硬化 | 右下肢 | 0.5×109 | 0.1×106(0.2×104细胞/kg) |
2 | 男 | 66 | 闭塞性动脉硬化 | 左下肢 | 16.7×109 | 5.0×106(8×104细胞/kg) |
3 | 男 | 48 | 血栓闭塞性脉管炎 | 双上肢 | 9.2×109 | 9.2×106(14×104细胞/kg) |
4 | 男 | 48 | 血栓闭塞性脉管炎 | 右上肢 | 6.9×109 | 5.5×106(9×104细胞/kg) |
细胞移植的临床评价
主观症状和血管造影术的评价
表2.
病例 | 观察期 | 情况 | VAS | Fontatine分级 | 血管造影 |
1 | 11月 | 麻木、静息痛 | 7→7 | III→II | 没有改变 |
2 | 3月 | 麻木、静息痛 | 2→0 | III→II | 没有改变 |
3 | 3月 | 溃疡 | 6→3 | 不可分级 | — |
4 | 1周 | 溃疡 | 3→1 | 不可分级 | 没有进行 |
从主观角度,4个病例中的3个观察到疼痛的改善。
另外,移植1个月后,在病例3的血管造影中观察到血管再生(图3)。
客观评价
表3.
病例 | 观察期 | ABPI | 指(趾)容积描记 | 温谱图 | LDPI | TdPO2 |
1 | 11月 | 0.24→0.4 | 改善 | 中度改善 | 没有改变 | 没有改变 |
2 | 3月 | 0.49→0.66 | 改善 | 没有改变 | 没有改变 | 没有改变 |
3 | 3月 | 没有进行 | 改善 | 中度改善 | 中度改善 | 改善 |
4 | 1周 | 没有进行 | 改善 | 没有进行 | 没有进行 | 没有进行 |
在某些病例中注意到了ABPI和TdPO2的改善。病例2中看到在踏板试验中行走距离从160m到915m的明显改善。
上述结果表明可以通过施用促红细胞生成素动员造血干细胞进入外周血液,和通过将外周单核细胞移植到局部缺血的骨骼肌中的血管生成疗法来治疗外周闭塞性动脉疾病。
而且,在第一次施用EPO一周后回收的外周血单核细胞中CD34阳性细胞的含量等于或高于两周后回收的单核细胞中的CD34阳性细胞含量,这表明在施用EPO一周后回收的单核细胞能够提供等于或大于两周后回收的单核细胞的血管生成的治疗效果。
工业实用性
本发明的方法和组合物对于治疗诸如外周血管障碍的局部缺血疾病是有用的。
Claims (6)
1.促红细胞生成素与单核细胞联合用于制备治疗局部缺血疾病的药物的用途,其中所述促红细胞生成素用于动员单核细胞进入外周血液,且其中所述单核细胞从施用促红细胞生成素后3-12天的受试者的外周血液收集。
2.促红细胞生成素与单核细胞联合用于制备刺激血管再生的药物的用途,其中所述促红细胞生成素用于动员单核细胞进入外周血液,且其中所述单核细胞从施用促红细胞生成素后3-12天的受试者的外周血液收集。
3.从预先施用了促红细胞生成素的受试者的外周血液分离的单核细胞用于制备用于移植以治疗局部缺血疾病的药物的用途,其中红细胞生成素在从受试者收集外周血液之前3-12天施用。
4.从预先施用了促红细胞生成素的受试者的外周血液分离的单核细胞用于制备用于移植以刺激血管再生的药物的用途,,其中红细胞生成素在从受试者收集外周血液之前3-12天施用。
5.促红细胞生成素用于制备用于移植以治疗局部缺血疾病的药物的用途,其中促红细胞生成素在从受试者收集外周血液之前3-12天向受试者施用,其中外周血单核细胞从受试者收集,和其中收集的外周血单核细胞向受试者的目标位点施用。
6.促红细胞生成素用于制备用于移植以刺激受试者血管再生的药物的用途,其中促红细胞生成素在从受试者收集外周血液之前3-12天向受试者施用,其中外周血单核细胞从受试者收集,和其中收集的外周血单核细胞向受试者的目标位点施用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP158998/2006 | 2006-06-07 | ||
JP2006158998 | 2006-06-07 | ||
PCT/JP2007/061525 WO2007142288A1 (ja) | 2006-06-07 | 2007-06-07 | エリスロポエチンを用いた虚血性疾患の治療 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101460188A CN101460188A (zh) | 2009-06-17 |
CN101460188B true CN101460188B (zh) | 2013-09-04 |
Family
ID=38801534
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2007800209636A Expired - Fee Related CN101460188B (zh) | 2006-06-07 | 2007-06-07 | 使用促红细胞生成素的局部缺血疾病的治疗 |
Country Status (17)
Country | Link |
---|---|
US (1) | US20090280094A1 (zh) |
EP (1) | EP2047859A4 (zh) |
JP (2) | JP5326079B2 (zh) |
KR (1) | KR20090031547A (zh) |
CN (1) | CN101460188B (zh) |
AR (1) | AR061269A1 (zh) |
AU (1) | AU2007255717B2 (zh) |
BR (1) | BRPI0712063A2 (zh) |
CA (1) | CA2654154A1 (zh) |
HK (1) | HK1128419A1 (zh) |
IL (1) | IL195648A0 (zh) |
MX (1) | MX2008015392A (zh) |
NO (1) | NO20085098L (zh) |
NZ (1) | NZ573792A (zh) |
RU (1) | RU2008152746A (zh) |
TW (1) | TW200815026A (zh) |
WO (1) | WO2007142288A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0712063A2 (pt) * | 2006-06-07 | 2011-12-20 | Chugai Pharmaceutical Co Ltd | tratamento de doenças isquêmicas usando eritropoietina |
