JP2018521132A - 組織損傷の治療に有用な医薬組成物 - Google Patents
組織損傷の治療に有用な医薬組成物 Download PDFInfo
- Publication number
- JP2018521132A JP2018521132A JP2018521490A JP2018521490A JP2018521132A JP 2018521132 A JP2018521132 A JP 2018521132A JP 2018521490 A JP2018521490 A JP 2018521490A JP 2018521490 A JP2018521490 A JP 2018521490A JP 2018521132 A JP2018521132 A JP 2018521132A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- day
- amd3100
- tissue damage
- tacrolimus
- 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.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 134
- 230000000451 tissue damage Effects 0.000 title claims abstract description 63
- 231100000827 tissue damage Toxicity 0.000 title claims abstract description 63
- 238000011282 treatment Methods 0.000 title abstract description 50
- 210000000130 stem cell Anatomy 0.000 claims abstract description 144
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 76
- 229940125721 immunosuppressive agent Drugs 0.000 claims abstract description 54
- 239000003446 ligand Substances 0.000 claims abstract description 53
- 230000001483 mobilizing effect Effects 0.000 claims abstract description 43
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 42
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 41
- 239000000203 mixture Substances 0.000 claims abstract description 37
- 108091008324 binding proteins Proteins 0.000 claims abstract description 17
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 124
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 111
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 claims description 108
- 229960002169 plerixafor Drugs 0.000 claims description 102
- 208000027418 Wounds and injury Diseases 0.000 claims description 86
- 229960001967 tacrolimus Drugs 0.000 claims description 84
- 206010052428 Wound Diseases 0.000 claims description 73
- 238000000034 method Methods 0.000 claims description 61
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 33
- 208000020431 spinal cord injury Diseases 0.000 claims description 30
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 claims description 27
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 claims description 27
- 238000002054 transplantation Methods 0.000 claims description 27
- 208000023275 Autoimmune disease Diseases 0.000 claims description 21
- 210000000056 organ Anatomy 0.000 claims description 17
- 102000023732 binding proteins Human genes 0.000 claims description 16
- 239000002576 chemokine receptor CXCR4 antagonist Substances 0.000 claims description 15
- 229940121384 cxc chemokine receptor type 4 (cxcr4) antagonist Drugs 0.000 claims description 15
- 208000027866 inflammatory disease Diseases 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- 206010062016 Immunosuppression Diseases 0.000 claims description 13
- 238000010254 subcutaneous injection Methods 0.000 claims description 13
- 239000007929 subcutaneous injection Substances 0.000 claims description 13
- 206010009887 colitis Diseases 0.000 claims description 12
- 230000001363 autoimmune Effects 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 8
- QLVSJMZJSABWRX-UHFFFAOYSA-N 2-[4-[6-amino-2-[[4-[[3-(cyclohexylamino)propylamino]methyl]cyclohexyl]methylamino]pyrimidin-4-yl]piperazin-1-yl]ethylphosphonic acid Chemical compound N=1C(N)=CC(N2CCN(CCP(O)(O)=O)CC2)=NC=1NCC(CC1)CCC1CNCCCNC1CCCCC1 QLVSJMZJSABWRX-UHFFFAOYSA-N 0.000 claims description 7
- CWJJHESJXJQCJA-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)-1-[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methanamine Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CNCC1=CC=CC=N1 CWJJHESJXJQCJA-UHFFFAOYSA-N 0.000 claims description 7
- 208000011231 Crohn disease Diseases 0.000 claims description 6
- 206010056340 Diabetic ulcer Diseases 0.000 claims description 4
- 238000003745 diagnosis Methods 0.000 claims description 4
- UNSKIISCJFJWTL-WIDVRGBZSA-N meridamycin Chemical compound C1C(O)C(C)C(O)CC(O)CC(O)\C(C)=C\C(C)CC(C)C(O)C(/CC)=C/CC(C(\C)=C\C(C)C(C)O)OC(=O)C2CCCN2C(=O)C(=O)C2(O)C(C)CCC1O2 UNSKIISCJFJWTL-WIDVRGBZSA-N 0.000 claims description 4
