JP2019506386A - Llp2a−ビスホスホネート化合物を用いて骨壊死を処置する方法 - Google Patents
Llp2a−ビスホスホネート化合物を用いて骨壊死を処置する方法 Download PDFInfo
- Publication number
- JP2019506386A JP2019506386A JP2018536772A JP2018536772A JP2019506386A JP 2019506386 A JP2019506386 A JP 2019506386A JP 2018536772 A JP2018536772 A JP 2018536772A JP 2018536772 A JP2018536772 A JP 2018536772A JP 2019506386 A JP2019506386 A JP 2019506386A
- Authority
- JP
- Japan
- Prior art keywords
- bone
- pharmaceutical composition
- llp2a
- osteonecrosis
- administered
- 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.)
- Pending
Links
- 206010031264 Osteonecrosis Diseases 0.000 title claims abstract description 145
- 238000000034 method Methods 0.000 title claims abstract description 111
- 229940122361 Bisphosphonate Drugs 0.000 title claims abstract description 53
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 87
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 37
- 150000004663 bisphosphonates Chemical class 0.000 claims abstract description 33
- 229940079593 drug Drugs 0.000 claims abstract description 33
- 239000000816 peptidomimetic Substances 0.000 claims abstract description 31
- 239000003446 ligand Substances 0.000 claims abstract description 28
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229940062527 alendronate Drugs 0.000 claims abstract description 19
- 210000000988 bone and bone Anatomy 0.000 claims description 153
- 239000003862 glucocorticoid Substances 0.000 claims description 92
- 230000003902 lesion Effects 0.000 claims description 60
- 210000001519 tissue Anatomy 0.000 claims description 60
- 210000000689 upper leg Anatomy 0.000 claims description 33
- 230000002792 vascular Effects 0.000 claims description 30
- 230000030833 cell death Effects 0.000 claims description 22
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 210000003423 ankle Anatomy 0.000 claims description 10
- 230000007423 decrease Effects 0.000 claims description 10
- 210000001847 jaw Anatomy 0.000 claims description 10
- 210000002832 shoulder Anatomy 0.000 claims description 10
- 230000000472 traumatic effect Effects 0.000 claims description 10
- 210000000707 wrist Anatomy 0.000 claims description 10
- 210000001624 hip Anatomy 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 210000003127 knee Anatomy 0.000 claims description 9
- 208000013435 necrotic lesion Diseases 0.000 claims description 9
- 241000699670 Mus sp. Species 0.000 description 77
- 239000000203 mixture Substances 0.000 description 62
- 238000011282 treatment Methods 0.000 description 58
- 150000001875 compounds Chemical group 0.000 description 44
- 229940068196 placebo Drugs 0.000 description 38
- 239000000902 placebo Substances 0.000 description 38
- 235000002639 sodium chloride Nutrition 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 29
- 102000003982 Parathyroid hormone Human genes 0.000 description 25
- 108090000445 Parathyroid hormone Proteins 0.000 description 25
- 229960001319 parathyroid hormone Drugs 0.000 description 25
- 239000000199 parathyroid hormone Substances 0.000 description 25
- 210000001185 bone marrow Anatomy 0.000 description 24
- 239000003263 anabolic agent Substances 0.000 description 23
- 229940124325 anabolic agent Drugs 0.000 description 23
- 210000002449 bone cell Anatomy 0.000 description 23
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 23
- 241001465754 Metazoa Species 0.000 description 20
- 150000003839 salts Chemical class 0.000 description 20
- 229960003957 dexamethasone Drugs 0.000 description 19
- -1 alkaline earth metal salts Chemical class 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000000546 pharmaceutical excipient Substances 0.000 description 15