DK3150701T3 (en) | 2009-06-05 | 2019-01-14 | Fujifilm Cellular Dynamics Inc | REPROGRAMMING T-CELLS AND HEMATOPOIETIC CELLS |
FR2957799B1 (fr) * | 2010-03-26 | 2012-08-17 | Inst Des Vaisseaux Et Du Sang | Compositions proangiogeniques, leur procede de preparation et leurs utilisations |
CN101940594B (zh) * | 2010-08-27 | 2013-12-04 | 上海士腾生物技术有限公司 | 用于治疗缺血性心血管疾病的制剂及其制备方法 |
CN101940590B (zh) * | 2010-08-27 | 2013-09-18 | 上海士腾生物技术有限公司 | 促进创伤愈合的制剂及其制备方法 |
JP5582983B2 (ja) * | 2010-11-24 | 2014-09-03 | 楠本化成株式会社 | 水系沈降防止剤 |
US10130660B2 (en) | 2013-06-05 | 2018-11-20 | Seoul National University R&Db Foundation | Peripheral blood stem cells with improved angiogenic properties and use thereof |
DE102017116204B4 (de) | 2017-07-18 | 2024-06-27 | Universität Rostock | Verfahren zur Vorhersage der Antwort auf die kardiovaskuläre Regeneration |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004087063A2 (en) * | 2003-03-27 | 2004-10-14 | Janssen Pharmaceutica Nv | Use of erythropoietin in stroke recovery |
CN1764470A (zh) * | 2003-03-27 | 2006-04-26 | 詹森药业有限公司 | 促红细胞生成素在中风康复中的用途 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62501010A (ja) | 1984-12-04 | 1987-04-23 | ジェネティックス・インスチチュ−ト・インコ−ポレ−テッド | エリトロポエチンの生産方法 |
US4677195A (en) | 1985-01-11 | 1987-06-30 | Genetics Institute, Inc. | Method for the purification of erythropoietin and erythropoietin compositions |
KR100221066B1 (ko) | 1989-10-13 | 1999-10-01 | 스튜어트 엘.왓트 | 에리트로포이에틴 유사체와 그를 포함하는 제약학적 조성물 |
TWI240627B (en) | 1996-04-26 | 2005-10-01 | Chugai Pharmaceutical Co Ltd | Erythropoietin solution preparation |
DE19857609A1 (de) * | 1998-12-14 | 2000-06-15 | Hannelore Ehrenreich | Verwendung von Erythropoietin zur Behandlung von cerebralen Ischämien des Menschen |
JP4583029B2 (ja) | 2001-10-29 | 2010-11-17 | クルセル ホランド ベー ヴェー | 所定の翻訳後修飾を有する蛋白質の製造方法及び製造手段 |
US6784154B2 (en) * | 2001-11-01 | 2004-08-31 | University Of Utah Research Foundation | Method of use of erythropoietin to treat ischemic acute renal failure |
US20040009908A1 (en) * | 2002-07-10 | 2004-01-15 | Stamler Jonathan S. | Methods for treating or preventing ischemic injury |
DE10234192B4 (de) * | 2002-07-26 | 2009-11-26 | Epoplus Gmbh Co.Kg | Verwendung von Erythropoetin |
US20050058622A1 (en) * | 2002-12-06 | 2005-03-17 | Lyman Stewart D. | Methods of using Flt3-Ligand in hematopoietic cell transplantation procedures incorporating nonmyeloablative conditioning regimens |
US20040198663A1 (en) * | 2003-04-04 | 2004-10-07 | Baker John E. | Method of treating cardiac ischemia by using erythropoietin |
DE102004004509B4 (de) * | 2004-01-23 | 2010-07-01 | Epoplus Gmbh Co.Kg | Einsatz von niedrig dosiertem Erythropoietin zur Stimulation endothelialer Vorläuferzellen sowie zur Organregeneration und Progressionsverlangsamung von Endorganschäden |
JP2007217283A (ja) * | 2004-03-30 | 2007-08-30 | Niigata Tlo:Kk | 血管新生促進剤および血管新生療法 |