- DGKUOWHAUIWQTM-UHFFFAOYSA-N meridamycin Natural products C1C(O)C(C)C(O)CC(O)CC(O)C(C)=CC(C)CC(C)C(O)C(CC)=CCC(C(C)=CC(C)C(C)O)OC(=O)C2CCCCN2C(=O)C(=O)C2(O)C(C)CCC1O2 DGKUOWHAUIWQTM-UHFFFAOYSA-N 0.000 claims description 4
- 238000010255 intramuscular injection Methods 0.000 claims description 3
- 239000007927 intramuscular injection Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 abstract description 21
- 102000014914 Carrier Proteins Human genes 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 49
- 239000011780 sodium chloride Substances 0.000 description 46
- 241000699670 Mus sp. Species 0.000 description 41
- 241001465754 Metazoa Species 0.000 description 31
- 239000003814 drug Substances 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 28
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 28
- 241000700159 Rattus Species 0.000 description 27
- 210000003491 skin Anatomy 0.000 description 23
- 230000006378 damage Effects 0.000 description 22
- 206010012601 diabetes mellitus Diseases 0.000 description 22
- 230000035876 healing Effects 0.000 description 22
- 229940079593 drug Drugs 0.000 description 21
- 229960003444 immunosuppressant agent Drugs 0.000 description 19
- 230000001861 immunosuppressant effect Effects 0.000 description 18
- 230000029663 wound healing Effects 0.000 description 15
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 14
- 229940109239 creatinine Drugs 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000011284 combination treatment Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 208000014674 injury Diseases 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 241000282412 Homo Species 0.000 description 11
- 210000001185 bone marrow Anatomy 0.000 description 11
- 210000003734 kidney Anatomy 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 241000282887 Suidae Species 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 239000011550 stock solution Substances 0.000 description 9
- 238000007920 subcutaneous administration Methods 0.000 description 9
- 238000001356 surgical procedure Methods 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 241000282898 Sus scrofa Species 0.000 description 8
- 230000007850 degeneration Effects 0.000 description 8
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- 230000002195 synergetic effect Effects 0.000 description 8
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 7
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 238000002648 combination therapy Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000007918 intramuscular administration Methods 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 7
- 210000005259 peripheral blood Anatomy 0.000 description 7
- 239000011886 peripheral blood Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 208000028389 Nerve injury Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 150000001720 carbohydrates Chemical class 0.000 description 6
- 235000014633 carbohydrates Nutrition 0.000 description 6
- 230000002354 daily effect Effects 0.000 description 6
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 6
- 230000001976 improved effect Effects 0.000 description 6
- 230000008764 nerve damage Effects 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 6
- 230000036573 scar formation Effects 0.000 description 6
- 229960002930 sirolimus Drugs 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 201000003126 Anuria Diseases 0.000 description 5
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 5
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 5
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 230000003907 kidney function Effects 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000002062 proliferating effect Effects 0.000 description 5
- 230000007115 recruitment Effects 0.000 description 5
- 230000001172 regenerating effect Effects 0.000 description 5
- 230000008929 regeneration Effects 0.000 description 5
- 238000011069 regeneration method Methods 0.000 description 5
- 210000000278 spinal cord Anatomy 0.000 description 5