- 239000007788 liquid Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 210000004204 blood vessel Anatomy 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000033115 angiogenesis Effects 0.000 description 10
- 230000001640 apoptogenic effect Effects 0.000 description 10
- 230000036770 blood supply Effects 0.000 description 10
- 238000007469 bone scintigraphy Methods 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 235000019197 fats Nutrition 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000010172 mouse model Methods 0.000 description 10
- 230000001338 necrotic effect Effects 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 10
- 108010049264 Teriparatide Proteins 0.000 description 9
- 239000003937 drug carrier Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 229920002472 Starch Polymers 0.000 description 8
- 229930006000 Sucrose Natural products 0.000 description 8
- 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 8
- 239000002253 acid Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 210000002745 epiphysis Anatomy 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 229960004793 sucrose Drugs 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 235000001727 glucose Nutrition 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 210000000963 osteoblast Anatomy 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 6
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 6
- 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 6
- 230000037396 body weight Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000003086 colorant Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 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 5
- 210000001789 adipocyte Anatomy 0.000 description 5
- 238000002591 computed tomography Methods 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000600 sorbitol Substances 0.000 description 5
- 235000010356 sorbitol Nutrition 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- 206010058822 Bone marrow necrosis Diseases 0.000 description 4
- 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 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 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 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 229920001615 Tragacanth Polymers 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 230000037182 bone density Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000013505 freshwater Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 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 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 230000000366 juvenile effect Effects 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 210000004940 nucleus Anatomy 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 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 3
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 241000906034 Orthops Species 0.000 description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011260 co-administration Methods 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000002872 contrast media Substances 0.000 description 3
- 230000001054 cortical effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000000399 orthopedic effect Effects 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- 208000030016 Avascular necrosis Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 2
- 150000008574 D-amino acids Chemical class 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 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 2
- 102100038566 Endomucin Human genes 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 150000008575 L-amino acids Chemical class 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