JP2006158998A (ja) | 2004-12-02 | 2006-06-22 | Nippon Sheet Glass Co Ltd | ロッドの反り選別装置 |
HUE035655T2 (en) * | 2005-08-05 | 2018-05-28 | Araim Pharmaceuticals Inc | Tissue protective peptides and their use |
BRPI0712063A2 (pt) * | 2006-06-07 | 2011-12-20 | Chugai Pharmaceutical Co Ltd | tratamento de doenças isquêmicas usando eritropoietina |
-
2007
- 2007-06-07 BR BRPI0712063-0A patent/BRPI0712063A2/pt not_active IP Right Cessation
- 2007-06-07 JP JP2008520614A patent/JP5326079B2/ja active Active
- 2007-06-07 CA CA002654154A patent/CA2654154A1/en not_active Abandoned
- 2007-06-07 US US12/303,669 patent/US20090280094A1/en not_active Abandoned
- 2007-06-07 WO PCT/JP2007/061525 patent/WO2007142288A1/ja active Application Filing
- 2007-06-07 NZ NZ573792A patent/NZ573792A/en not_active IP Right Cessation
- 2007-06-07 KR KR1020097000110A patent/KR20090031547A/ko not_active Application Discontinuation
- 2007-06-07 MX MX2008015392A patent/MX2008015392A/es active IP Right Grant
- 2007-06-07 TW TW096120549A patent/TW200815026A/zh unknown
- 2007-06-07 AU AU2007255717A patent/AU2007255717B2/en not_active Ceased
- 2007-06-07 AR ARP070102478A patent/AR061269A1/es not_active Application Discontinuation
- 2007-06-07 EP EP07744855A patent/EP2047859A4/en not_active Withdrawn
- 2007-06-07 CN CN2007800209636A patent/CN101460188B/zh not_active Expired - Fee Related
- 2007-06-07 RU RU2008152746/15A patent/RU2008152746A/ru not_active Application Discontinuation
-
2008
- 2008-12-02 IL IL195648A patent/IL195648A0/en unknown
- 2008-12-08 NO NO20085098A patent/NO20085098L/no not_active Application Discontinuation
-
2009
- 2009-08-20 HK HK09107647.3A patent/HK1128419A1/xx not_active IP Right Cessation
-
2013
- 2013-03-15 JP JP2013054102A patent/JP2013116919A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004087063A2 (en) * | 2003-03-27 | 2004-10-14 | Janssen Pharmaceutica Nv | Use of erythropoietin in stroke recovery |
CN1764470A (zh) * | 2003-03-27 | 2006-04-26 | 詹森药业有限公司 | 促红细胞生成素在中风康复中的用途 |
Non-Patent Citations (4)
Title |
---|
Endothelial progenitor cell proliferation and differeniation is regulated by erythropoietin Rapid Communication;Ferdinand H Bahlmann等;《Kidney International, Nature》;20031101;第64卷(第5期);1468-1452 * |
Ferdinand H Bahlmann等.Endothelial progenitor cell proliferation and differeniation is regulated by erythropoietin Rapid Communication.《Kidney International, Nature》.2003,第64卷(第5期),1468-1452. |
LosordoDouglasW等.Therapeuticangiogenesisandvasculogenesisforischemicdisease.PartI angiogenic cytokines.《Circulation》.2004 |
Therapeutic angiogenesis and vasculogenesis for ischemic disease.Part I,angiogenic cytokines;Losordo Douglas W等;《Circulation》;20040601;第109卷(第21期);1524-4539 * |
Also Published As
Publication number | Publication date |
---|---|
IL195648A0 (en) | 2011-08-01 |