- 230000002269 spontaneous effect Effects 0.000 description 5
- 208000034656 Contusions Diseases 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 208000008960 Diabetic foot Diseases 0.000 description 4
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 206010056677 Nerve degeneration Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000001574 biopsy Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 208000034526 bruise Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000001332 colony forming effect Effects 0.000 description 4
- 239000003246 corticosteroid Substances 0.000 description 4
- 229960001334 corticosteroids Drugs 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 210000003414 extremity Anatomy 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 210000002429 large intestine Anatomy 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- JJVZSYKFCOBILL-MKMRYRNGSA-N motixafortide Chemical group NCCCC[C@@H]1NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H]2CCCN2C(=O)[C@H](CCCCN)NC1=O)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)c1ccc(F)cc1 JJVZSYKFCOBILL-MKMRYRNGSA-N 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 231100000241 scar Toxicity 0.000 description 4
- 230000036560 skin regeneration Effects 0.000 description 4
- -1 506BD Chemical compound 0.000 description 3
- 108010072524 BKT140 Proteins 0.000 description 3
- 108010061299 CXCR4 Receptors Proteins 0.000 description 3
- 102000012000 CXCR4 Receptors Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 208000003790 Foot Ulcer Diseases 0.000 description 3
- 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 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 3
- 208000004210 Pressure Ulcer Diseases 0.000 description 3
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 229960002170 azathioprine Drugs 0.000 description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000009266 disease activity Effects 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 229960002706 gusperimus Drugs 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 3
- 244000309715 mini pig Species 0.000 description 3
- 230000007659 motor function Effects 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 3
- 229960004866 mycophenolate mofetil Drugs 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 210000001778 pluripotent stem cell Anatomy 0.000 description 3
- 229940072288 prograf Drugs 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001568 sexual effect Effects 0.000 description 3
- 210000002536 stromal cell Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IDINUJSAMVOPCM-UHFFFAOYSA-N 15-Deoxyspergualin Natural products NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 206010011985 Decubitus ulcer Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- 229920000855 Fucoidan Polymers 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 102000000646 Interleukin-3 Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 208000034693 Laceration Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 206010028116 Mucosal inflammation Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 229940083963 Peptide antagonist Drugs 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 208000026137 Soft tissue injury Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241001647839 Streptomyces tsukubensis Species 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 238000002266 amputation Methods 0.000 description 2
- ZDQSOHOQTUFQEM-PKUCKEGBSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-PKUCKEGBSA-N 0.000 description 2
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004534 cecum Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940047120 colony stimulating factors Drugs 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 230000008508 epithelial proliferation Effects 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- SWZTYAVBMYWFGS-UHFFFAOYSA-N fingolimod hydrochloride Chemical compound Cl.CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 SWZTYAVBMYWFGS-UHFFFAOYSA-N 0.000 description 2