- 108010080627 LLP2A compound Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000029725 Metabolic bone disease Diseases 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 206010049088 Osteopenia Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108700020797 Parathyroid Hormone-Related Proteins 0.000 description 2
- 102000043299 Parathyroid hormone-related Human genes 0.000 description 2
- 208000006735 Periostitis Diseases 0.000 description 2
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 2
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 108010061228 Sialomucins Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102100038803 Somatotropin Human genes 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 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 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 238000007470 bone biopsy Methods 0.000 description 2
- 230000008468 bone growth Effects 0.000 description 2
- 230000010072 bone remodeling Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000008355 cartilage degradation Effects 0.000 description 2
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 239000000032 diagnostic agent Substances 0.000 description 2
- 229940039227 diagnostic agent Drugs 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229940009626 etidronate Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- XOXYHGOIRWABTC-UHFFFAOYSA-N gentisin Chemical compound C1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 XOXYHGOIRWABTC-UHFFFAOYSA-N 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 210000002758 humerus Anatomy 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000010603 microCT Methods 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 210000003460 periosteum Anatomy 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000012857 radioactive material Substances 0.000 description 2
- 238000002601 radiography Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- 229960005460 teriparatide Drugs 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical class OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 2
- 210000003954 umbilical cord Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000007998 vessel formation Effects 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 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
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- 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 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 description 1
- DDKMATGXLMCTOX-UHFFFAOYSA-N 2-[4-[(2-methylphenyl)carbamoylamino]phenyl]acetic acid Chemical compound CC1=CC=CC=C1NC(=O)NC1=CC=C(CC(O)=O)C=C1 DDKMATGXLMCTOX-UHFFFAOYSA-N 0.000 description 1
- AUVALWUPUHHNQV-UHFFFAOYSA-N 2-hydroxy-3-propylbenzoic acid Chemical compound CCCC1=CC=CC(C(O)=O)=C1O AUVALWUPUHHNQV-UHFFFAOYSA-N 0.000 description 1
- JKYKXTRKURYNGW-UHFFFAOYSA-N 3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(O)=C(O)C(S(O)(=O)=O)=C2 JKYKXTRKURYNGW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000017234 Bone cyst Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010051763 Bone marrow oedema Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 0 C[C@@](C1OC1NC1(CCCCC1)C(N)=O)NC([C@@](*(CNC(C=Cc1cnccc1)=O)=C)NC(Cc(cc1)ccc1NC(Nc1c(C)cccc1)=O)=O)=O Chemical compound C[C@@](C1OC1NC1(CCCCC1)C(N)=O)NC([C@@](*(CNC(C=Cc1cnccc1)=O)=C)NC(Cc(cc1)ccc1NC(Nc1c(C)cccc1)=O)=O)=O 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940123150 Chelating agent Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-L D-glucarate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O DSLZVSRJTYRBFB-LLEIAEIESA-L 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 206010023230 Joint stiffness Diseases 0.000 description 1