CA2654154A1 (en) | 2007-12-13 |
AU2007255717A1 (en) | 2007-12-13 |
WO2007142288A1 (ja) | 2007-12-13 |
JP2013116919A (ja) | 2013-06-13 |
BRPI0712063A2 (pt) | 2011-12-20 |
MX2008015392A (es) | 2009-05-05 |
JP5326079B2 (ja) | 2013-10-30 |
US20090280094A1 (en) | 2009-11-12 |
HK1128419A1 (en) | 2009-10-30 |
RU2008152746A (ru) | 2010-07-20 |
EP2047859A1 (en) | 2009-04-15 |
KR20090031547A (ko) | 2009-03-26 |
AR061269A1 (es) | 2008-08-13 |
NZ573792A (en) | 2011-09-30 |
JPWO2007142288A1 (ja) | 2009-10-29 |
EP2047859A4 (en) | 2010-05-05 |
NO20085098L (no) | 2009-02-27 |
CN101460188A (zh) | 2009-06-17 |
AU2007255717B2 (en) | 2013-07-11 |
TW200815026A (en) | 2008-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101460188B (zh) | 使用促红细胞生成素的局部缺血疾病的治疗 | |
Scheven et al. | In vitro osteoclast generation from different bone marrow fractions, including a highly enriched haematopoietic stem cell population | |
US7863043B2 (en) | Stem cell populations and methods of use | |
EP0831888B1 (en) | Methods for increasing hematopoietic cells | |
WO2007136673A2 (en) | Treatment of disc degenerative disease and compositions for same | |
CN101848991A (zh) | 分离的细胞群 | |
Horak et al. | Evaluation of mesenchymal stem cell therapy for sepsis: a randomized controlled porcine study | |
US20220031743A1 (en) | Transplantation of mitochondria into lymphoid organ and composition therefor | |
CN106470676A (zh) | 用于非细胞毒性干细胞移植的方法和组合物 | |
Brzóska et al. | Participation of stem cells from human cord blood in skeletal muscle regeneration of SCID mice | |
WO2004100972A1 (ja) | 組織破壊を伴う疾患の予防及び/または治療剤 | |
Kidd et al. | In vivo expansion of the megakaryocyte progenitor cell population in adult CD26-deficient mice | |
CN102580058B (zh) | 含有epo衍生物的血液相关疾病的治疗剂 | |
CN108728393B (zh) | Vcam-1+单核细胞及其衍生细胞在促进造血干细胞归巢的应用 | |
KR20060107745A (ko) | G-csf 를 함유하는 선유아세포 동원제 및 창상 치료제 | |
JPH08127539A (ja) | ヒトil−11を含有する末梢血幹細胞増加剤 | |
AU780468B2 (en) | Method for enhancing hematopoiesis | |
Douer et al. | High-Dose Chemotherapy and Autologous Bone Marrow Plus Peripheral Blood Stem Cell Transplantation for Patients with Lymphoma or Metastatic Breast Cancer: Use of Marker Genes to Investigate Hematopoietic Reconstitution in Adults. University of Southern California, Norris Cancer Center, Los Angeles, California | |
KR20240034745A (ko) | 동물의 골관절염 치료용 중간엽 줄기세포 | |
Ghalie et al. | Sequential transplants using mobilized peripheral blood progenitor cells | |
Buckle et al. | Assays for macrophage inflammatory proteins | |
KR20040044436A (ko) | 혈구생성의 자극제로서 골 형성 성장 올리고펩티드 | |
MXPA97009244A (en) | Methods to increase hematopoyeti cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1128419 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1128419 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130904 Termination date: 20140607 |
|
EXPY | Termination of patent right or utility model |