- 230000003325 follicular Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 208000035861 hematochezia Diseases 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 229940076264 interleukin-3 Drugs 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960000681 leflunomide Drugs 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- 230000001400 myeloablative effect Effects 0.000 description 2
- IDINUJSAMVOPCM-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-INIZCTEOSA-N 0.000 description 2
- 238000013188 needle biopsy Methods 0.000 description 2
- 238000013059 nephrectomy Methods 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 208000015891 sexual disease Diseases 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000009168 stem cell therapy Methods 0.000 description 2
- 238000009580 stem-cell therapy Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000011277 treatment modality Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- MDAXKAUIABOHTD-UHFFFAOYSA-N 1,4,8,11-tetraazacyclotetradecane Chemical group C1CNCCNCCCNCCNC1 MDAXKAUIABOHTD-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 description 1
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 1
- 108010060188 4-fluorobenzoyl-TN-14003 Proteins 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100036850 C-C motif chemokine 23 Human genes 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 108010048913 CTCE-0214 Proteins 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 229940122739 Calcineurin inhibitor Drugs 0.000 description 1
- 101710192106 Calcineurin-binding protein cabin-1 Proteins 0.000 description 1
- 102100024123 Calcineurin-binding protein cabin-1 Human genes 0.000 description 1
- 102000004173 Cathepsin G Human genes 0.000 description 1
- 108090000617 Cathepsin G Proteins 0.000 description 1
- 102000004171 Cathepsin K Human genes 0.000 description 1
- 108090000625 Cathepsin K Proteins 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 description 1
- 101710087078 Dipeptidyl peptidase 1 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000004452 Fucus evanescens Species 0.000 description 1
- YPINZEGNLULHHT-UHFFFAOYSA-N Fujimycin Natural products COC1CC(CCC1O)C=C(/C)C2OC(=O)C3CCCCCN3C(=O)C(=O)C4(O)OC(C(CC4C)OC)C(OC)C(C)CC(=CC(CC=C)C(=O)CC(O)C2C)C YPINZEGNLULHHT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 1
- 101000713081 Homo sapiens C-C motif chemokine 23 Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 1
- GRSZFWQUAKGDAV-KQYNXXCUSA-N IMP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-KQYNXXCUSA-N 0.000 description 1
- 108010041012 Integrin alpha4 Proteins 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102100026019 Interleukin-6 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Natural products C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 1
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- 210000004322 M2 macrophage Anatomy 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 101710111747 Peptidyl-prolyl cis-trans isomerase FKBP12 Proteins 0.000 description 1
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 1
- 101710111682 Peptidyl-prolyl cis-trans isomerase FKBP1A Proteins 0.000 description 1
- 102000009658 Peptidylprolyl Isomerase Human genes 0.000 description 1
- 108010020062 Peptidylprolyl Isomerase Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 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
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 229960002616 ancestim Drugs 0.000 description 1
- 108700024685 ancestim Proteins 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000003975 animal breeding Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000001494 anti-thymocyte effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 229960004669 basiliximab Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940064804 betadine Drugs 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 229950000814 burixafor Drugs 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000013354 cell banking Methods 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 229940107810 cellcept Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 