- 238000012313 Kruskal-Wallis test Methods 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000027414 Legg-Calve-Perthes disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229920000057 Mannan Polymers 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].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)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000004067 Osteocalcin Human genes 0.000 description 1
- 108090000573 Osteocalcin Proteins 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000012288 TUNEL assay Methods 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 210000001691 amnion Anatomy 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000004221 bone function Effects 0.000 description 1
- 230000005309 bone marrow development Effects 0.000 description 1
- 229940028101 boniva Drugs 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-N calcium;phosphoric acid Chemical compound [Ca+2].OP(O)(O)=O.OP(O)(O)=O YYRMJZQKEFZXMX-UHFFFAOYSA-N 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
- 150000001721 carbon Chemical group 0.000 description 1
- 229940075510 carbopol 981 Drugs 0.000 description 1
- UHBYWPGGCSDKFX-UHFFFAOYSA-N carboxyglutamic acid Chemical compound OC(=O)C(N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 210000003074 dental pulp Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 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 1
- 229960005139 epinephrine Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 239000001761 ethyl methyl cellulose Substances 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 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
- 230000001747 exhibiting effect Effects 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 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
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 210000004095 humeral head Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical class CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 238000012829 orthopaedic surgery Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000005059 placental tissue Anatomy 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229920003133 pregelled starch Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229940107023 reclast Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000002784 sclerotic effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 229940112726 skelid Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000002426 superphosphate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- 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
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/63—Arthropods
- A61K35/64—Insects, e.g. bees, wasps or fleas
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Developmental Biology & Embryology (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Insects & Arthropods (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Animal Husbandry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
本出願は、あらゆる目的のためにその全体が本明細書に組み入れられる、2016年1月14日に出願された米国特許仮出願第62/278,921号に対する優先権を請求する。
本発明は、National Institutes of Healthにより認可された、助成金番号AR0631366の下での政府支援により行われた。米国政府は本発明においてある一定の権利を有する。
骨壊死は、無血管性壊死としても知られ、骨の領域における血液供給の障害によってその領域における骨が死んでしまう障害である。2種類の骨壊死の外傷性骨壊死および非外傷性骨壊死が存在する。外傷性骨壊死では、骨折または脱臼などの骨への損傷が該骨において血管を傷つける。非外傷性骨壊死では、血液供給の障害および骨壊死は、直接的な外傷または損傷なしに起こる。いくつかの場合では、患者における骨の死滅の原因は不明である(特発性骨壊死)。
LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む。
LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む。
LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む。
を有する。
を有する。
I. 序論
骨壊死は、骨への血液供給の一時的なまたは永続的な喪失に起因する骨疾患である。適切な血液供給がないと、骨組織は死に、最終的には骨および周囲の関節の圧潰につながる可能性がある。
別段の定義がない限り、本明細書で用いられる全ての技術的および科学的用語は概して、本発明が属する技術分野における当業者によって通常理解されるものと同じ意味を有する。概して、本明細書において用いられる命名法、および以下に記載の細胞培養、分子生物学、および化学における実験手法は、当技術分野において周知かつ通常利用されるものである。
1つの局面では、本発明は、骨壊死を予防および/もしくは処置するための、骨壊死組織において血管密度を増大させるための、または骨壊死組織において細胞死を予防するもしくは低減させるための、単独でまたは間葉系幹細胞および/もしくはタンパク質同化剤との組み合わせで用いることができる、アレンドロネートなどのビスホスホネートとコンジュゲートされたペプチド模倣リガンドに、例えばLLP2Aに関する。
いくつかの態様では、LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲート(例えば、LLP2A-Ale)を含む薬学的組成物は、骨壊死を処置するため、骨壊死組織において血管密度を増大させるため、または骨壊死組織において細胞死を予防するかもしくは低減させるために、間葉系幹細胞(MSC)と一緒に共投与される。
いくつかの態様では、LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲート(例えば、LLP2A-Ale)を含む薬学的組成物は、骨壊死を処置するため、骨壊死組織において血管密度を増大させるため、または骨壊死組織において細胞死を予防するかもしくは低減させるために、タンパク質同化剤と共に共投与される。
いくつかの態様では、本明細書に記載の組成物(例えば、LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲート(例えば、LLP2A-Ale)、間葉系幹細胞、および/またはタンパク質同化剤を含む組成物)は、薬学的に許容される担体または賦形剤を含む薬学的組成物として提供される。製剤および投与のための技術の詳細は、科学文献および特許文献に十分に記載されており、例えば、REMINGTON'S PHARMACEUTICAL SCIENCES, Mack Publishing Co, Easton PAの最新版を参照されたい。
1つの局面では、本明細書に記載される組成物(例えば、LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲート(例えば、LLP2A-Ale)を含む組成物)は、骨壊死を予防および/もしくは処置するため、血管密度を増大させるため、または骨壊死組織において細胞死を低減させるために用いられる。いくつかの態様では、方法は、
LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む。
少なくとも1つの骨に骨壊死を有するかまたは骨壊死を有することが疑われる対象を特定する工程;および
LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む。
少なくとも1つの骨に骨壊死の1つまたは複数の症状を有する対象を特定する工程:
LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程:および
少なくとも1つの骨を検査して、投与する工程の前と比べた骨壊死の1つまたは複数の症状の変化を特定する工程
を含む。
以下の実施例は、特許請求の範囲に記載の発明を例示するために提供され、該発明を限定するために提供されない。
グルココルチコイド誘導性骨壊死の56日マウスモデルにおけるLLP2A-Aleの使用
骨壊死は、骨、特に関節における骨への血流の低下によって特徴付けられる疾患である。血液供給の低下は骨の死と崩壊をもたらす。図1は、グルココルチコイド誘導性骨壊死の病期を図示する。骨壊死は、疾患がどの程度まで進行しているかを指す病期(IからV)に分類される。外傷性骨壊死では、最初に血液供給が低下し、骨細胞の死がもたらされ、次いで、死んだ骨の部位が骨の使用を支持できないために、骨の圧潰がもたらされる(図1、上腕骨)。
グルココルチコイド誘導性骨壊死の90日マウスモデルにおけるLLP2A-Aleの使用
この試験は、LLP2A-Aleがマウスにおいて確立された外傷性骨壊死を元に戻すまたは処置することができるかどうかを決定するために行われた。
動物および実験方法
LLP2A-Aleの有効性を、グルココルチコイド誘導性骨壊死のマウスモデルを用いる90日試験を通じて評価した。7週齢の雄マウス(BALB/c(n=80, Jackson laboratories, USA)を、12時間明暗周期で20℃に維持した清潔な換気された動物室に収容した。全動物を、UC Davis Committee on Animal Researchの承認を受けたUSDA動物取扱いガイドラインにしたがって取り扱った。マウスに水および標準的な市販の齧歯類用固形飼料(22/5 Rodent Diet; Teklad, Madison, WI)を自由に与えた。動物を、プラセボ群(新鮮水)またはグルココルチコイドのみ(飲用水中に4 mg/Lデキサメタゾン(Dex))のいずれかに体重無作為化し、90日間処置した。次に、30日目に、Dex処置マウスをDex単独、Dex+250 μg/kg LLP2A-Ale、Dex+500 μg/kg LLP2A-AleおよびDex+750 μg/kg LLP2A-Aleに再無作為化した。LLP2A-Ale処置を30、45、60および75日目に与えた。加えて、0.1 mg/kgメトトレキサートを、グルココルチコイドを受ける全ての群において1〜42日目に皮下注射によって週に2回投与した。
右および左の遠位大腿骨の両方を、10%中性緩衝化ホルマリン中に固定し、3日間振とうさせ、次いで、骨が十分に脱灰されるまで5%EDTA中で脱灰した。次に検体を漸増濃度のエタノールで処理し、パラフィン中に包埋した。組織切片を5マイクロメートルの切片に切断し、ヘマトキシリンおよびエオシンで染色し、20×拡大率での明視野光学顕微鏡によって骨壊死の存在について評価した。実験法は、全ての目的でその全体が参照によって本明細書に組み入れられる、Mohan et al., Calif Tissue Int(2016) doi:10.1007/s00223-016-0195-6にも記載される。骨壊死を以下の変化:(1)空胞化した骨小腔、(2)空胞化した骨小腔および隣接する骨髄の壊死の部位における濃縮した骨細胞の核、(3)骨髄における過剰な脂肪細胞の存在、(4) 軟骨分解、および(5)血管中のフィブリン血栓の存在の全てを要件とするとして骨壊死を定義する、Yang el al.,(a mouse model for glucocorticoid-induced osteonecrosis: Effect of a steroid holiday. J Orthop Res. 2009; 27: 169-75)によって報告された改変基準を用いて、骨壊死を検出した。加えて、遠位大腿骨骨端における海綿骨体積、脂肪体積、洞様毛細血管体積、および骨芽細胞表面を測定した。空胞化した骨小腔密度を、各試料について遠位大腿骨骨端領域全体内での空胞化した骨小腔/総骨細胞によって算出した。各切片を2名の経験のある組織学者がスコア化し、次いで、さらなる2人の経験のある組織学者がコンセンサスリーディングを行った。
体重
プラセボ群でのBALB/cマウスの体重は、90日の実験期間にわたって、ベースライン体重とは有意に異なる(p<0.05)体重の増加を有したが、これは他の群では観察されなかった。全てのデキサメタゾン(Dex)処置動物の体重は、7日目から90日目までプラセボと比較して有意に低かった(p<0.05)。
骨壊死の証拠は、Dex処置マウスにおいて遠位大腿骨の骨端の全体にわたって存在した。図7に示すように、Dex単独処置群は少なくとも3つ、または5つ全ての骨壊死の特徴(Yang el alによって報告された改変基準を用いて決定される)を示し、Dex+LLP2A-Ale処置群のいずれかにおける対象の数より有意に高かった。骨壊死の3つまたはそれ以上の特徴を有する試料:PL(0%);Dexのみの群14/16(88%);Dex+LLP2A-Ale 250 μg/kg 12/16(75%);Dex+LLP2A-Ale 500 μg/kg 9/16(56%)およびLLP2A-Ale 750 μg/kg 11/16(69%)。Dexのみの群では、LLP2A-Ale処置群での試料の44〜62%と比較して、試料の75%が10%またはそれ以上の空胞化した骨小腔を有した(図8A〜B)。また、図8A〜Bに示されるように、LLP2A-Ale処置群では、Dex処置群と比較して、より多くの試料が10%未満の空胞化した骨小腔を呈した。
図9Aおよび9Bに示すように、プラセボ処置マウス由来の骨端の組織切片は、骨壊死の証拠を何ら示さず、数個の骨髄脂肪細胞および洞様毛細血管が骨髄中に観察された。Dex処置マウス由来の骨端の組織切片(図9C〜9F)は、大きな空胞化した骨小腔(図9Dおよび9F、黒矢印)、および骨細胞の核濃縮によって特徴付けられる壊死性の骨梁を示した。一部のデキサメタゾン処置マウスは、壊死性骨髄(図9E、緑矢印)および脂肪組織(図9D、9E、および9F、青矢印)によって囲まれた、関節軟骨(図9D、黄色矢印)の減少を呈した。これらのデータは、グルココルチコイド誘導性骨壊死が90日試験の間このマウスモデルにおいて観察されることを示す。
図10Aに示すように、3種類の投与量のLLP2A-Ale処置は全て、Dex処置マウスの脂肪体積と比較して脂肪体積を低減させ、骨壊死病変の修復の証拠を示した。図10Bに示すように、3種類の投与量のLLP2A-Ale処置は全て、プラセボまたはDex単独処置と比較して洞様毛細血管体積を増加させた。250 μg/kgを上回ってLLP2A-Ale処置を増加させることは、洞様毛細血管体積のわずかな減少をもたらした。これらのデータは、LLP2A-Ale処置が、血管新生を増大させることによって骨壊死性病変を修復できることを示唆する。
図11Aから11Fに示すように、LLP2A-Ale処置マウス由来の骨端の組織切片は、洞様毛細血管形成の増大を示し、該洞様毛細血管は、壊死性骨髄内に突き出る(図11B)または骨髄壊死が観察されない骨髄中を占有した(図11E&11F)。図11Eでは、いくつかの骨芽細胞が、骨梁表面および洞様毛細血管の近くで観察された(黄色矢印)。これらのデータは、骨壊死後のLLP2A-Ale処置が、デキサメタゾン単独と比較して、空胞化した骨小腔/濃縮核の数、骨髄における脂肪細胞密度を減少させるよう見え、洞様毛細血管赤血球体積を増大させ、および骨髄の細胞充実性を維持するよう観察されたことを示唆する。加えて、LLP2A-Ale処置は、骨髄内のフィブリンの量を低減させると考えられ、かつ骨壊死が存在する骨端部位において骨表面上に存在する骨芽細胞の数を増大させ、新たな骨形成を刺激する能力を示唆した。
マウスモデルにおいてグルココルチコイド誘導性骨壊死および血管分布の減少を予防するためのLLP2A-AleおよびhPTH(1-34)の使用
この試験は、LLP2A-AleまたはhPTH(1-34)の30日間または45日間にわたる投与がグルココルチコイド誘導性骨壊死を予防し、マウスにおける遠位大腿骨内の血管分布を維持できるかどうか決定するために行われた。
動物および実験方法
LLP2A-AleおよびhPTH(1-34)の有効性を、グルココルチコイド誘導性骨壊死のマウスモデルを用いて30および45日の試験を通じて評価した。7週齢の雄BALB/cマウスを、30または45日間のプラセボ群(新鮮水)、グルココルチコイドのみ(飲用水中に4 mg/Lデキサメタゾン(Dex))、Dex+250 μg/kg LLP2A-Ale、Dex+500 μg/kg LLP2A-Ale、またはDex+40 μg/kg hPTH(週に5回投与)に無作為化した。30または45日目にマウスを屠殺した。試験のエンドポイントには、遠位大腿骨における骨壊死の組織学的証拠、骨量、および血管の広がり(CD31およびエンドムチンの発現)が挙げられ、実施例2に記載のように実施された。ノンパラメトリックなクラスカル・ウォリス検定を用いて、群間の差を判定した。
骨壊死の有症率
骨壊死の証拠は、Dex処置マウスでは遠位大腿骨の骨端全体にわたって存在した。図12に示すように、Dex単独処置群は、LLP2A-AleまたはhPTH処置群におけるマウスより有意に高いパーセンテージの骨壊死有症率を有した。グルココルチコイド誘導性骨壊死の発生率は、Dex単独では30日目に57%および45日目に73%であり、LLP2A-AleおよびhPTH(1-34)処置はどちらも、付随的なGC誘導性骨壊死病変を予防した。
Dex処置マウス由来の骨端の組織切片は、30日および45日目でプラセボと比較して海綿骨体積および骨梁幅の有意な低下を示した(p<0.05)。骨梁数は45日目に有意に低下した(p<0.05)。これに対して、LLP2A-AleおよびhPTH(1-34)処置動物はどちらも、30日および45日目にDex群と比較して高い骨体積と低い骨梁間隔を有した(p<0.05)。加えて、LLP2A-Ale、hPTH(1-34)、またはプラセボ処置と比較して、Dex処置は、30および45日目にCD31およびエンドムチン発現の両方の染色強度を低下させた(データは示さず)。これらのデータは、グルココルチコイド誘導性骨壊死が30および45日試験を通じてこのマウスモデルにおいて観察されることを示す。
Dex処置は海綿骨減少および骨壊死病変を誘導した。LLP2A-AleおよびhPTH処置はどちらも、骨壊死の発生率および重症度を低下させ、遠位大腿骨の血管完全性を維持した。
Claims (52)
- LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む、該対象において骨壊死を処置する方法。 - 前記投与する工程の前に、少なくとも1つの骨に少なくとも1つの骨壊死性病変(osteonecrotic lesion)を有する対象を特定する工程をさらに含む、請求項1または2に記載の方法。
- 前記少なくとも1つの骨が、大腿、股関節、膝、肩、足首、手首、または顎の骨である、請求項3に記載の方法。
- 前記特定する工程が、前記少なくとも1つの骨の磁気共鳴画像化を含む、請求項3または4に記載の方法。
- 前記特定する工程が、少なくとも3.5 cm2の大きさを有する少なくとも1つの骨壊死性病変を検出することを含む、請求項3から5のいずれか一項に記載の方法。
- 前記特定する工程が、少なくとも5 cm2の大きさを有する少なくとも1つの骨壊死性病変を検出することを含む、請求項6に記載の方法。
- 前記投与する工程の後に、前記少なくとも1つの骨壊死性病変の大きさを測定する工程、および、該投与する工程の前の該骨壊死性病変の大きさと比べた該骨壊死性病変の大きさの減少を検出する工程をさらに含む、請求項3から7のいずれか一項に記載の方法。
- 前記骨壊死が外傷性骨壊死である、請求項1から8のいずれか一項に記載の方法。
- 前記骨壊死が、グルココルチコイド誘導性骨壊死またはアルコール誘導性骨壊死である、請求項1から8のいずれか一項に記載の方法。
- 外因性間葉系幹細胞を投与する工程をさらに含む、請求項1から10のいずれか一項に記載の方法。
- 前記薬学的組成物および前記外因性間葉系幹細胞が同時に投与される、請求項11に記載の方法。
- 前記薬学的組成物および前記外因性間葉系幹細胞が連続的に投与される、請求項11に記載の方法。
- 前記薬学的組成物が全身的に投与される、請求項1から13のいずれか一項に記載の方法。
- 前記薬学的組成物が局所的に投与される、請求項1から13のいずれか一項に記載の方法。
- 前記薬学的組成物が、前記少なくとも1つの骨壊死性病変の部位に局所的に投与される、請求項15に記載の方法。
- 前記薬学的組成物が静脈内に投与される、請求項1から14のいずれか一項に記載の方法。
- 前記薬学的組成物が注射によって投与される、請求項1から16のいずれか一項に記載の方法。
- LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む、骨壊死組織において血管密度を増大させる方法。 - 前記投与する工程の前に、少なくとも1つの骨に少なくとも1つの骨壊死性病変を有する対象を特定する工程をさらに含む、請求項19または20に記載の方法。
- 前記少なくとも1つの骨が、大腿、股関節、膝、肩、足首、手首、または顎の骨である、請求項21に記載の方法。
- 前記特定する工程が、前記少なくとも1つの骨の磁気共鳴画像化を含む、請求項21または22に記載の方法。
- 前記特定する工程が、少なくとも3.5 cm2の大きさを有する少なくとも1つの骨壊死性病変を検出することを含む、請求項21から23のいずれか一項に記載の方法。
- 前記特定する工程が、少なくとも5 cm2の大きさを有する少なくとも1つの骨壊死性病変を検出することを含む、請求項24に記載の方法。
- 前記骨壊死が外傷性骨壊死である、請求項19から25のいずれか一項に記載の方法。
- 前記骨壊死が、グルココルチコイド誘導性骨壊死またはアルコール誘導性骨壊死である、請求項19から25のいずれか一項に記載の方法。
- 外因性間葉系幹細胞を投与する工程をさらに含む、請求項19から27のいずれか一項に記載の方法。
- 前記薬学的組成物および前記外因性間葉系幹細胞が同時に投与される、請求項28に記載の方法。
- 前記薬学的組成物および前記外因性間葉系幹細胞が連続的に投与される、請求項28に記載の方法。
- 前記薬学的組成物が全身的に投与される、請求項19から30のいずれか一項に記載の方法。
- 前記薬学的組成物が局所的に投与される、請求項19から30のいずれか一項に記載の方法。
- 前記薬学的組成物が、前記少なくとも1つの骨壊死性病変の部位に局所的に投与される、請求項32に記載の方法。
- 前記薬学的組成物が静脈内に投与される、請求項19から31のいずれか一項に記載の方法。
- 前記薬学的組成物が注射によって投与される、請求項19から33のいずれか一項に記載の方法。
- LLP2Aペプチド模倣リガンドとビスホスホネート薬とのコンジュゲートを含む薬学的組成物を、対象に投与する工程
を含む、骨壊死組織において細胞死を予防するかまたは低減させる方法。 - 前記投与する工程の前に、少なくとも1つの骨に少なくとも1つの骨壊死性病変を有する対象を特定する工程をさらに含む、請求項36または37に記載の方法。
- 前記少なくとも1つの骨が、大腿、股関節、膝、肩、足首、手首、または顎の骨である、請求項38に記載の方法。
- 前記特定する工程が、前記少なくとも1つの骨の磁気共鳴画像化を含む、請求項38または39に記載の方法。
- 前記特定する工程が、少なくとも3.5 cm2の大きさを有する少なくとも1つの骨壊死性病変を検出することを含む、請求項38から40のいずれか一項に記載の方法。
- 前記特定する工程が、少なくとも5 cm2の大きさを有する少なくとも1つの骨壊死性病変を検出することを含む、請求項41に記載の方法。
- 前記骨壊死が外傷性骨壊死である、請求項36から42のいずれか一項に記載の方法。
- 前記骨壊死が、グルココルチコイド誘導性骨壊死またはアルコール誘導性骨壊死である、請求項36から42のいずれか一項に記載の方法。
- 外因性間葉系幹細胞を投与する工程をさらに含む、請求項36から44のいずれか一項に記載の方法。
- 前記薬学的組成物および前記外因性間葉系幹細胞が同時に投与される、請求項45に記載の方法。
- 前記薬学的組成物および前記外因性間葉系幹細胞が連続的に投与される、請求項45に記載の方法。
- 前記薬学的組成物が全身的に投与される、請求項36から51のいずれか一項に記載の方法。
- 前記薬学的組成物が局所的に投与される、請求項36から47のいずれか一項に記載の方法。
- 前記薬学的組成物が、前記少なくとも1つの骨壊死性病変の部位に局所的に投与される、請求項49に記載の方法。
- 前記薬学的組成物が静脈内に投与される、請求項36から48のいずれか一項に記載の方法。
- 前記薬学的組成物が注射によって投与される、請求項36から50のいずれか一項に記載の方法。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022015347A JP2022064986A (ja) | 2016-01-14 | 2022-02-03 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
JP2024063291A JP2024074977A (ja) | 2016-01-14 | 2024-04-10 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662278921P | 2016-01-14 | 2016-01-14 | |
US62/278,921 | 2016-01-14 | ||
PCT/US2017/013482 WO2017123977A1 (en) | 2016-01-14 | 2017-01-13 | Methods of treating osteonecrosis with llp2a-bisphosphonate compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022015347A Division JP2022064986A (ja) | 2016-01-14 | 2022-02-03 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019506386A true JP2019506386A (ja) | 2019-03-07 |
JP2019506386A5 JP2019506386A5 (ja) | 2020-02-13 |
Family
ID=59311460
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018536772A Pending JP2019506386A (ja) | 2016-01-14 | 2017-01-13 | Llp2a−ビスホスホネート化合物を用いて骨壊死を処置する方法 |
JP2022015347A Pending JP2022064986A (ja) | 2016-01-14 | 2022-02-03 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
JP2024063291A Pending JP2024074977A (ja) | 2016-01-14 | 2024-04-10 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022015347A Pending JP2022064986A (ja) | 2016-01-14 | 2022-02-03 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
JP2024063291A Pending JP2024074977A (ja) | 2016-01-14 | 2024-04-10 | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 |
Country Status (7)
Country | Link |
---|---|
US (2) | US20190076448A1 (ja) |
EP (1) | EP3402803A4 (ja) |
JP (3) | JP2019506386A (ja) |
KR (1) | KR20180102154A (ja) |
CN (1) | CN108601949A (ja) |
AU (1) | AU2017207449A1 (ja) |
WO (1) | WO2017123977A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114159580A (zh) * | 2013-10-04 | 2022-03-11 | 加利福尼亚大学董事会 | 采用llp2a-二膦酸盐/酯偶联物和间充质干细胞治疗炎症 |
CN114887034B (zh) * | 2022-07-14 | 2022-10-28 | 中山莱博瑞辰生物医药有限公司 | LLP2A-Ale在制备用于治疗和/或预防外周血淋巴细胞减少症的药物中的用途 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1365769T3 (da) * | 2001-02-06 | 2011-05-16 | Sydney Children S Hospitals Network Randwick And Westmead Incorporating The Royal Alexandra Hospital | Lægemiddel til behandling af osteonekrose og til behandling af patienter med risiko for at udvikle osteonekrose |
JP5539993B2 (ja) * | 2008-09-23 | 2014-07-02 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 薬物送達のためのナノ担体 |
WO2012031228A2 (en) * | 2010-09-02 | 2012-03-08 | The Regents Of The University Of California | Llp2a-bisphosphonate conjugates for osteoporosis treatment |
CN114159580A (zh) * | 2013-10-04 | 2022-03-11 | 加利福尼亚大学董事会 | 采用llp2a-二膦酸盐/酯偶联物和间充质干细胞治疗炎症 |
-
2017
- 2017-01-13 KR KR1020187023354A patent/KR20180102154A/ko unknown
- 2017-01-13 CN CN201780006923.XA patent/CN108601949A/zh active Pending
- 2017-01-13 JP JP2018536772A patent/JP2019506386A/ja active Pending
- 2017-01-13 AU AU2017207449A patent/AU2017207449A1/en not_active Abandoned
- 2017-01-13 WO PCT/US2017/013482 patent/WO2017123977A1/en active Application Filing
- 2017-01-13 EP EP17739064.8A patent/EP3402803A4/en not_active Withdrawn
-
2018
- 2018-07-13 US US16/034,890 patent/US20190076448A1/en not_active Abandoned
-
2020
- 2020-08-18 US US16/996,401 patent/US20210205338A1/en active Pending
-
2022
- 2022-02-03 JP JP2022015347A patent/JP2022064986A/ja active Pending
-
2024
- 2024-04-10 JP JP2024063291A patent/JP2024074977A/ja active Pending
Non-Patent Citations (6)
Title |
---|
ACTA ORTHOPAEDICA, vol. 83(5), JPN6020042310, 2012, pages 511 - 514, ISSN: 0004605440 * |
ANN.N.Y.ACAD.SCI., vol. 1218(2011), JPN6020042307, pages 33 - 37, ISSN: 0004605438 * |
BONE, vol. 70(2015), JPN6020042312, pages 62 - 65, ISSN: 0004605441 * |
J MED ASSOC THAI, vol. 95, no. 2, JPN6020042308, 2012, pages 275 - 278, ISSN: 0004605439 * |
JOURNAL OF BONE AND MINERAL RESEARCH, vol. 30, no. 1, JPN6020042314, 2015, pages 143 - 0150, ISSN: 0004605442 * |
日本臨床, vol. 第65巻, 増刊号9, JPN6020042300, 28 November 2007 (2007-11-28), pages 537 - 541, ISSN: 0004605437 * |
Also Published As
Publication number | Publication date |
---|---|
JP2024074977A (ja) | 2024-05-31 |
US20210205338A1 (en) | 2021-07-08 |
EP3402803A1 (en) | 2018-11-21 |
EP3402803A4 (en) | 2019-09-04 |
CN108601949A (zh) | 2018-09-28 |
JP2022064986A (ja) | 2022-04-26 |
US20190076448A1 (en) | 2019-03-14 |
KR20180102154A (ko) | 2018-09-14 |
AU2017207449A1 (en) | 2018-08-09 |
WO2017123977A1 (en) | 2017-07-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6262723B2 (ja) | オキシステロールアナログoxy133は、骨発生及びヘッジホッグシグナル伝達を誘導し、脂肪生成を阻害する | |
CN104507951B (zh) | 诱导骨生成和hedgehog信号传导且抑制脂肪形成的氧固醇类似物氧固醇化合物149 | |
US11612639B2 (en) | Methods and compositions for rejuvenating skeletal muscle stem cells | |
JP2024074977A (ja) | Llp2a-ビスホスホネート化合物を用いて骨壊死を処置する方法 | |
CN112451486A (zh) | 用顺铂脂质复合物预防癌症的肺部复发 | |
JP2011518169A (ja) | 骨増殖を変化させるための化合物及び方法 | |
WO2020163766A1 (en) | Periosteal skeletal stem cells in bone repair | |
KR20070061864A (ko) | 유기 화합물의 용도 | |
KR20160088891A (ko) | 골다공증 치료 및 예방을 위한 가스트린 길항제(eg yf476, 네타제피드) | |
CA2383574A1 (en) | Method for reducing the risk of cancer | |
Vashghani Farahani et al. | The effects of pentoxifylline adminstration on fracture healing in a postmenopausal osteoporotic rat model | |
JP5485704B2 (ja) | 骨吸収と骨形成の不均衡を是正するための方法ならびにキット及び組成物 | |
Shi | Systemic Therapy of Inactivated-Bisphosphonate-Conjugated PEGylated NELL-1 (BP-NELL-PEG) for Spaceflight-Induced Osteoporosis | |
JP6499287B2 (ja) | 特発性大腿骨頭壊死症の発症予防及び/又は進行抑制剤 | |
US20230295262A1 (en) | Programmed cells for targeted articular cartilage and bone regeneration | |
Velicu | Spaceflight-Induced Osteoarthritis in Temporomandibular Joint (TMJ), a Non-Weight-Bearing Joint, and Treatment with Bisphosphonate-Modified PEGylated rNell-1 (BP-NELL-PEG) | |
Lu et al. | Farrerol suppresses osteoclast differentiation and postmenopausal osteoporosis by inhibiting the nuclear factor kappa B signaling pathway | |
Zahid et al. | Efficacy of Bisphosphonates and Recombinant Parathyroid Hormone in Treatment of Osteoporosis in Pakistan | |
JP6508670B2 (ja) | 軟骨変性抑制剤 | |
JP2006143603A (ja) | 骨疾患治療用医薬複合剤 | |
JP2021121646A (ja) | 週2回の頻度でテリパラチド又はその塩を投与することを特徴とする、骨粗鬆症の予防又は治療方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180801 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191227 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20191227 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20201109 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20210120 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210205 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210507 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20211004 |