230000008951 colonic inflammation Effects 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 101150080418 ddp-1 gene Proteins 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000005081 epithelial layer Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- ZNOLGFHPUIJIMJ-UHFFFAOYSA-N fenitrothion Chemical compound COP(=S)(OC)OC1=CC=C([N+]([O-])=O)C(C)=C1 ZNOLGFHPUIJIMJ-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 102000054766 genetic haplotypes Human genes 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 230000003661 hair follicle regeneration Effects 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 235000013902 inosinic acid Nutrition 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940074383 interleukin-11 Drugs 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006609 metabolic stress Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000009525 mild injury Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- 229950000844 mizoribine Drugs 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 229940074923 mozobil Drugs 0.000 description 1
- 210000002894 multi-fate stem cell Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- BLUYEPLOXLPVCJ-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxyethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC[C@H](O)NC(=O)CCCCCCNC(N)=N BLUYEPLOXLPVCJ-INIZCTEOSA-N 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229940029345 neupogen Drugs 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000030786 positive chemotaxis Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229940112971 protopic Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229940099538 rapamune Drugs 0.000 description 1
- 201000010727 rectal prolapse Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940063122 sandimmune Drugs 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000037152 sensory function Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000037851 severe atopic dermatitis Diseases 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 244000000000 soil microbiome Species 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000001032 spinal nerve Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 230000003878 venous anastomosis Effects 0.000 description 1
- 108010057559 voclosporin Proteins 0.000 description 1
- PCAKWSFRPYRIOO-ZZZSXDPUSA-N way-124466 Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1CC(C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@@](O)([C@H](C)C[C@@H]2OC)O[C@@H]2C[C@H](OC)/C(C)=C/C(N2C(N(C=3C=CC=CC=3)C(=O)N32)=O)C=CC3[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@@H](O)/C(C)=C/[C@@H](C)C(=O)C1 PCAKWSFRPYRIOO-ZZZSXDPUSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000001325 yolk sac Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
AF併用剤注射剤
試薬:AMD3100及びタクロリムス(粉末)をSigma-Aldrich (St. Louis, MO)から入手した。
タクロリムス製剤:タクロリムス粉末の疎水性及び水溶液(例えば、生理食塩水)中のその溶解度が低いため、タクロリムス粉末を100%エタノール(全容量の8%)、ヒマシ油(総容量の2%)、及び注射用滅菌生理食塩水(全容量の90%)の混合液中に溶解した。タクロリムスは、C44H69NO12・H2Oの実験式と822.03の式量を有する。
AMD3100製剤:24mgのAMD3100を5.9mgの塩化ナトリウムを含む滅菌水に溶解し、必要に応じて塩酸及び水酸化ナトリウムを用いてpH6.0〜7.5に調整した。AMD3100の分子量は502.79g/molである。
AF併用剤:約1:10から1:100のタクロリムス対AMD3100の重量比に従って、可溶化されたタクロリムスをAMD3100溶液に加えた。例えば、0.2mg/0.2mlのFK506を20mg/0.8mlのAMD3100に添加して、20mgのAMD3100と0.2mgのFK506を含む1mlの組成物を作製した。体重60kgの患者では、AMD3100の投与量は約0.24mg/kg/日であり、従って14.4mgのAMD3100と0.144mgのタクロリムスを含む組成物0.72mlが患者に投与される(0.0024mg/kg)。
造血性コロニー形成細胞(CFC)アッセイは、細胞試料の造血前駆細胞含有量を定量及び評価する方法として、ヒト及び動物モデルにおける研究及び臨床応用に広範に使用されている。幹細胞動員活性は、動員された末梢血試料中のCFCアッセイを用いて測定することができる。CFCは分裂し、光学顕微鏡で検出可能なより成熟した細胞のコロニーに分化することができる。これは、薬剤により動員された多能性幹細胞系統の定量化を可能にする。
幹細胞療法は、火傷創治癒の質を改善し、瘢痕の形成を低下させ、皮膚を再建することができる。高価で時間がかかる、熱傷を治療するための内因性幹細胞の調製の必要性を避けるために、この試験は、AF併用剤により内因性骨髄幹細胞が薬理学的に動員されて火傷を治療することができることを示す。
FK506粉末(Sigma)とAMD3100粉末(Sigma)(いずれも、溶液の調製に使用する前は、−20℃で保存した)から、AF併用薬物組成物(AMD3100+FK506)を調製した。最終的に調製した溶液(組成物Iと組成物II;下記参照)を、使用するまで4℃で保存した。
組成物I(ラット及びマウスなどのげっ歯類に使用):
FK506
ストック溶液(12mg/ml)=120mgのFK粉末+5mlの95%EtOH+5mlのクレマフォア(Cremaphor)
FK溶液(0.6mg/ml)=1mlのFKストック溶液+19mlのリン酸緩衝化生理食塩水(PBS)
AMD3100
ストック溶液(12mg/ml)=120mgのAMD3100粉末+10mlのH2O(2.5〜3mgの塩化ナトリウムを含み、必要に応じて塩酸及び水酸化ナトリウムを用いてでpH6.0〜7.5に調整)
AMD3100溶液(1.2mg/ml)=1mlのAMD3100溶液+9mlのPBS
AF併用剤(AMD3100 1mg/ml;FK506 0.1mg/ml)=10mlのAMD3100溶液+2mlのFK506溶液=12mgのAMD3100+1.2mgのFK506/12ml=1mgのAMD3100+0.1mgのFK506/ml。AMD3100/FK506比=10/1。
ストック溶液:室温(1.0mlバイアルにアリコートした)
ラット及びマウスへの投与:1ml/kg
ラットへの投与(1ml/kg):与えた容量(ml)=体重(g)×1ml/1000g。例えば、250gのラットに0.25mlの皮下注射を行う。
組成物II(ブタなどの大型動物に使用):
FK506
ストック溶液(12mg/ml)=120mgのFK粉末+5mlの95%EtOH+5mlのクレマフォア
FK溶液(6mg/ml)=10mlのFKストック溶液+10mlのPBS
AMD3100
ストック溶液(22mg/ml)=2200mgのAMD3100粉末+100mlのH2O
AF併用剤(AMD3100 1mg/ml;FK506 0.21mg/ml)=90mlのAMD3100ストック溶液+10mlのFK506溶液=1980mgのAMD3100+60mgのFK506/100ml。AMD3100/FK506比=33/1。
ブタへの投与:0.05ml/kg:与えた容量(ml)=体重(kg)×0.05ml/1kg。例えば、50kgのブタに2.5mlの皮下注射を行う。
糖尿病性潰瘍を治療するための本医薬組成物及び方法の有用性を証明するために、糖尿病のラットモデルを用いて以下の試験を行った。
高齢者の創傷治癒障害は大きな臨床的問題である。高齢のマウスモデルにおける創傷の治療により、高齢のヒトにおける創傷治癒を増強するための本発明の組成物と方法の有用性を示すために、以下の試験を行った。後述するようにAF併用剤は、高齢マウスの創傷治癒の質を改善し、創傷引張強度を上昇させた。
IBDを治療する際の本組成物及び方法の有用性は、ヒトIBDのマウスモデルにおいて証明された。
DSS−大腸炎の誘発のために3%デキストラン硫酸ナトリウム(DSS)(7日間)を使用した。マウスをランダムに2つの実験群に分け、1日目から9日目まで、生理食塩水又はAF併用剤(AMD3100 1mg/kgと低用量FK506 0.1mg/kg、1日おき)の皮下注射を行った。10日目に、AF併用剤治療マウスと比較して生理食塩水治療したマウスにおいて、血便と軟便(図9A)及びより短い大腸と拡大した盲腸(図9B)が観察された。組織学的分析は、生理食塩水で治療したマウスの固有層/粘膜において陰窩の消失、破壊、又は短縮、及び炎症細胞の見かけの浸潤を示した(図9C)。対照的に、AF併用剤で治療したDSSマウスでは、顕著な腸上皮表面損傷又は表面上皮細胞の消失は観察されなかった。生理食塩水で治療したマウス(対照)の疾患活動度指数(DAI)は徐々に増加し、DSS除去の1日後の8日目にピークに達した(図10)。しかしながら、AF併用剤で治療したマウスでは、DAIは7日目まで増加しなかった。対照マウスと比較してAF併用剤治療マウスでは、DAIはほとんど50%低かった(図10)。CD133+幹細胞及びKi67+増殖細胞を、生理食塩水対照及びAF治療マウスからの大腸の粘膜において、二重免疫蛍光染色法により測定した。7日間のDSS治療により、大腸陰窩に損傷が生じ(図9C)、陰窩の下部のCD133+幹細胞及びKi67+増殖細胞の数が減少した(図11、左パネル;明るい染色)。しかしながら、CD133+幹細胞とKi67+増殖細胞及び陰窩組織像は、AF併用剤治療したマウスで大きく回復した(図11、右パネル;明るい染色、及び図9C)。
使用した動物施設の条件下で、C57BL/6 IL−10KOマウスは3〜4カ月齢の間に自発性大腸炎(IBD)を発症した。IBDを有する動物を、AF併用剤(n=7)又は生理食塩水(対照)で1日おきに3週間治療し、治療の1週間後に殺処分した。生理食塩水で治療したマウスの大腸の肉眼的及び組織学的検査は、中程度から重度の大腸炎及び陰窩の分岐を伴う上皮過形成を示した(図12Aと12B)。AF併用剤で治療したマウスは、野生型対照と同様に、最小の炎症を示した(図12C)。
SCIの治療のための本発明の組成物及び方法の有用性を、以下のように証明した。SCIの臨床的に関連した打撲ラットモデルは、軽度の損傷を模倣するために12.5mmの高さからの荷重落下を用いて作製した。損傷を受けたラットをランダムに3群に分け、1日目から29日目まで又は5日目から29日目まで、生理食塩水、AF併用剤を皮下注射した(皮下注射、1日おき)。Basso, Beattie and Bresnahan 運動機能評価スケール(BBBスコア)の平均を使用して、関節の動き、後肢の動き、足踏み、四肢の協調、胴体の位置、足の配置、及び尾の位置を評価した。ラット群のBBBスコア間の統計的差を分析して、SCIからの回復を評価した。このデータは、AF併用剤が、SCIの1日後と5日後に治療を受けた打撲ラットのBBBスケールを有意に改善し得ることを示した(図13)。12.5mmの打撲損傷に予想されるように、空洞の形成が治療群(図14A)と対照群(図14B)で見られた。しかしながら、AF併用剤で治療した脊髄中の空洞は、対照群の空洞よりも形成が不充分であった。すなわち対照は、より顕著な空洞を示し、これは中央管に沿って中心点からさらに伸びていた。群間の面積測定値は、対照群(図14C)と比較してAF併用剤治療群は空洞サイズの約3倍の有意な減少を示したが、これは、AF併用剤による治療が、このレベルの打撲損傷について通常予測される神経変性の進行を制限することを示している。これらの結果は、AF併用剤による自己由来幹細胞の薬理学的動員が、脊髄修復/再生を促進し、脊髄損傷における機能回復を促進することを示す。
大きな全層創傷及び軟部組織損傷を治療するための本発明の医薬組成物及び方法の有用性を、以下の試験により証明された。分割厚さの皮膚同種移植片を移植した全層切除創を、マサチューセッツ総合病院(Massachusetts General Hospital, Boston, MA)の移植生物学研究センター(Transplantation Biology Research Center)から得たミニブタで行った。移植ブタを、皮膚移植直後及び1日おきに6週間、AF併用剤で治療した。図15に示すように、皮膚同種移植片は移植後4週間以内に徐々に拒絶され、創傷床は新たに生成された組織で満たされた。新たに生成された組織は、赤紫色の上皮のような薄い膜で覆われていた。半透明で薄い赤紫色の皮膚は、7週間後にピンクがかった赤色に変化し、移植後12週間で毛髪を伴う正常な皮膚になった。これらの結果は、AF併用剤治療によりインサイチュ皮膚再生が誘発され、自己由来幹細胞を同種移植部位に動員し採し、皮膚同種移植片が組織の幹細胞再生の足場として機能することを示す。
臓器移植拒絶反応を予防し臓器移植レシピエントにおける長期生存を促進するための本発明の医薬組成物及び方法の有用性を、マサチューセッツ総合病院群のミニブタの完全な主要組織適合性遺伝子座(ブタ白血球抗原[ブタ白血球抗原[SLA])ミスマッチにわたって実施された腎臓移植の以下の試験により証明した。
SLAで同定されたドナーブタ及びレシピエントブタ(体重50〜80kg)は、マサチューセッツ総合病院(Boston, MA)の移植生物学研究センターから入手した。これらのブタの免疫原性の特徴は既に記載されている(30)。2ハプロタイプの完全MHCクラスI及びクラスIIミスマッチドナー及びレシピエントを腎臓移植に使用した。全てのレシピエントは、臓器移植前に顕著なインビトロ抗ドナー細胞傷害アッセイ応答(>20%の特異的溶解)を示した。この試験については、治験審査委員会(動物実験委員会(Animal Care and Use Committee))の承認が得られた。全ての動物飼育及び治療は、国立医学研究会(National Society of Medical Research )により企画された「実験動物管理の原則」(“Principles of Laboratory Animal Care”)、及び米国研究会議の米国実験動物資源協会 (Institute of Laboratory Animal Resources, National Research Council)が準備した「実験動物のケア及び使用のためのガイド」(“Guide for the Care and Use of Laboratory Animals”)に従っており、全米アカデミー出版局(National Academies Press)により公表され、2011年に改訂された。
腎臓移植に使用された外科的操作は、Kirkman RL, et al. Transplantation in miniature swine. VI. Factors influencing survival of renal allografts. Transplantation 1979; 28: 18-23に記載されており、その全開示内容は参照により本明細書に組み込まれる。簡単に述べると、ドナー腎臓をフラッシュし、冷生理食塩水で3〜6時間維持した後、再灌流した。レシピエントに両側腎切除術を行った。大動脈及び下大静脈を、腎動脈及び静脈の終末側動脈及び静脈吻合に用いた。腎臓移植は、膀胱尿細管吻合により行った。Silastic中心静脈留置カテーテルを、外科的に外頸静脈又は内頸静脈に配置した。カテーテルは、インビトロアッセイ及び腎機能と全血タクロリムスレベルのモニタリングのための頻繁な血液サンプリングを容易にした。
腎機能は、連続した血清クレアチニンレベルにより監視された。血清クレアチニン及び血中尿素窒素レベルは、Johns HopkinsのPhenotyping Laboratory of the Department of Comparative Medicineで分析された。生検は、開放型又は経皮的超音波誘導法によるコア針生検を用いて移植レシピエントに対して実施した。腎臓同種移植片拒絶は、血清クレアチニンの10mg/dL超までの持続的上昇又は無尿症(ブタ血清クレアチニンについての正常な検査値は1〜3mg/dL)と定義された。同種移植拒絶反応は、全ての症例において組織学的に確認された。
腎臓同種移植片について、コア針生検又はウェッジ生検を行った。急性拒絶反応のスコア化は、バンフ分類(Solez K, et al. Banff 07 classification of renal allograft pathology: Updates and future directions. Am J Transplant 2008; 8: 753-760を参照)(その全開示内容は参照により本明細書に組み込まれる)に基づくものであった。マッソントリクローム染色は、標準的なプロトコールに従って行った。
AF併用剤の予想外の相乗効果は、以下のようにさらに証明された。8〜12週齢の雄ルイスラットをイソフルランで麻酔した。背部の皮膚を剃毛し、ベタジンと70%エタノールで洗浄した。4つの切除創を、正中線の両側の1cm、肋骨縁と腸骨稜の中間点の上下1cmに配置し、ペンでマークした。滅菌使い捨て生検パンチ(直径5mm、Miltex)をマークの中心に縦に整列させ、同時に圧力及びねじりを加えて、皮膚及び皮筋層を打ち抜いた。同じ操作を繰り返し、各動物に4つの創傷を生じさせた。動物が意識を取り戻した後、1匹ずつ収容した。
Claims (33)
- (a)少なくとも1種の幹細胞動員物質;(b)少なくとも1種の免疫抑制剤;及び(c)医薬的に許容し得る担体を含む医薬組成物。
- 医薬組成物が、皮下注射又は筋肉内注射用に製剤化される、請求項1に記載の医薬組成物。
- 少なくとも1種の幹細胞動員物質がCXCR4アンタゴニストを含む、請求項1に記載の医薬組成物。
- CXCR4アンタゴニストが、AMD3100、TG−0054、又はAMD3465を含む、請求項3に記載の医薬組成物。
- CXCR4アンタゴニストがAMD3100を含む、請求項4に記載の医薬組成物。
- 少なくとも1種の免疫抑制剤がFK結合タンパク質リガンドを含む、請求項1に記載の医薬組成物。
- 少なくとも1種の免疫抑制剤がタクロリムスを含む、請求項1に記載の医薬組成物。
- タクロリムスが、免疫抑制のための正常な用量の約1/10で存在する、請求項7に記載の医薬組成物。
- 少なくとも1種の免疫抑制剤がタクロリムスを含み、少なくとも1種の幹細胞動員物質がAMD3100を含む、請求項1に記載の医薬組成物。
- タクロリムスとAMD3100とが約1/10〜約1/100の比率で存在する、請求項9に記載の医薬組成物。
- (a)タクロリムス;(b)AMD3100;及び(c)医薬的に許容し得る担体を含む医薬組成物であって、タクロリムスとAMD3100とが約1/10〜約1/100の比率で存在する医薬組成物。
- 医薬組成物が皮下注射用に製剤化される、請求項11に記載の医薬組成物。
- (a)タクロリムス;(b)AMD3100;及び(c)医薬的に許容し得る担体からなる医薬組成物であって、タクロリムスとAMD3100とが約1/10〜約1/100の比率で存在し、医薬組成物が皮下注射用に製剤化される医薬組成物。
- (a)タクロリムス;及び(b)AMD3100から本質的になる医薬組成物であって、タクロリムスとAMD3100とが約1/10〜約1/100の比率で存在し、医薬組成物が筋肉内注射用に製剤化される医薬組成物。
- (a)CXCR4アンタゴニスト、及び(b)FK結合タンパク質リガンドを含む医薬組成物。
- FK結合タンパク質リガンドが、タクロリムス又はその類似体、メリダマイシン又はFKBPの合成リガンド(SLF)を含む、請求項15に記載の医薬組成物。
- CXCR4アンタゴニストが、AMD3100、TG−0054、又はAMD3465を含む、請求項15に記載の医薬組成物。
- 医薬組成物が、タクロリムスとAMD3100の実質的に同時の投与のために製剤化される、請求項1〜17のいずれか1項に記載の医薬組成物。
- 請求項1〜17のいずれか1項に記載の医薬組成物を投与する工程を含む、患者の組織損傷を治療する方法。
- 組織損傷が、火傷、創傷、臓器移植、脊髄損傷、及び自己免疫疾患若しくは炎症性疾患のうちの1つを含む、請求項19に記載の方法。
- 自己免疫性又は炎症性疾患がIBDである、請求項20に記載の方法。
- IBDが大腸炎又はクローン病として現れる、請求項21に記載の方法。
- 創傷が糖尿病性潰瘍である、請求項20に記載の方法。
- 医薬組成物が、皮下、経口的、筋肉内、静脈内、又は腹腔内投与される、請求項19に記載の方法。
- 医薬組成物が1日おきに投与される、請求項19に記載の方法。
- 医薬組成物が、組織損傷が発生したか又は観察された日と同じ日に投与される、請求項19に記載の方法。
- 対象の組織損傷を治療する方法であって、対象に請求項1〜17のいずれか1項に記載の医薬組成物を、組織損傷が発生したか又は観察された日に1回以上投与する工程、組織損傷が発生したか又は観察された日の約1ヵ月後に1回以上投与する工程、組織損傷が発生したか又は観察された日の約2ヵ月後に1回以上投与する工程、及び組織損傷が発生したか又は観察された日の約3ヵ月後に1回以上投与する工程を含む方法。
- 医薬組成物が、経口的、筋肉内、静脈内、又は腹腔内投与される、請求項27に記載の方法。
- 組織損傷が、臓器移植、火傷、創傷、自己免疫性又は炎症性疾患の診断、及び自己免疫性又は炎症性疾患のエピソードの発生からなる群から選択される、請求項27に記載の方法。
- 自己免疫性又は炎症性疾患がIBDである、請求項29に記載の方法。
- IBDが、大腸炎又はクローン病として現れる、請求項30に記載の方法。
- 創傷が糖尿病性潰瘍である、請求項29に記載の方法。
- 請求項27に記載の方法であって、
(a)組織損傷が発生したか又は観察された日に、及び再度、組織損傷が発生したか又は観察された日の約2、4、6、及び8日後に;
(b)組織損傷が発生したか又は観察された日のほぼ1ヵ月目に、及び、組織損傷が発生したか又は観察された日の1カ月目のほぼ2、4、6、及び8日後に;
(c)組織損傷が発生したか又は観察された日のほぼ2ヵ月目に、及び、組織損傷が発生したか又は観察された日の2カ月目のほぼ2、4、6、及び8日後に;ならびに
(d)組織損傷が発生したか又は観察された日のほぼ3ヵ月目に、及び、組織損傷が発生したか又は観察された日の3カ月目のほぼ2、4、6、及び8日後に、1回以上投与される方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562193138P | 2015-07-16 | 2015-07-16 | |
US62/193,138 | 2015-07-16 | ||
PCT/US2016/042507 WO2017011750A1 (en) | 2015-07-16 | 2016-07-15 | Pharmaceutical compositions useful for the treatment of tissue injury |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018521132A true JP2018521132A (ja) | 2018-08-02 |
JP7010817B2 JP7010817B2 (ja) | 2022-01-26 |
Family
ID=57758309
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018521490A Active JP7010817B2 (ja) | 2015-07-16 | 2016-07-15 | 組織損傷の治療に有用な医薬組成物 |
Country Status (9)
Country | Link |
---|---|
US (2) | US20180200232A1 (ja) |
EP (1) | EP3322435A4 (ja) |
JP (1) | JP7010817B2 (ja) |
KR (1) | KR20180026538A (ja) |
CN (1) | CN108367052A (ja) |
AU (2) | AU2016293581B2 (ja) |
CA (1) | CA2992299C (ja) |
IL (1) | IL256919B1 (ja) |
WO (1) | WO2017011750A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021007192A1 (en) * | 2019-07-08 | 2021-01-14 | The Board Of Regents Of The University Of Texas System | Use of immune modulators to improve nerve regeneration |
CA3198248A1 (en) * | 2020-11-10 | 2022-05-19 | Zhaoli Sun | Formulations, methods, kits, and dosage forms |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10813917B2 (en) * | 2009-12-11 | 2020-10-27 | Medregen, Llc | Treatment methods utilizing stem cell mobilizers and immunosuppressive agents |
US8951529B2 (en) * | 2009-12-22 | 2015-02-10 | Icahn School Of Medicine At Mount Sinai | Methods of using small compounds to enhance myeloid derived suppressor cell function for treating autoimmune diseases |
US20130338183A1 (en) * | 2010-12-07 | 2013-12-19 | The Johns Hopkins University | Compositions and methods for mobilizing stem cells |
PL3030232T3 (pl) * | 2013-04-29 | 2022-11-07 | Medregen, Llc | Gojenie ran poprzez autologiczną mobilizację komórek macierzystych |
-
2016
- 2016-07-15 AU AU2016293581A patent/AU2016293581B2/en active Active
- 2016-07-15 KR KR1020187004461A patent/KR20180026538A/ko not_active Application Discontinuation
- 2016-07-15 EP EP16825248.4A patent/EP3322435A4/en active Pending
- 2016-07-15 CA CA2992299A patent/CA2992299C/en active Active
- 2016-07-15 US US15/744,502 patent/US20180200232A1/en not_active Abandoned
- 2016-07-15 JP JP2018521490A patent/JP7010817B2/ja active Active
- 2016-07-15 IL IL256919A patent/IL256919B1/en unknown
- 2016-07-15 CN CN201680053764.4A patent/CN108367052A/zh active Pending
- 2016-07-15 WO PCT/US2016/042507 patent/WO2017011750A1/en active Application Filing
-
2022
- 2022-11-30 AU AU2022279453A patent/AU2022279453A1/en active Pending
-
2023
- 2023-03-24 US US18/189,741 patent/US20230255931A1/en active Pending
Non-Patent Citations (3)
Title |
---|
EXPERT. OPIN. DRUG SAF., (2007), 6, [5], P.479-485, JPN6020023092, ISSN: 0004442856 * |
J. INVEST. DERMATOL., (2014), 134, [9], P.2458-2468 & SUPPLEMENTARY INFORMATION, JPN6020023090, ISSN: 0004442855 * |
WORLD J. GASTROENTEROL., (2010), 16, [23], P.2873-2880, JPN6020023094, ISSN: 0004442857 * |
Also Published As
Publication number | Publication date |
---|---|
US20180200232A1 (en) | 2018-07-19 |
US20230255931A1 (en) | 2023-08-17 |
IL256919A (en) | 2018-03-29 |
IL256919B1 (en) | 2024-04-01 |
WO2017011750A1 (en) | 2017-01-19 |
EP3322435A4 (en) | 2018-12-26 |
KR20180026538A (ko) | 2018-03-12 |
EP3322435A1 (en) | 2018-05-23 |
AU2022279453A1 (en) | 2023-02-02 |
AU2016293581B2 (en) | 2022-09-01 |
JP7010817B2 (ja) | 2022-01-26 |
CN108367052A (zh) | 2018-08-03 |
AU2016293581A1 (en) | 2018-02-08 |
CA2992299A1 (en) | 2017-01-19 |
CA2992299C (en) | 2023-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11291657B2 (en) | Methods of treating inflammatory bowel disease with AMD3100 and Tacrolimus | |
US20230255931A1 (en) | Pharmaceutical compositions useful for the treatment of tissue injury | |
US8394763B2 (en) | Cyclic undecapeptides and derivatives as multiple sclerosis therapies | |
US20210251954A1 (en) | Methods of recruiting sdf-producing macrophages | |
US20140219952A1 (en) | Methods of treatment using stem cell mobilizers | |
US20220354833A1 (en) | Alvelestat for use in the treatment of graft rejection, bronchiolitis obliterans syndrome and graft versus host disease | |
JP2018515584A (ja) | 組織再生及び衰えた組織機能の回復を刺激するための作用物質としてのジカルボン酸のビスアミド誘導体 | |
US20130338183A1 (en) | Compositions and methods for mobilizing stem cells | |
EP3808368A2 (en) | Treatment methods utilizing stem cell mobilizers and immunosuppressive agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190711 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200630 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200930 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210209 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210507 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210810 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20211214 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220113 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7010817 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |