JP2021532087A - ビスホスホネート・キノロン複合体及びそれらの用途 - Google Patents
ビスホスホネート・キノロン複合体及びそれらの用途 Download PDFInfo
- Publication number
- JP2021532087A JP2021532087A JP2021500846A JP2021500846A JP2021532087A JP 2021532087 A JP2021532087 A JP 2021532087A JP 2021500846 A JP2021500846 A JP 2021500846A JP 2021500846 A JP2021500846 A JP 2021500846A JP 2021532087 A JP2021532087 A JP 2021532087A
- Authority
- JP
- Japan
- Prior art keywords
- group
- bone
- substituted
- linker
- quinolone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 bisphosphonate quinolone compound Chemical class 0.000 claims abstract description 203
- 229940122361 Bisphosphonate Drugs 0.000 claims abstract description 145
- 150000004663 bisphosphonates Chemical class 0.000 claims abstract description 127
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims abstract description 120
- 238000000034 method Methods 0.000 claims abstract description 69
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 54
- 125000003277 amino group Chemical group 0.000 claims abstract description 44
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 39
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 210000000988 bone and bone Anatomy 0.000 claims description 201
- 150000001875 compounds Chemical class 0.000 claims description 130
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 113
- 206010031252 Osteomyelitis Diseases 0.000 claims description 105
- 239000000203 mixture Substances 0.000 claims description 87
- 125000003118 aryl group Chemical group 0.000 claims description 80
- 229960003405 ciprofloxacin Drugs 0.000 claims description 75
- 238000011282 treatment Methods 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 239000007943 implant Substances 0.000 claims description 61
- 239000000463 material Substances 0.000 claims description 59
- 229940124307 fluoroquinolone Drugs 0.000 claims description 58
- 208000015181 infectious disease Diseases 0.000 claims description 58
- 125000001424 substituent group Chemical group 0.000 claims description 57
- 208000006389 Peri-Implantitis Diseases 0.000 claims description 47
- 150000007660 quinolones Chemical class 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 229960003702 moxifloxacin Drugs 0.000 claims description 31
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims description 27
- 241000894006 Bacteria Species 0.000 claims description 25
- 238000001356 surgical procedure Methods 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 230000002265 prevention Effects 0.000 claims description 21
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims description 18
- 229940046231 pamidronate Drugs 0.000 claims description 18
- 206010031264 Osteonecrosis Diseases 0.000 claims description 17
- 201000001245 periodontitis Diseases 0.000 claims description 17
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 16
- 208000008960 Diabetic foot Diseases 0.000 claims description 16
- 208000020084 Bone disease Diseases 0.000 claims description 15
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical class C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 claims description 14
- 229940062527 alendronate Drugs 0.000 claims description 14
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 claims description 14
- 229950011129 minodronic acid Drugs 0.000 claims description 14
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 14
- 229960004276 zoledronic acid Drugs 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 claims description 12
- 229950010733 neridronic acid Drugs 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000003306 quinoline derived antiinfective agent Substances 0.000 claims description 9
- 208000006386 Bone Resorption Diseases 0.000 claims description 8
- 230000024279 bone resorption Effects 0.000 claims description 8
- 229960002353 nemonoxacin Drugs 0.000 claims description 8
- AVPQPGFLVZTJOR-RYUDHWBXSA-N nemonoxacin Chemical compound COC1=C(N2C[C@@H](N)C[C@H](C)C2)C=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 AVPQPGFLVZTJOR-RYUDHWBXSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 7
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 7
- 229960003923 gatifloxacin Drugs 0.000 claims description 7
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- 229960003177 sitafloxacin Drugs 0.000 claims description 6
- QKDHBVNJCZBTMR-LLVKDONJSA-N (R)-temafloxacin Chemical compound C1CN[C@H](C)CN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F QKDHBVNJCZBTMR-LLVKDONJSA-N 0.000 claims description 5
- RUXPNBWPIRDVTH-UHFFFAOYSA-N Amifloxacin Chemical compound C1=C2N(NC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 RUXPNBWPIRDVTH-UHFFFAOYSA-N 0.000 claims description 5
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 claims description 5
- AIJTTZAVMXIJGM-UHFFFAOYSA-N Grepafloxacin Chemical compound C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 AIJTTZAVMXIJGM-UHFFFAOYSA-N 0.000 claims description 5
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 5
- QIPQASLPWJVQMH-DTORHVGOSA-N Orbifloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(F)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F QIPQASLPWJVQMH-DTORHVGOSA-N 0.000 claims description 5
- VMKVDAAFMQKZJS-LFIBNONCSA-N acorafloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCC\C(=C(/F)CN)C1 VMKVDAAFMQKZJS-LFIBNONCSA-N 0.000 claims description 5
- 229950009484 amifloxacin Drugs 0.000 claims description 5
- QFFGVLORLPOAEC-SNVBAGLBSA-N besifloxacin Chemical compound C1[C@H](N)CCCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QFFGVLORLPOAEC-SNVBAGLBSA-N 0.000 claims description 5
- 229960004024 besifloxacin Drugs 0.000 claims description 5
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 claims description 5
- 229950001320 clinafloxacin Drugs 0.000 claims description 5
- 229960004385 danofloxacin Drugs 0.000 claims description 5
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 claims description 5
- 229950006412 delafloxacin Drugs 0.000 claims description 5
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 claims description 5
- 229950001733 difloxacin Drugs 0.000 claims description 5
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960002549 enoxacin Drugs 0.000 claims description 5
- 229960003170 gemifloxacin Drugs 0.000 claims description 5
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 claims description 5
- 229960000642 grepafloxacin Drugs 0.000 claims description 5
- 229960003376 levofloxacin Drugs 0.000 claims description 5
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 claims description 5
- 229960002422 lomefloxacin Drugs 0.000 claims description 5
- JYJTVFIEFKZWCJ-UHFFFAOYSA-N nadifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCC(O)CC1 JYJTVFIEFKZWCJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960003808 nadifloxacin Drugs 0.000 claims description 5
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 5
- 229960001180 norfloxacin Drugs 0.000 claims description 5
- 229960004780 orbifloxacin Drugs 0.000 claims description 5
- 229960004576 temafloxacin Drugs 0.000 claims description 5
- 229960000497 trovafloxacin Drugs 0.000 claims description 5
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 claims description 5
- ZNPOCLHDJCAZAH-UCQKPKSFSA-N zabofloxacin Chemical compound CO\N=C1\CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CNC1 ZNPOCLHDJCAZAH-UCQKPKSFSA-N 0.000 claims description 5
- 229950005850 zabofloxacin Drugs 0.000 claims description 5
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 claims description 4
- XAGMUUZPGZWTRP-ZETCQYMHSA-N LSM-5745 Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1C1(N)CC1 XAGMUUZPGZWTRP-ZETCQYMHSA-N 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 230000000735 allogeneic effect Effects 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 229960002625 pazufloxacin Drugs 0.000 claims description 4
- 229960001248 pradofloxacin Drugs 0.000 claims description 4
- LZLXHGFNOWILIY-APPDUMDISA-N pradofloxacin Chemical compound C12=C(C#N)C(N3C[C@H]4NCCC[C@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 LZLXHGFNOWILIY-APPDUMDISA-N 0.000 claims description 4
- 230000002147 killing effect Effects 0.000 claims description 3
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 2
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 claims description 2
- UUZPPAMZDFLUHD-VUJLHGSVSA-N alatrofloxacin Chemical compound C([C@@H]1[C@H]([C@@H]1C1)NC(=O)[C@H](C)NC(=O)[C@@H](N)C)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F UUZPPAMZDFLUHD-VUJLHGSVSA-N 0.000 claims description 2
- 229960000919 alatrofloxacin Drugs 0.000 claims description 2
- 229960001699 ofloxacin Drugs 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- 230000002159 abnormal effect Effects 0.000 claims 1
- 150000004664 etidronic acid derivatives Chemical class 0.000 claims 1
- 229960004236 pefloxacin Drugs 0.000 claims 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 125000005647 linker group Chemical group 0.000 description 113
- 239000003242 anti bacterial agent Substances 0.000 description 79
- 229940088710 antibiotic agent Drugs 0.000 description 60
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 44
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 44
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 43
- 230000003115 biocidal effect Effects 0.000 description 43
- 229940009626 etidronate Drugs 0.000 description 40
- 125000000623 heterocyclic group Chemical group 0.000 description 40
- 238000009472 formulation Methods 0.000 description 38
- 239000003814 drug Substances 0.000 description 37
- 125000004414 alkyl thio group Chemical group 0.000 description 35
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 35
- 241000158640 Acanthodactylus aureus Species 0.000 description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 32
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 32
- 238000010586 diagram Methods 0.000 description 31
- 229940079593 drug Drugs 0.000 description 31
- 230000000694 effects Effects 0.000 description 31
- 230000000844 anti-bacterial effect Effects 0.000 description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 29
- 241001465754 Metazoa Species 0.000 description 27
- 125000003368 amide group Chemical group 0.000 description 27
- 125000005110 aryl thio group Chemical group 0.000 description 27
- 230000027455 binding Effects 0.000 description 26
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 26
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 26
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 26
- 125000005499 phosphonyl group Chemical group 0.000 description 26
- 108090000765 processed proteins & peptides Chemical group 0.000 description 26
- 238000012360 testing method Methods 0.000 description 25
- 238000013459 approach Methods 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 201000010099 disease Diseases 0.000 description 21
- 230000001580 bacterial effect Effects 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 125000003342 alkenyl group Chemical group 0.000 description 19
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 125000000304 alkynyl group Chemical group 0.000 description 18
- 241000282472 Canis lupus familiaris Species 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 17
- 125000004093 cyano group Chemical group *C#N 0.000 description 17
- 230000012010 growth Effects 0.000 description 17
- 230000000813 microbial effect Effects 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 208000035143 Bacterial infection Diseases 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 208000022362 bacterial infectious disease Diseases 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 229940127557 pharmaceutical product Drugs 0.000 description 16
- 241000700159 Rattus Species 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 15
- 125000005842 heteroatom Chemical group 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 15
- 244000052769 pathogen Species 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 125000000547 substituted alkyl group Chemical group 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000000699 topical effect Effects 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- 210000001847 jaw Anatomy 0.000 description 14
- 238000002560 therapeutic procedure Methods 0.000 description 14
- 229920001184 polypeptide Polymers 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 102000004196 processed proteins & peptides Human genes 0.000 description 13
- 125000005017 substituted alkenyl group Chemical group 0.000 description 13
- 125000005415 substituted alkoxy group Chemical group 0.000 description 13
- 125000004426 substituted alkynyl group Chemical group 0.000 description 13
- 125000003107 substituted aryl group Chemical group 0.000 description 13
- 125000000542 sulfonic acid group Chemical group 0.000 description 13
- 229910052717 sulfur Inorganic materials 0.000 description 13
- 125000000539 amino acid group Chemical group 0.000 description 12
- 229940088516 cipro Drugs 0.000 description 12
- 238000013461 design Methods 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 230000009885 systemic effect Effects 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 11
- 238000011161 development Methods 0.000 description 11
- 230000018109 developmental process Effects 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 230000007774 longterm Effects 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 230000008901 benefit Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 230000007547 defect Effects 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- HEDOODBJFVUQMS-UHFFFAOYSA-N n-[2-(5-methoxy-1h-indol-3-yl)ethyl]-n-methylpropan-2-amine Chemical group COC1=CC=C2NC=C(CCN(C)C(C)C)C2=C1 HEDOODBJFVUQMS-UHFFFAOYSA-N 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 230000008685 targeting Effects 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 235000015278 beef Nutrition 0.000 description 9
- 230000004097 bone metabolism Effects 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011593 sulfur Chemical group 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 229910052757 nitrogen Chemical group 0.000 description 8
- 238000012552 review Methods 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 7
- 108010035532 Collagen Proteins 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 7
- 239000013641 positive control Substances 0.000 description 7
- 230000000069 prophylactic effect Effects 0.000 description 7
- 230000008439 repair process Effects 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 206010005940 Bone and joint infections Diseases 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 229920001436 collagen Polymers 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 238000007918 intramuscular administration Methods 0.000 description 6
- 230000003902 lesion Effects 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 230000002459 sustained effect Effects 0.000 description 6
- 0 *C(C(C*(C1I*1)C1=C(*)**C(*)=C11)C1=O)=O Chemical compound *C(C(C*(C1I*1)C1=C(*)**C(*)=C11)C1=O)=O 0.000 description 5
- 241000282465 Canis Species 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 5
- 208000037581 Persistent Infection Diseases 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- 239000012620 biological material Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000004568 cement Substances 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 229940015872 ibandronate Drugs 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 231100000682 maximum tolerated dose Toxicity 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 5
- 230000001717 pathogenic effect Effects 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 206010011953 Decreased activity Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 208000029534 Infectious Bone disease Diseases 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 208000003926 Myelitis Diseases 0.000 description 4
- 206010031256 Osteomyelitis chronic Diseases 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 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 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- 230000000536 complexating effect Effects 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000035876 healing Effects 0.000 description 4
- 208000013210 hematogenous Diseases 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 238000002847 impedance measurement Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 230000000366 juvenile effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 238000010603 microCT Methods 0.000 description 4
- 230000002906 microbiologic effect Effects 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 230000000399 orthopedic effect Effects 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 230000003239 periodontal effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000011477 surgical intervention Methods 0.000 description 4
- 238000007910 systemic administration Methods 0.000 description 4
- 231100000057 systemic toxicity Toxicity 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 231100000607 toxicokinetics Toxicity 0.000 description 4
- 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 4
- KQEKGWRRNULYAL-UHFFFAOYSA-N 1,1-bis(dimethoxyphosphoryl)ethanol Chemical compound COP(=O)(OC)C(C)(O)P(=O)(OC)OC KQEKGWRRNULYAL-UHFFFAOYSA-N 0.000 description 3
- RJTQMWKXFLVXPU-UHFFFAOYSA-N 1-dimethoxyphosphorylethanone Chemical compound COP(=O)(OC)C(C)=O RJTQMWKXFLVXPU-UHFFFAOYSA-N 0.000 description 3
- 241001024600 Aggregatibacter Species 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 3
- 208000037408 Device failure Diseases 0.000 description 3
- PNGSTRLTLGBOEO-UHFFFAOYSA-N OC(OP(O)=O)OP(O)=O Chemical compound OC(OP(O)=O)OP(O)=O PNGSTRLTLGBOEO-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 241000605861 Prevotella Species 0.000 description 3
- 102100029143 RNA 3'-terminal phosphate cyclase Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000191940 Staphylococcus Species 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000003044 adaptive effect Effects 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000032770 biofilm formation Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical group NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010668 complexation reaction Methods 0.000 description 3
- 230000001054 cortical effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 239000004053 dental implant Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000012990 dithiocarbamate Substances 0.000 description 3
- 229960003722 doxycycline Drugs 0.000 description 3
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 238000007726 management method Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 3
- 229960004023 minocycline Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000003642 osteotropic effect Effects 0.000 description 3
- HJZKOAYDRQLPME-UHFFFAOYSA-N oxidronic acid Chemical compound OP(=O)(O)C(O)P(O)(O)=O HJZKOAYDRQLPME-UHFFFAOYSA-N 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 3
- 239000004926 polymethyl methacrylate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 229910052727 yttrium Inorganic materials 0.000 description 3
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 2
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 2
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 2
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 2
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 2
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 2
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 2
- 125000005955 1H-indazolyl group Chemical group 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- SLDBAXYJAIRQMX-UHFFFAOYSA-N 3-ethylthiophene Chemical class CCC=1C=CSC=1 SLDBAXYJAIRQMX-UHFFFAOYSA-N 0.000 description 2
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- 125000005986 4-piperidonyl group Chemical group 0.000 description 2
- 241000186046 Actinomyces Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000606125 Bacteroides Species 0.000 description 2
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000589876 Campylobacter Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 241001535083 Dialister Species 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
- 241000588877 Eikenella Species 0.000 description 2
- 241000588914 Enterobacter Species 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 241000605909 Fusobacterium Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000606790 Haemophilus Species 0.000 description 2
- 101000699762 Homo sapiens RNA 3'-terminal phosphate cyclase Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010024500 Limb malformation Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 101100346764 Mus musculus Mtln gene Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000006174 Newman-Kwart rearrangement reaction Methods 0.000 description 2
- KUFMXPZUZBPFCT-UHFFFAOYSA-N P(O)(OCOP(O)=O)=O Chemical class P(O)(OCOP(O)=O)=O KUFMXPZUZBPFCT-UHFFFAOYSA-N 0.000 description 2
- 241000122116 Parvimonas Species 0.000 description 2
- 241000191992 Peptostreptococcus Species 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 2
- 241000605894 Porphyromonas Species 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- 150000004661 S-thiocarbamates Chemical class 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000607720 Serratia Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 241001470488 Tannerella Species 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 241000589886 Treponema Species 0.000 description 2
- 241001148134 Veillonella Species 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 241000607734 Yersinia <bacteria> Species 0.000 description 2
- TZTKYLSDAUTWFG-XHSSBPLZSA-N [(8R,9S,13S,14S)-3,17-dihydroxy-13-methyl-15-phosphono-7,8,9,11,12,14,16,17-octahydro-6H-cyclopenta[a]phenanthren-15-yl]phosphonic acid Chemical compound C[C@]12CC[C@H]3[C@H]([C@@H]1C(CC2O)(P(=O)(O)O)P(=O)(O)O)CCC4=C3C=CC(=C4)O TZTKYLSDAUTWFG-XHSSBPLZSA-N 0.000 description 2
- BBAWTPDTGRXPDG-UHFFFAOYSA-N [1,3]thiazolo[4,5-b]pyridine Chemical compound C1=CC=C2SC=NC2=N1 BBAWTPDTGRXPDG-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000002924 anti-infective effect Effects 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- 150000001540 azides Chemical group 0.000 description 2
- 125000003943 azolyl group Chemical group 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000005512 benztetrazolyl group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000002805 bone matrix Anatomy 0.000 description 2
- 229940112869 bone morphogenetic protein Drugs 0.000 description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 125000004623 carbolinyl group Chemical group 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229960003260 chlorhexidine Drugs 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000001804 debridement Methods 0.000 description 2
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000004821 effect on bone Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 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
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000004926 indolenyl group Chemical group 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 125000004936 isatinoyl group Chemical group N1(C(=O)C(=O)C2=CC=CC=C12)C(=O)* 0.000 description 2
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 2
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 2
- 125000005438 isoindazolyl group Chemical group 0.000 description 2
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 208000029985 osteonecrosis of the jaw Diseases 0.000 description 2
- 231100000380 osteotoxicity Toxicity 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 description 2
- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 2
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 2
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 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
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 125000004928 piperidonyl group Chemical group 0.000 description 2
- 229960005235 piperonyl butoxide Drugs 0.000 description 2
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 150000003141 primary amines Chemical group 0.000 description 2
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 238000012175 pyrosequencing Methods 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical group 0.000 description 2
- 150000003871 sulfonates Chemical group 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical group C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- 230000009278 visceral effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 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
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- 108020004465 16S ribosomal RNA Proteins 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- IXQGCWUGDFDQMF-UHFFFAOYSA-N 2-Ethylphenol Chemical compound CCC1=CC=CC=C1O IXQGCWUGDFDQMF-UHFFFAOYSA-N 0.000 description 1
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 1
- UJNWGFBJUHIJKK-UHFFFAOYSA-N 2-[2-[4-(3-methylphenyl)piperazin-1-yl]ethyl]quinoline Chemical compound CC1=CC=CC(N2CCN(CCC=3N=C4C=CC=CC4=CC=3)CC2)=C1 UJNWGFBJUHIJKK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- RLYOPPJABLAKCZ-UHFFFAOYSA-N 2-butoxycarbonylbenzenecarboperoxoic acid Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OO RLYOPPJABLAKCZ-UHFFFAOYSA-N 0.000 description 1
- JCCCMAAJYSNBPR-UHFFFAOYSA-N 2-ethylthiophene Chemical compound CCC1=CC=CS1 JCCCMAAJYSNBPR-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- HMNKTRSOROOSPP-UHFFFAOYSA-N 3-Ethylphenol Chemical compound CCC1=CC=CC(O)=C1 HMNKTRSOROOSPP-UHFFFAOYSA-N 0.000 description 1
- AMKPQMFZCBTTAT-UHFFFAOYSA-N 3-ethylaniline Chemical class CCC1=CC=CC(N)=C1 AMKPQMFZCBTTAT-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- HRXZRAXKKNUKRF-UHFFFAOYSA-N 4-ethylaniline Chemical class CCC1=CC=C(N)C=C1 HRXZRAXKKNUKRF-UHFFFAOYSA-N 0.000 description 1
- HXDOZKJGKXYMEW-UHFFFAOYSA-N 4-ethylphenol Chemical compound CCC1=CC=C(O)C=C1 HXDOZKJGKXYMEW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000606749 Aggregatibacter actinomycetemcomitans Species 0.000 description 1
- 208000002679 Alveolar Bone Loss Diseases 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 102000003916 Arrestin Human genes 0.000 description 1
- 108090000328 Arrestin Proteins 0.000 description 1
- 206010060968 Arthritis infective Diseases 0.000 description 1
- 108010009565 Bio-Gide Proteins 0.000 description 1
- 208000000595 Bisphosphonate-Associated Osteonecrosis of the Jaw Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 244000132059 Carica parviflora Species 0.000 description 1
- 235000014653 Carica parviflora Nutrition 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010009260 Cleft lip and palate Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010011703 Cyanosis Diseases 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 238000007400 DNA extraction Methods 0.000 description 1
- 208000006558 Dental Calculus Diseases 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- 208000003790 Foot Ulcer Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 238000012313 Kruskal-Wallis test Methods 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- 101710122864 Major tegument protein Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 150000004660 O-thiocarbamates Chemical class 0.000 description 1
- BWDGLLGNNPHQHY-UHFFFAOYSA-N OP(=O)P(O)(O)=O Chemical compound OP(=O)P(O)(O)=O BWDGLLGNNPHQHY-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010031253 Osteomyelitis acute Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 101710148592 PTS system fructose-like EIIA component Proteins 0.000 description 1
- 101710169713 PTS system fructose-specific EIIA component Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000006735 Periostitis Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 101150109738 Ptger4 gene Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000283984 Rodentia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 101710199973 Tail tube protein Proteins 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241001416177 Vicugna pacos Species 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 108010055615 Zein Proteins 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 210000004504 adult stem cell Anatomy 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229920003232 aliphatic polyester Polymers 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000002355 alkine group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000011482 antibacterial activity assay Methods 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- SCJNCDSAIRBRIA-DOFZRALJSA-N arachidonyl-2'-chloroethylamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCCl SCJNCDSAIRBRIA-DOFZRALJSA-N 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 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 1
- 210000004763 bicuspid Anatomy 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000005313 bioactive glass Substances 0.000 description 1
- 230000008238 biochemical pathway Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000001680 brushing effect Effects 0.000 description 1
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical compound OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 208000016653 cleft lip/palate Diseases 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000011365 complex material Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000010219 correlation analysis Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000000551 dentifrice Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- CCVPHUGQSNUIBB-UHFFFAOYSA-N dimethoxyphosphoryl acetate Chemical compound COP(=O)(OC)OC(C)=O CCVPHUGQSNUIBB-UHFFFAOYSA-N 0.000 description 1
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002514 epidermal stem cell Anatomy 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 230000007236 host immunity Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 210000004086 maxillary sinus Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- AWIJRPNMLHPLNC-UHFFFAOYSA-N methanethioic s-acid Chemical compound SC=O AWIJRPNMLHPLNC-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100001224 moderate toxicity Toxicity 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 1
- 239000002070 nanowire Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940127249 oral antibiotic Drugs 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- VHFGEBVPHAGQPI-MYYQHNLBSA-N oritavancin Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@@](C)(NCC=4C=CC(=CC=4)C=4C=CC(Cl)=CC=4)C2)OC2=CC=C(C=C2Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@@H](O)[C@H](C)O1 VHFGEBVPHAGQPI-MYYQHNLBSA-N 0.000 description 1
- 229960001607 oritavancin Drugs 0.000 description 1
- 108010006945 oritavancin Proteins 0.000 description 1
- 238000010883 osseointegration Methods 0.000 description 1
- 230000002177 osteoclastogenic effect Effects 0.000 description 1
- 230000003256 osteocytic effect Effects 0.000 description 1
- 230000000010 osteolytic effect Effects 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229940097134 periochip Drugs 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000004537 potential cytotoxicity Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000026749 regulation of bone remodeling Effects 0.000 description 1
- 230000005558 regulation of bone resorption Effects 0.000 description 1
- 230000026011 regulation of ossification Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000003385 ring cleavage reaction Methods 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 208000015339 staphylococcus aureus infection Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical group 0.000 description 1
- 238000003239 susceptibility assay Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000005287 template synthesis Methods 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000009864 tensile test Methods 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 230000001550 time effect Effects 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- WVPSKSLAZQPAKQ-SOSAQKQKSA-N trovafloxacin Chemical compound C([C@H]1C([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-SOSAQKQKSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—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
- 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
- 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
- A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/552—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Biophysics (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Biomedical Technology (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
本願は2018年7月9日に出願された「ビスホスホネート・キノロン・バイオコンジュゲート及びそれらの使用(BISPHOSPHONATE QUINOLONE BIOCONJUGATES AND USES THEREOF)」という標題の同時係属中の米国仮特許出願第62/695,583号の利益とその仮特許出願に基づく優先権も主張するものであり、その仮出願の内容の全体を参照により本明細書に援用する。
本発明は、NIH/NIDCRによって支給された研究助成番号第R41DE025789−01号及びR42DE025789−02号、並びにNIH/NIAMSによって支給された研究助成番号第R43AR073727号の政府支援によって行われた。米国政府は本発明に対して一定の権利を有する。
R3はH又はOCH3のいずれかであり得、
R4はHであり得、
R5はH又はFであり得る。
本明細書において別途明示されない限り、以下の定義が提供される。
感染性骨疾患、すなわち骨髄炎は、ヒト医療及び獣医医療における世界的な大問題であり、四肢欠損に関わる後遺症及び死亡の可能性のために深刻な問題であり得る。骨髄炎に対する治療アプローチは主に抗菌剤によるものであり、長期間のアプローチであることが多く、多くの症例で感染を管理するために外科的介入を伴う。長骨骨髄炎の大半の症例における原因病原体は黄色ブドウ球菌(Staphylococcus aureus)の感染、及び該当するバイオフィルムであり、それらの黄色ブドウ球菌はそれらのプランクトン型(浮遊型)の対応物と対照的に骨に結合する。他の骨感染症及び該当するバイオフィルムが広範囲のグラム陽性細菌とグラム陰性細菌の両方から生じることが知られている。
BPキノロン複合体
本明細書はBPキノロン化合物、複合体及びそれらの製剤を提供する。BPはリンカーを介してキノロンに複合体化され得る。複数の実施形態において前記リンカーは分離可能リンカーである。前記キノロンはリンカーを介して分離可能に前記BPに結合し得る。したがって、幾つかの実施形態では前記BPキノロン複合体は骨、骨移植片、又は代替骨移植片に、又はその近傍に前記キノロンを選択的に送達し、且つ、分離することができる(図2)。換言すると、例えば、BPフルオロキノロン複合体は骨及び/又は骨の近接領域へのフルオロキノロンの標的化送達を提供することができる。
R2は、
R3はH又はOCH3のいずれかであり得、
R4はHであり得、
R5はH又はFであり得る。
本明細書は本明細書中のいずれかの1つ又は複数の態様又は実施形態のどこかに記載される量のBPキノロン化合物又は複合体を含有し得る医薬製剤をはじめとする製剤も説明する。その量は有効量であり得る。その量は細菌の増殖及び/又は繁殖を抑制するのに有効であり得る。その量は細菌を殺菌するのに有効であり得る。医薬製剤を含む製剤は様々な経路を介した送達向けに製剤化能であり、且つ、医薬的に許容可能なキャリアを含有し得る。全般的にRemmington’s Pharmaceutical Sciences、Meade Publishing社、イーストン、ペンシルバニア州(第20版、2000年)の中に技術と製剤を見出すことができ、その開示全体を参照により本明細書に援用する。全身投与には筋肉内注射、静脈内注射、腹腔内注射、及び皮下注射を含む注射が有用である。注射用に本発明の治療組成物は溶液中に、例えばハンクス液又はリンゲル液などの生理学的に適合する緩衝液中に製剤可能である。さらに、前記BPキノロン複合体及び/又はそれらの構成要素は固形形態で製剤され、使用直前に再溶解又は懸濁され得る。凍結乾燥形態も含まれる。前記BPキノロン複合体の医薬製剤を含む製剤は少なくとも無菌であり、且つ、発熱性物質を含まないことを特徴とし得る。これらの製剤はヒト用及び獣医用に使用される製剤を含む。
本明細書のいずれか1つ又は複数の態様又は実施形態に記載される前記BPキノロン化合物又は複合体及びその製剤は錠剤、カプセル剤、単回投与注射バイアル、又は単回投与注入バイアルなどの単位剤形で、又は上記製剤の場合のように骨移植材料と混合するための所定の用量として提供され得る。適切な場合、本明細書に記載される剤形はマイクロカプセル化され得る。いずれかの成分の放出を長期化するように、又は持続させるように前記剤形を調製することも可能である。幾つかの実施形態では放出が遅くなっている成分は前記複合型活性薬剤であり得る。他の実施形態では補助成分の放出が遅くなっている。成分の放出を遅くするための適切な方法には前記成分をポリマー、ワックス、ゲル等の材料で被覆すること、又はその材料の中に包埋することが含まれるがこれらに限定されない。遅延放出製剤は、例えば“Pharmaceutical dosage form tablets,” eds.Liberman et.al.(New York,Marcel Dekker,Inc.,1989),“Remington−The science and practice of pharmacy”,20th ed.,Lippincott Williams & Wilkins,Baltimore,MD,2000、及び“Pharmaceutical dosage forms and drug delivery systems”,6th Edition,Ansel et al.,(Media,PA: Williams and Wilkins,1995)などの標準的な参照文献の中に記載されているように調製され得る。これらの参照文献は賦形剤、材料、装置、並びに錠剤及びカプセル剤の調製方法、並びに錠剤及びペレット剤、カプセル剤、及び顆粒剤の遅延放出剤形についての情報を提供する。その遅延放出はどこでも約1時間〜約3か月又はそれ以上の期間にわたり得る。
前記製剤は(細菌の抑制及び/又は殺菌に有効な)有効量の本明細書のいずれか1つ又は複数の態様又は実施形態に記載されるBPキノロン化合物又は複合体を含有し得る。幾つかの実施形態ではその有効量は本明細書に記載される前記BPキノロン複合体の約0.001pg〜約1,000g又はそれ以上までの範囲にある。幾つかの実施形態では本明細書に記載される前記BPキノロン複合体の有効量は体重に対して約0.001mg/kg〜約1,000mg/kgまでの範囲であり得る。さらに他の実施形態では前記BPキノロン複合体の有効量は製剤全体の%(重量/重量)、%(重量/体積)、又は%(体積/体積)で約1%〜約99%又はそれ以上までの範囲であり得る。幾つかの実施形態では前記BPキノロン複合体の有効量は骨髄炎及びその全ての亜型(例えば糖尿病足骨髄炎)、顎骨壊死、及び歯周炎の原因因子であるStaphylococcus、Pseudomonas、Aggregatibacter、Actinomyces、Streptococcus、Haemophilus、Salmonella、Serratia、Enterobacter、Fusobacterium、Bacteroides、Porphyromonas、Prevotella、Veillonella、Campylobacter、Peptostreptococcus、Eikenella、Treponema、Dialister、Micromonas、Yersinia、Tannerella、及びEscherichiaのあらゆる株又は種を含むがこれらに限定されない細菌を殺菌するのに有効である。
有効量を含む特定量の本明細書のいずれか1つ又は複数の態様又は実施形態に記載される前記BPキノロン化合物、複合体及びそれらの製剤はそれらを必要とする対象に投与可能である。幾つかの実施形態ではそれらを必要とする前記対象は骨感染症、骨疾患、骨障害、又はその症状を有する可能性がある。幾つかの実施形態ではそれらを必要とする前記対象は骨感染症、骨疾患、骨障害、又はその症状を有することが疑われる可能性があるか、他の場合としてそのようなものを有する傾向を持つ可能性がある。幾つかの実施形態ではそれらを必要とする前記対象は骨髄炎、骨壊死、プロテーゼ周囲感染症、及び/又はインプラント周囲炎を発症する危険性を有する場合がある。複数の実施形態において前記疾患又は障害は骨髄炎及びその全ての亜型、骨壊死、インプラント周囲炎、又は歯周炎であり得る。幾つかの実施形態ではそれらを必要とする前記対象は細菌などの微生物が感染している骨を有する。幾つかの実施形態では前記細菌はStaphylococcus、Pseudomonas、Aggregatibacter、Actinomyces、Streptococcus、Haemophilus、Salmonella、Serratia、Enterobacter、Fusobacterium、Bacteroides、Porphyromonas、Prevotella、Veillonella、Campylobacter、Peptostreptococcus、Eikenella、Treponema、Dialister、Micromonas、Yersinia、Tannerella、またはEscherichiaのあらゆる株又は種であり得る。幾つかの実施形態では前記細菌はバイオフィルムを形成し得る。幾つかの実施形態では必要とする対象に特定量、例えば有効量の本明細書に記載されるBPキノロン複合体又はその製剤を投与することにより前記対象において骨髄炎を治療することが可能である。幾つかの実施形態では本明細書において提供される前記組成物及び化合物は骨壊死の治療及び/又は予防、骨延長法、口唇口蓋裂修復、重症の歯槽上欠損の修復、顎骨再構築、並びに骨及び/又は関節の他のあらゆる再構築又は修復に使用可能である。
感染性骨疾患、すなわち骨髄炎は、ヒト医療及び獣医医療における世界的な大問題であり、四肢欠損に関わる後遺症及び死亡の可能性のために深刻な問題であり得る(Lew,et al.,Osteomyelitis.Lancet 2004;364:369−79; Desrochers,et al,Limb amputation and prosthesis.Vet Clin North Am Food Anim Pract 2014;30:143−55; Stoodley,et al.,Orthopaedic biofilm infections.Curr Orthop Pract 2011;22:558−63; Huang,et al.,Chronic osteomyelitis increases long−term mortality risk in the elderly: a nationwide population−based cohort study.BMC Geriatr 2016;16:72)。骨髄炎に対する治療アプローチは主に抗菌剤によるものであり、長期間のアプローチであることが多く、多くの症例で感染を管理するために外科的介入を伴う。長骨骨髄炎の大半の症例における原因病原体が黄色ブドウ球菌のバイオフィルムであり、定義によるとこれらの微生物はそれらのプランクトン型(浮遊型)の対応物と対照的に骨(図1)に結合する(Wolcott,et al.,Biofilms and chronic infections.J Am Med Assoc 2008;299:2682−2684)。
前記BP複合体に含めることが可能なキノロンの非限定的な例
フッ素化キノロン
現在の治療アプローチの限界を考慮すると、骨/バイオフィルム標的化抗菌剤を開発することは、本分野における顕著な進歩である。本明細書において提供される前記BP−抗生物質(BP−Ab)複合体は骨内及び骨結合バイオフィルム内の貧弱な抗生物質薬物動態又は生物学的利用率に関連する多くの難点を克服することが可能である。これらの化合物は「ターゲット・リリースアプローチ」を介して感染を減少させることができ、そのアプローチは全身毒性及び/又は他の(例えば非感染)組織における薬品曝露に関する懸念を低減することができる。前記BP−Ab複合体は代替骨移植片に組み込み可能である。前記BP−AbはBP−フルオロキノロン複合体であり得る。幾つかの例では、前記BP−Abは図3に示されるようにビスホスホネート−カルバメート−シプロフロキサシン(BCC、化合物6)であり得る。図3の例示構造体は本明細書においてBCC(化合物6)とも呼ばれる。骨移植片に組み込まれると前記BP−Ab骨移植材料をBP−Ab−骨移植片と呼ぶことも可能である。例えば、その抗生物質がフルオロキノロンであるときにそれをBP−FQ−骨移植片と呼ぶことも可能である。これらの化合物は効果的にハイドロキシアパタイト(HA)/骨に吸着することが可能であり、且つ、経時的な持続的分離とバイオフィルム病原体に対する抗菌効果を達成することが可能である。本明細書において提供される前記化合物と前記化合物を組み込む移植材料をインプラント周囲炎の補助的治療又は予防のための抗感染性代替骨移植片として使用することが可能である。前記複合体は持続性分離カイネティクスで前記移植材料から局所的に放出され、我々が本明細書中の何処かで提供される他の結果の中でこれまでにインビトロ及びインビボで実証してきたように、細菌活性又は骨破壊活性が存在する中で切断されることになる。この様に前記移植片は現在の送達経路と比較して高い局所的濃度のFQ、例えばシプロフロキサシンを提供することができる。まとめると、本明細書において提供される前記化合物及び骨移植材料は、強力な多座配位静電相互作用を介して前記移植材料中のカルシウム/HAに結合した安全な、又は薬理学的に不活性の(非骨吸収抑制性)BP部分に複合体化されている抗生物質を含有することが可能であり、その抗生物質は経時的に分離する。それはこの状況で幾つかの現在の臨床アプローチとして既存の骨移植材料と単純に混合されて泥状物になる局所抗生物質を単に表すだけではない。したがって、リン酸カルシウム鉱物質(HA)に結合したこの化学吸着薬品は本分野における大きな進歩であり、バイオフィルム病原体に対する効果的な殺菌活性のためのインプラント周囲骨への抗生物質送達における限界の多くを克服する。
その他のBP−Ab複合体の設計と合成(図4)
例えば、カルバメート系リンカー(例えばカルバメート、S−チオカルバメート、及びO−チオカルバメート)を介してBP(例えば4−ヒドロキシフェニルエチリデンBP(BP1、図4)、そのヒドロキシ含有類似体(BP2、図4;比較的に高い骨親和性を有する)、及びパミドロネート(BP3、図4)に複合体化されているシプロフロキサシン及びモキシフロキサシンを使用して追加のBP−Ab複合体を設計することが可能である。図5はO−チオカルバメートリンカーを含むBP−Ab複合体の合成についての例となる合成スキームを示している。ニューマン・クワート転位を介するO−チオカルバメート結合を有する複合体の異性体化によってS−チオカルバメート結合(易変性がわずかに高い)を有する複合体を得ることができる(参照番号47、48)。これらの標的の急速合成の実現可能性を実証するための予備的な化学が既に実施されている。したがって、骨親和性の付加はα−OH含有性BPを使用してよく実証されている(49)。付加された骨親和性によって骨表面における前記複合体の濃度が上昇し、比較的に高い薬品の局所的濃度が短期及び長期にわたって容易に達成される。α−OHビスホスホネートエステルはホスホノホスフェートに再構成されやすいのでα−OH含有性BP(BP2及びパミドロネート、図4)を有する複合体の合成のためにそのα−OHはtert−ブチルジメチルシリル(TBS)基によって保護されてよい(スキーム2、図6)(50)。その後、α−O−TBS BP2エステルは4−ニトロフェニルクロロホルマートによって活性化され、そして図5に示されているように同様にシプロフロキサシン又はモキシフロキサシンと反応する。α−O−TBS BP3エステルについては、フェノール基を有するリンカー(例えば、リンカー1(レゾルシノール)、リンカー2(ヒドロキノン)、リンカー3(4−ヒドロキシフェニル酢酸)、図20)を使用してBPと抗菌剤を係留する。ここではリンカー3を使用する合成経路が例として示されている(スキーム3、図7)。全てのBP−Ab複合体を識別するためにそれらの特性を1H、31P、及び13CのNMR、MS、HPLC、並びに元素分析によって分析する。
SPSS 22.0(IBM社、アーモンク、ニューヨーク州)及びExcel 2016(Microsoft社、レドモンド、ワシントン州)を使用して統計計算を行う。全ての動物試験についてサンプルサイズの見積もりをするためにG Power 3ソフトウェア58を使用して検定力分析を実施した。これらの動物試験からのデータ収集の後にデータ(パラメトリック又は非パラメトリック)の分布を理解し、且つ、平均値、標準誤差、標準偏差、尖度と歪度、及び95%信頼レベルを生成するために定量結果をまず記述統計学によって分析する。場合に応じてクラスカル・ウォリス検定、ANOVA、又は混合線形モデルを用いてそのデータを分析し、群と群とを比較するときにα=0.05のレベルで統計学的有意性を実施する。所見をさらに確認するために独立t検定を活用するポストホック検定とダネットの多重比較検定も実施する。全ての動物実験は、結果の質、信頼性、有効性、及び再現性を確保するために動物実験について報告するためのARRIVEガイドライン59を使用して記載されている。
前記BP−Ab複合体を移植片及び移植器具に組み込むことができる。複数の実施形態において、ほんのわずかな例を挙げるとBioOss(登録商標)(Geistlich Pharma AG社、スイス)又はMinerOss(登録商標)(BioHorizons社、バーミングハム、アラバマ州)の牛骨材料など、既に認可されている骨移植製品に前記BP−Ab複合体のうちの1又は複数を組み込むことができる。歯科代替骨移植片として使用される支持材料と前記BP−Ab複合体を混合することが可能である。その製品は無機牛骨材料に吸着された前記複合体を含むことになる。この材料によって骨移植片移植領域への抗生物質の局所送達が行われて細菌感染率とインプラント周囲炎及び他の感染症などの関連の歯科病理が減少する。我々の製品の歯科応用にはインプラント周囲炎の治療ばかりか抜歯窩の維持、堤又は洞底の拳上術、歯周炎の予防又は治療、骨髄炎又は骨壊死の治療又は予防、又はそのような骨移植片が有益であり得る他の口腔歯周外科用途が含まれ得るだろう。前記BP−フルオロキノロン複合体材料は本質的に代替骨移植片に吸着されることになり、我々の予備的データは感染症の場合では骨破壊領域への持続的放出を示しており、それによって我々の製品は抗生物質を感染部位へより効果的に送達することができ、前記複合体化合物のどちらの成分に対する全身曝露も無視できる。
1. http://www.aaid.com/about/press_room/dental_implants_faq.html
2. Quirynen M,De Soete M,van Steenberghe D.Infectious risks for oral implants: a review of the literature.Clinical Oral Implants Research.2002;13(1):1−19.doi: 10.1034/j.1600−0501.2002.130101.x.PubMed PMID: 12005139.
3. Norowski PA,Jr.,Bumgardner JD.Biomaterial and antibiotic strategies for peri−implantitis: a review.J Biomed Mater Res B Appl Biomater.2009;88(2):530−43.doi: 10.1002/jbm.b.31152.PubMed PMID: 18698626.
4. Salvi GE,Cosgarea R,Sculean A.Prevalence and Mechanisms of Peri−implant Diseases.J Dent Res.2016.doi: 10.1177/0022034516667484.PubMed PMID: 27680028.
5. Meijer HJA,Raghoebar GM,de Waal YCM,Vissink A.Incidence of peri−implant mucositis and peri−implantitis in edentulous patients with an implant−retained mandibular overdenture during a 10−year follow−up period.Journal of Clinical Periodontology.2014;41(12):1178−83.doi: 10.1111/jcpe.12311.PubMed PMID: 25229397.
6. Jemt T,Olsson M,Stenport VF.Incidence of First Implant Failure: A Retroprospective Study of 27 Years of Implant Operations at One Specialist Clinic.Clinical Implant Dentistry and Related Research.2015;17:E501−E10.doi: 10.1111/cid.12277.PubMed PMID: 25536273.
7. Wolcott RD,Ehrlich GD.Biofilms and chronic infections.Jama−Journal of the American Medical Association.2008;299(22):2682−4.doi: 10.1001/jama.299.22.2682.PubMed PMID: 18544729.
8. Costerton JW,Cheng KJ,Geesey GG,Ladd TI,Nickel JC,Dasgupta M,Marrie TJ.Bacterial biofilms in nature and disesae.Annual Review of Microbiology.1987;41:435−64.PubMed PMID: 3318676.
9. Costerton JW,Geesey GG,Cheng KJ.How bacteria stick.Scientific American.1978;238(1):86−95.PubMed PMID: 635520.
10. Kumar PS,Mason MR,Brooker MR,O’Brien K.Pyrosequencing reveals unique microbial signatures associated with healthy and failing dental implants.J Clin Periodontol 2012;39(5):425−33.doi: 10.1111/j.1600−051X.2012.01856.x.PubMed PMID: 22417294; PubMed Central PMCID: PMC3323747.
11. Shibli JA,Melo L,Ferrari DS,Figueiredo LC,Faveri M,Feres M.Composition of supra and subgingival biofilm of subjects with healthy and diseased implants.Clin Oral Implants Res.2008;19(10):975−82.doi: 10.1111/j.1600−0501.2008.01566.x.PubMed PMID: 18828812.
12. Stoodley P,Ehrlich GD,Sedghizadeh PP,Hall−Stoodley L,Baratz ME,Altman DT,Sotereanos NG,Costerton JW,DeMeo P.Orthopaedic Biofilm Infections.Curr Orthop Pract.2011;22(6):558−63.PubMed PMID: 22323927; PubMed Central PMCID: PMC3272669.
13. Javed F,AlGhamdi AST,Ahmed A,Mikami T,Ahmed HB,Tenenbaum HC.Clinical efficacy of antibiotics in the treatment of peri−implantitis.International Dental Journal.2013;63(4):169−76.doi: 10.1111/idj.12034.PubMed PMID: 23879251.
14. Smeets R,Henningsen A,Jung O,Heiland M,Hammacher C,Stein JM.Definition,etiology,prevention and treatment of peri−implantitis − a review.Head Face Med.2014;10.doi: 10.1186/1746−160x−10−34.PubMed PMID: 25185675; PubMed Central PMCID: PMC4164121.
15. Leonhardt A,Dahlen G,Renvert S.Five−year clinical,microbiological,and radiological outcome following treatment of peri−implantitis in man.J Periodontol.2003;74(10):1415−22.doi: 10.1902/jop.2003.74.10.1415.PubMed PMID: 14653386.
16. Mombelli A.Microbiology and antimicrobial therapy of peri−implantitis.Periodontol 2000.2002;28:177−89.PubMed PMID: 12013341.
17. Levison ME,Levison JH.Pharmacokinetics and Pharmacodynamics of Antibacterial Agents.Infect Dis Clin North Am.2009;23(4):75−89.doi: 10.1016/j.idc.2009.06.008.PubMed PMID: 24484576; PubMed Central PMCID: PMC4079031
18. Kaur K,Sikri P.Evaluation of the effect of allograft with doxycycline versus the allograft alone in the treatment of infrabony defects: A controlled clinical and radiographical study.Dent Res J (Isfahan).2013;10(2):238−46.PubMed PMID: 23946743; PubMed Central PMCID: PMC3731967.
19. Inzana JA,Schwarz EM,Kates SL,Awad HA.Biomaterials approaches to treating implant−associated osteomyelitis.Biomaterials.2016;81:58−71.doi: 10.1016/j.biomaterials.2015.12.012.PubMed PMID: 26724454.
20. Schmitt CM,Moest T,Lutz R,Neukam FW,Schlegel KA.Anorganic bovine bone (ABB) vs.autologous bone (AB) plus ABB in maxillary sinus grafting.A prospective non−randomized clinical and histomorphometrical trial.Clin Oral Implants Res.2015;26(9):1043−50.doi: 10.1111/clr.12396.PubMed PMID: 24730602.
21. Kluin OS,van der Mei HC,Busscher HJ,Neut D.Biodegradable vs non−biodegradable antibiotic delivery devices in the treatment of osteomyelitis.Expert Opin Drug Deliv.2013;10(3):341−51.doi: 10.1517/17425247.2013.751371.PubMed PMID: 23289645.
22. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019537s073,020780s030lbl.pdf
23. Nancollas GH,Tang R,Phipps RJ,Henneman Z,Gulde S,Wu W,Mangood A,Russell RGG,Ebetino FH.Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite.Bone.2006;38(5):617−27.doi: 10.1016/j.bone.2005.05.003.PubMed PMID: 16046206.
24. Russell RGG,Watts NB,Ebetino FH,Rogers MJ.Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy.Osteoporos Int 2008;19(6):733−59.doi: 10.1007/s00198−007−0540−8.PubMed PMID: 18214569.
25. Kavanagh KL,Guo KD,Dunford JE,Wu XQ,Knapp S,Ebetino FH,Rogers MJ,Russell RGG,Oppermann U.The molecular mechanism of nitrogen−containing bisphosphonates as anti osteoporosis drugs.Proc Natl Acad Sci U S A.2006;103(20):7829−34.doi: 10.1073/pnas.0601643103.PubMed PMID: 16684881; PubMed Central PMCID: PMC1472530.
26. Kashemirov BA,Bala JLF,Chen X,Ebetino FH,Xia Z,Russell RGG,Coxon FP,Roelofs AJ,Rogers MJ,McKenna CE.Fluorescently labeled risedronate and related analogues: ”magic linker” synthesis.Bioconjug Chem.2008;19(12):2308−10.doi: 10.1021/bc800369c.PubMed PMID: 19032080.
27. Junka AF,Szymczyk P,Smutnicka D,Kos M,Smolina I,Bartoszewicz M,Chlebus E,Turniak M,Sedghizadeh PP.Microbial biofilms are able to destroy hydroxyapatite in the absence of host immunity in vitro.J Oral Maxillofac Surg.2015;73(3):451−64.doi: 10.1016/j.joms.2014.09.019.PubMed PMID: 25544303.
28. Sedghizadeh PP,Kumar SKS,Gorur A,Schaudinn C,Shuler CF,Costerton JW.Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy.J Oral Maxillofac Surg 2008;66(4):767−75.doi: 10.1016/j.joms.2007.11.035.PubMed PMID: 18355603.
29. Sedghizadeh PP,Kumar SKS,Gorur A,Schaudinn C,Shuler CF,Costerton JW.Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy.J Am Dent Assoc.2009;140(10):1259−65.PubMed PMID: 19797556.
30. Zhang SF,Gangal G,Uludag H.’Magic bullets’ for bone diseases: progress in rational design of bone−seeking medicinal agents.Chem Soc Rev 2007;36(3):507−31.doi: 10.1039/b512310k.PubMed PMID: 17325789.
31. Herczegh P,Buxton TB,McPherson JC,Kovacs−Kulyassa A,Brewer PD,Sztaricskai F,Stroebel GG,Plowman KM,Farcasiu D,Hartmann JF.Osteoadsorptive bisphosphonate derivatives of fluoroquinolone antibacterials.J Med Chem.2002;45(11):2338−41.doi: 10.1021/jm0105326.PubMed PMID: 12014972.
32. Buxton TB,Walsh DS,Harvey SB,McPherson JC,Hartmann JF,Plowman KM.Bisphosphonate−ciprofloxacin bound to Skelite (TM) is a prototype for enhancing experimental local antibiotic delivery to injured bone.British Journal of Surgery.2004;91(9):1192−6.doi: 10.1002/bjs.4644.PubMed PMID: 15449273.
33. Tanaka KSE,Houghton TJ,Kang T,Dietrich E,Delorme D,Ferreira SS,Caron L,Viens F,Arhin FF,Sarmiento I,Lehoux D,Fadhil I,Laquerre K,Liu J,Ostiguy V,Poirier H,Moeck G,Parr TR,Far AR.Bisphosphonated fluoroquinolone esters as osteotropic prodrugs for the prevention of osteomyelitis.Bioorg Med Chem.2008;16(20):9217−29.doi: 10.1016/j.bmc.2008.09.010.PubMed PMID: 18815051.
34. Houghton TJ,Tanaka KSE,Kang T,Dietrich E,Lafontaine Y,Delorme D,Ferreira SS,Viens F,Arhin FF,Sarmiento I,Lehoux D,Fadhil I,Laquerre K,Liu J,Ostiguy V,Poirier H,Moeck G,Parr TR,Far AR.Linking Bisphosphonates to the Free Amino Groups in Fluoroquinolones: Preparation of Osteotropic Prodrugs for the Prevention of Osteomyelitis.J Med Chem.2008;51(21):6955−69.doi: 10.1021/jm801007z.PubMed PMID: 18834106.
35. Tanaka KSE,Dietrich E,Ciblat S,Metayer C,Arhin FF,Sarmiento I,Moeck G,Parr TR,Far AR.Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis.Bioorg Med Chem Lett.2010;20(4):1355−9.doi: 10.1016/j.bmcl.2010.01.006.PubMed PMID: 20097069.
36. Arns S,Gibe R,Moreau A,Morshed MM,Young RN.Design and synthesis of novel bone−targeting dual−action pro−drugs for the treatment and reversal of osteoporosis.Bioorganic & Medicinal Chemistry.2012;20(6):2131−40.doi: 10.1016/j.bmc.2012.01.024.PubMed PMID: 22341574.
37. Liu CC,Hu S,Chen G,Georgiou J,Arns S,Kumar NS,Young RN,Grynpas MD.Novel EP4 Receptor Agonist−Bisphosphonate Conjugate Drug (C1) Promotes Bone Formation and Improves Vertebral Mechanical Properties in the Ovariectomized Rat Model of Postmenopausal Bone Loss.J Bone Miner Res.2015;30(4):670−80.doi: 10.1002/jbmr.2382.PubMed PMID: 25284325.
38. Morioka M,Kamizono A,Takikawa H,Mori A,Ueno H,Kadowaki SI,Nakao Y,Kato K,Umezawa K.Design,synthesis,and biological evaluation of novel estradiol−bisphosphonate conjugates as bone−specific estrogens.Bioorg Med Chem.2010;18(3):1143−8.doi: 10.1016/j.bmc.2009.12.041.PubMed PMID: 20071185
39. Katsarelis H,Shah NP,Dhariwal DK,Pazianas M.Infection and Medication−related Osteonecrosis of the Jaw.J Dent Res.2015;94(4):534−9.doi: 10.1177/0022034515572021.PubMed PMID: 25710950.
40. Lee SH,Chan RC,Chang SS,Tan YL,Chang KH,Lee MC,Chang HE,Lee CC.Use of bisphosphonates and the risk of osteonecrosis among cancer patients: a systemic review and meta−analysis of the observational studies.Support Care Cancer.2014;22(2):553−60.doi: 10.1007/s00520−013−2017−y.PubMed PMID: 24203085.
41. Moura LA,Ribeiro FV,Aiello TB,Duek EAD,Sallum EA,Nociti FH,Casati MZ,Sallum AW.Characterization of the release profile of doxycycline by PLGA microspheres adjunct to non−surgical periodontal therapy.J Biomater Sci Polym Ed 2015;26(10):573−84.doi: 10.1080/09205063.2015.1045249.PubMed PMID: 25917501
42. https://www.govtrack.us/congress/bills/114/hr34/text
43. EUCAST breakpoint tables for interpretation of MICs and zone diameters.2015.http://www.eucast.org/
44. McPherson JC,Runner R,Buxton TB,Hartmann JF,Farcasiu D,Bereczki I,Roth E,Tollas S,Ostorhazi E,Rozgonyi F,Herczegh P.Synthesis of osteotropic hydroxybisphosphonate derivatives of fluoroquinolone antibacterials.Eur J Med Chem.2012;47:615−8.doi: 10.1016/j.ejmech.2011.10.049.PubMed PMID: 22093760.
45. Freire MO,Sedghizadeh PP,Schaudinn C,Gorur A,Downey JS,Choi JH,Chen W,Kook JK,Chen C,Goodman SD,Zadeh HH.Development of an Animal Model for Aggregatibacter Actinomycetemcomitans Biofilm−Mediated Oral Osteolytic Infection: A Preliminary Study.J Periodontol.2011;82(5):778−89.doi: 10.1902/jop.2010.100263.PubMed PMID: 21222546.
46. Vacondio F,Silva C,Lodola A,Fioni A,Rivara S,Duranti A,Tontini A,Sanchini S,Clapper JR,Piomelli D,Mor M,Tarzia G.Structure−property relationships of a class of carbamate−based fatty acid amide hydrolase (FAAH) inhibitors: chemical and biological stability.ChemMedChem.2009;4(9):1495−504.doi: 10.1002/cmdc.200900120.PubMed PMID: 19554599; PubMed Central PMCID: PMCPMC3517974.
47. Lloyd−Jones GC,Moseley JD,Renny JS.Mechanism and application of the Newman−Kwart O −> S rearrangement of O−aryl thiocarbamates.Synthesis−Stuttgart.2008(5):661−89.doi: 10.1055/s−2008−1032179.
48. Moseley JD,Sankey RF,Tang ON,Gilday JP.The Newman−Kwart rearrangement re−evaluated by microwave synthesis.Tetrahedron.2006;62(19):4685−9.doi: 10.1016/j.tet.2005.12.063.
49. Ebetino FH,Hogan AM,Sun S,Tsoumpra MK,Duan X,Triffitt JT,Kwaasi AA,Dunford JE,Barnett BL,Oppermann U,Lundy MW,Boyde A,Kashemirov BA,McKenna CE,Russell RG.The relationship between the chemistry and biological activity of the bisphosphonates.Bone.2011;49(1):20−33.doi: 10.1016/j.bone.2011.03.774.PubMed PMID: 21497677.
50. Vachal P,Hale JJ,Lu Z,Streckfuss EC,Mills SG,MacCoss M,Yin DH,Algayer K,Manser K,Kesisoglou F,Ghosh S,Alani LL.Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis.J Med Chem.2006;49(11):3060−3.doi: 10.1021/jm060398v.PubMed PMID: 16722624.
51. Lopez−Piriz R,Sola−Linares E,Rodriguez−Portugal M,Malpica B,Diaz−Gumes I,Enciso S,Esteban−Tejeda L,Cabal B,Granizo JJ,Moya JS,Torrecillas R.Evaluation in a Dog Model of Three Antimicrobial Glassy Coatings: Prevention of Bone Loss around Implants and Microbial Assessments.Plos One.2015;10(10).doi: 10.1371/journal.pone.0140374.PubMed PMID: 26489088; PubMed Central PMCID: PMC4619200
52. Orti V,Bousquet P,Tramini P,Gaitan C,Mertens B,Cuisinier F.Benefits of mineralized bone cortical allograft for immediate implant placement in extraction sites: an in vivo study in dogs.J Periodontal Implant Sci.2016;46(5):291−302.doi: 10.5051/jpis.2016.46.5.291.PubMed PMID: 27800212; PubMed Central PMCID: PMC5083813.
53. Reizner W,Hunter JG,O’Malley NT,Southgate RD,Schwarz EM,Kates SL.A systematic review of animal models for Staphylococcus aureus osteomyelitis.European Cells & Materials.2014;27:196−212.PubMed PMID: 24668594; PubMed Central PMCID: PMC4322679.
54. Wancket LM.Animal Models for Evaluation of Bone Implants and Devices: Comparative Bone Structure and Common Model Uses.Vet Pathol 2015;52(5):842−50.doi: 10.1177/0300985815593124.PubMed PMID: 26163303.
55. Saber MH,Schwarzberg K,Alonaizan FA,Kelley ST,Sedghizadeh PP,Furlan M,Levy TA,Simon JH,Slots J.Bacterial Flora of Dental Periradicular Lesions Analyzed by the 454−Pyrosequencing Technology.J Endod.2012;38(11):1484−8.doi: 10.1016/j.joen.2012.06.037.PubMed PMID: 23063222.
56. Caporaso JG,Kuczynski J,Stombaugh J,Bittinger K,Bushman FD,Costello EK,Fierer N,Pena AG,Goodrich JK,Gordon JI,Huttley GA,Kelley ST,Knights D,Koenig JE,Ley RE,Lozupone CA,McDonald D,Muegge BD,Pirrung M,Reeder J,Sevinsky JR,Tumbaugh PJ,Walters WA,Widmann J,Yatsunenko T,Zaneveld J,Knight R.QIIME allows analysis of high−throughput community sequencing data.Nature Methods.2010;7(5):335−6.doi: 10.1038/nmeth.f.303.PubMed PMID: 20383131.
57. Battula S,Lee JW,Wen HB,Papanicolaou S,Collins M,Romanos GE.Evaluation of Different Implant Designs in a Ligature−Induced Peri−implantitis Model: A Canine Study.International Journal of Oral & Maxillofacial Implants.2015;30(3):534−45.doi: 10.11607/jomi.3737.PubMed PMID: 26009904.
58. Faul F,Erdfelder E,Buchner A,Lang AG.Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses.Behav Res Methods.2009;41(4):1149−60.doi: 10.3758/brm.41.4.1149.PubMed PMID: 19897823.
59. Kilkenny C,Browne W,Cuthill IC,Emerson M,Altman DG.Animal research: Reporting in vivo experiments: The ARRIVE guidelines.Br J Pharmacol.2010;160(7):1577−9.doi: 10.1111/j.1476−5381.2010.00872.x.PubMed PMID: 20649561; PubMed Central PMCID: PMC2936830.
60. Salvi GE,Lang NP.Diagnostic parameters for monitoring peri−implant conditions.Int J Oral Maxillofac Implants.2004;19:116−27.PubMed PMID: 15635952.
61.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072193.pdf
62. Jaehde U,Zurcher J,Sorgel F,Naber K,Schunack W.Metabolism of Ciprofloxacin in Humans following Oral and Intravenous Administration.Reviews of Infectious Diseases.1989;11:S1135.
63. Vancebryan K,Guay DRP,Rotschafer JC.Clinical pharmacokinetics of ciprofloxacin.Clin Pharmacokinet 1990;19(6):434−61.PubMed PMID: 2292168.
64. Baumans V,Brain PF,Brugere H,Clausing P,Jeneskog T,Perretta G.Pain and distress in laboratory rodents and lagomorphs.Report of the Federation of European Laboratory Animal Science Associations (FELASA) Working Group on Pain and Distress accepted by the FELASA Board of Management November 1992.Laboratory Animals.1994;28(2):97−112.doi: 10.1258/002367794780745308.PubMed PMID: 8035572.
65. Sedghizadeh PP,Jones AC,LaVallee C,Jelliffe RW,Le AD,Lee P,Kiss A,Neely M.Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate−related osteonecrosis of the jaw.Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115(2):224−32.doi: 10.1016/j.oooo.2012.08.455.PubMed PMID: 23246224; PubMed Central PMCID: PMC3545087.
66. O’Donnell JN,Gulati A,Lavhale MS,Sharma SS,Patel AJ,Rhodes NJ,Scheetz MH.Pharmacokinetics of centhaquin citrate in a rat model.J Pharm Pharmacol.2016;68(1):56−62.doi: 10.1111/jphp.12498.PubMed PMID: 26725913.
67. Neely MN,van Guilder MG,Yamada WM,Schumitzky A,Jelliffe RW.Accurate Detection of Outliers and Subpopulations With Pmetrics,a Nonparametric and Parametric Pharmacometric Modeling and Simulation Package for R.Ther Drug Monit.2012;34(4):467−76.doi: 10.1097/FTD.0b013e31825c4ba6.PubMed PMID: 22722776 PubMed Central PMCID: PMC3394880
68. Tatarinova T,Neely M,Bartroff J,van Guilder M,Yamada W,Bayard D,Jelliffe R,Leary R,Chubatiuk A,Schumitzky A.Two general methods for population pharmacokinetic modeling: non−parametric adaptive grid and non−parametric Bayesian.J Pharmacokinet Pharmacodyn.2013;40(2):189−99.doi: 10.1007/s10928−013−9302−8.PubMed PMID: 23404393; PubMed Central PMCID: PMC3630269.
69. Wacha H,Wagner D,Schafer V,Knothe H.Concentration of ciprofloxacin in bone tissue after single parenteral administration to patients older than 70 years.Infection.1990;18(3):173−6.PubMed PMID: 2365470.
本実施例は様々なBP複合体化合物及び合成スキームを示す。BP−カルバメート−モキシフロキサシンBP複合体及び合成スキームが図8において示されている。図9はBP−カルバメート−ガチフロキサシンBP複合体及び合成スキームを示している。図10はBP−p−ヒドロキシフェニル酢酸−シプロフロキサシンBP複合体及び合成スキームを示している。図11はBP−OH−シプロフロキサシンBP複合体及び合成スキームを示している。図12はBP−O−チオカルバメート−シプロフロキサシンBP複合体及び合成スキームを示している。図13はBP−S−チオカルバメート−シプロフロキサシンBP複合体及び合成スキームを示している。図14はBP−レゾルシノール−シプロフロキサシンBP複合体及び合成スキームを示している。図15はBP−ヒドロキノン−シプロフロキサシンBP複合体及び合成スキームを示している。
1.ジメチルアセチルホスホネート(37)
2.テトラメチル(1−ヒドロキシエチリデン)−ビスホスホネート(38)
下記のものは、本明細書における1つ又は複数の態様に記載されたものであり得るBP−キノロンの一般構造である。
以下は、本明細書の1つ又は複数の態様において記載したBPキノロン複合体の非限定的な例である。
骨に対するBPの親和性を利用するため、BP複合体による骨又はヒドロキシアパタイト(HA)への抗生物質の送達を伴う「ターゲット・リリース」ケミストリーアプローチを検討した。骨表面で代謝されて親抗生物質を分離する血清安定性の薬品−BPリンカーを使用した。新規なキノロン抗生物質エチドロネート−シプロフロキサシン(ECC)複合体であるBV81022、及びエチドロネート−モキシフロキサシン(ECX)複合体であるBV81051を設計し、合成し、ほとんどの骨髄炎症例の原因であるS.aureusのバイオフィルムに対する活性について試験した。
1)Coenye T,Nelis H.J.In vitro and in vivo model systems to study microbial biofilm formation.J Microbiol Methods 2010;83,89−105.
2)Saginur R,Stdenis M,Ferris W,Aaron,S.D,Chan F,Lee C,Ramotar K.Multiple combination bactericidal testing of staphylococcal biofilms from implant−associated infections.Antimicrob Agents Chemother 2006;50,55−61.
3)Sedghizadeh PP and Ebetino FH et al.Design,synthesis,and antimicrobial evaluation of a novel bone−targeting bisphosphonate−ciprofloxacin conjugate for the treatment of osteomyelitis biofilms.J Med Chem 2017;60,2326−43.
4)Atienza J.M,Zhu J,Wang X,Xu X,Abassi Y.Dynamic monitoring of cell adhesion and spreading on microelectronic sensor arrays.J Biomol Screen 2005;10,795−805.
Claims (34)
- 前記BPがα−OH含有BPであり、前記キノロンが前記BPに前記BPのジェミナルOHで直接的又は間接的に複合体化されている、請求項1に記載の化合物。
- 前記キノロンがフルオロキノロンである、請求項1又は請求項2に記載の化合物。
- 前記キノロンが、アラトロフロキサシン、アミフロキサシン、バロフロキサシン、ベシフロキサシン、カダゾリド、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、デラフロキサシン、ジフロキサシン、エノキサシン、エンロフロキサシン、フィナフロキサシン、フレロフロキサシン、フルメキン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、イバフロキサシン、JNJ−Q2、レボフロキサシン、ロメフロキサシン、マルボフロキサシン、モキシフロキサシン、ナジフロキサシン、ノルフロキサシン、オフロキサシン、オルビフロキサシン、パズフロキサシン、ペフロキサシン、プラドフロキサシン、プルリフロキサシン、ルフロキサシン、サラフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン、ザボフロキサシン、ネモノキサシン及びそれらの組み合わせからなる群より選択される、請求項1又は請求項2に記載の化合物。
- 前記ビスホスホネートが:修飾型又は非修飾型の、エチドロネート、メチレンヒドロキシビスホスホネート(MHBP)、リセドロネート、ゾレドロネート、ミノドロネート、ネリドロネート、パミドロネート、アレンドロネート及びそれらの組み合わせからなる群より選択される、請求項1に記載の化合物。
- 前記キノロン化合物がフルオロキノロンである、請求項7又は請求項8に記載の化合物。
- 前記キノロン化合物が:アラトロフロキサシン、アミフロキサシン、バロフロキサシン、ベシフロキサシン、カダゾリド、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、デラフロキサシン、ジフロキサシン、エノキサシン、エンロフロキサシン、フィナフロキサシン、フレロフロキサシン、フルメキン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、イバフロキサシン、JNJ−Q2、レボフロキサシン、ロメフロキサシン、マルボフロキサシン、モキシフロキサシン、ナジフロキサシン、ノルフロキサシン、オフロキサシン、オルビフロキサシン、パズフロキサシン、ペフロキサシン、プラドフロキサシン、プルリフロキサシン、ルフロキサシン、サラフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン、ザボフロキサシン、ネモノキサシン及びそれらの組み合わせからなる群より選択される、請求項7又は請求項8に記載の化合物。
- 前記キノロン化合物がシプロフロキサシン、モキシフロキサシン、シタフロキサシン又はネモノキサシンである、請求項7又は請求項8に記載の化合物。
- 前記リンカーがカルバメート、チオカルバメート、ヒドラジン又はカーボネート若しくはエステル又はウレアである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがカルバメートリンカー又はエステルリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがアルキルカルバメートリンカー又はアリールカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがO−チオアリールカルバメートリンカー又はチオアルキルカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがS−チオアリールカルバメートリンカー又はチオアルキルカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがフェニルカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがチオカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがO−チオカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- 前記リンカーがS−チオカルバメートリンカーである、請求項7〜請求項11のいずれか一項に記載の化合物。
- ある量の請求項1〜請求項20のいずれか一項に記載の化合物;及び
医薬的に許容可能なキャリア
を含む医薬製剤。 - 前記化合物の前記量が、細菌を死滅させるか、又は抑止するのに有効な量である、請求項21に記載の医薬製剤。
- 前記化合物の前記量が、異常な骨吸収を伴う骨疾患、骨粗鬆症、骨感染症、骨髄炎、骨壊死、インプラント周囲炎及び歯周炎を治療又は予防するのに有効な量である、請求項21に記載の医薬製剤。
- 骨感染症の治療を必要とする対象において骨感染症を治療する方法であって:
ある量の請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤を、骨感染症の治療を必要とする前記対象に投与すること
を含む方法。 - 骨髄炎の治療を必要とする対象において骨髄炎を治療する方法であって:
ある量の請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤を、骨髄炎の治療を必要とする前記対象に投与すること
を含む方法。 - インプラント周囲炎又は歯周炎の治療を必要とする対象においてインプラント周囲炎又は歯周炎を治療する方法であって、ある量の請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤を、インプラント周囲炎又は歯周炎の治療を必要とする前記対象に投与することを含む方法。
- 糖尿病足の治療を必要とする対象において糖尿病足を治療する方法であって、ある量の請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤を、糖尿病足の治療を必要とする前記対象に投与することを含む方法。
- ある量の請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤を対象に投与すること
を含む方法。 - 骨移植材料及び請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤を含む骨移植組成物であって、前記化合物又は医薬製剤が前記骨移植材料に付着している、前記骨移植材料と一体化している、前記骨移植材料に化学吸着されている、又は前記骨移植材料と混合されている骨移植組成物。
- 前記骨移植材料が自家移植骨材料、同種移植骨材料、異種移植骨材料、合成骨移植材料、又はそれらのあらゆる組合せである、請求項29に記載の骨移植組成物。
- 必要とする対象において請求項29又は請求項30に記載の骨移植組成物を移植することを含む方法。
- 骨手術部位若しくはインプラント手術部位又は骨移植が実施されている手術部位におけるバイオフィルム感染を予防する方法であって:
請求項1〜請求項20のいずれか一項に記載の化合物又はその医薬製剤をバイオフィルム感染の予防を必要とする対象に投与すること
を含む方法。 - 骨手術部位若しくはインプラント手術部位又は骨移植が実施されている手術部位におけるバイオフィルム感染を予防する方法であって:
請求項29又は請求項30に記載の骨移植組成物をバイオフィルム感染の予防を必要とする対象に移植すること
を含む方法。 - 骨感染症の治療を必要とする対象における骨感染症の治療用の医薬製剤の製造のための請求項1〜請求項20のいずれか一項に記載の組成物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862695583P | 2018-07-09 | 2018-07-09 | |
US62/695,583 | 2018-07-09 | ||
PCT/US2019/041063 WO2020014269A1 (en) | 2018-07-09 | 2019-07-09 | Bisphosphonate quinolone conjugates and uses thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2021532087A true JP2021532087A (ja) | 2021-11-25 |
JPWO2020014269A5 JPWO2020014269A5 (ja) | 2022-06-10 |
JP7501960B2 JP7501960B2 (ja) | 2024-06-18 |
Family
ID=69142455
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021500846A Active JP7501960B2 (ja) | 2018-07-09 | 2019-07-09 | ビスホスホネート・キノロン複合体及びそれらの用途 |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP3820565A4 (ja) |
JP (1) | JP7501960B2 (ja) |
CN (1) | CN112672787A (ja) |
CA (1) | CA3105829A1 (ja) |
WO (1) | WO2020014269A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112533612A (zh) * | 2018-06-26 | 2021-03-19 | 弗兰克·哈洛克·埃比蒂诺 | 骨靶向抗微生物噁唑烷酮相关化合物、其制剂及其用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015560A1 (en) * | 1996-10-09 | 1998-04-16 | Elizanor Biopharmaceuticals, Inc. | Diphosphonate therapeutic compounds |
JP2008536911A (ja) * | 2005-04-21 | 2008-09-11 | ターガンタ セラピュティクス,インコーポレイティド | ホスホン酸処理フルオロキノロン、その抗菌類似体および骨および関節感染の予防および治療方法 |
JP2009505974A (ja) * | 2005-08-11 | 2009-02-12 | ターガンタ セラピュティクス,インコーポレイティド | ホスホン化リファマイシン類および骨と関節感染の予防と治療のためのその投与法 |
-
2019
- 2019-07-09 CN CN201980058610.8A patent/CN112672787A/zh active Pending
- 2019-07-09 JP JP2021500846A patent/JP7501960B2/ja active Active
- 2019-07-09 CA CA3105829A patent/CA3105829A1/en active Pending
- 2019-07-09 EP EP19835178.5A patent/EP3820565A4/en active Pending
- 2019-07-09 WO PCT/US2019/041063 patent/WO2020014269A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015560A1 (en) * | 1996-10-09 | 1998-04-16 | Elizanor Biopharmaceuticals, Inc. | Diphosphonate therapeutic compounds |
JP2008536911A (ja) * | 2005-04-21 | 2008-09-11 | ターガンタ セラピュティクス,インコーポレイティド | ホスホン酸処理フルオロキノロン、その抗菌類似体および骨および関節感染の予防および治療方法 |
JP2009505974A (ja) * | 2005-08-11 | 2009-02-12 | ターガンタ セラピュティクス,インコーポレイティド | ホスホン化リファマイシン類および骨と関節感染の予防と治療のためのその投与法 |
Non-Patent Citations (5)
Title |
---|
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 16, no. 20, JPN6023014953, October 2008 (2008-10-01), pages 9217 - 9229, ISSN: 0005039235 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 21, JPN6023014955, 4 October 2018 (2018-10-04), pages 6955 - 6969, ISSN: 0005039236 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 6, JPN6023014956, 13 February 2017 (2017-02-13), pages 2326 - 2343, ISSN: 0005039237 * |
新実験化学講座15, JPN6021015686, 1976, pages 1074頁, ISSN: 0005039239 * |
野崎正勝 等, 創薬化学, vol. 第1版, JPN6012059719, 1995, pages 98 - 99, ISSN: 0005039238 * |
Also Published As
Publication number | Publication date |
---|---|
EP3820565A4 (en) | 2022-04-06 |
JP7501960B2 (ja) | 2024-06-18 |
EP3820565A1 (en) | 2021-05-19 |
CN112672787A (zh) | 2021-04-16 |
WO2020014269A9 (en) | 2020-03-05 |
CA3105829A1 (en) | 2020-01-16 |
WO2020014269A1 (en) | 2020-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11840549B2 (en) | Bisphosphonate quinolone conjugates and uses thereof | |
Sedghizadeh et al. | Design, synthesis, and antimicrobial evaluation of a novel bone-targeting bisphosphonate-ciprofloxacin conjugate for the treatment of osteomyelitis biofilms | |
Almoshari et al. | GSK3 inhibitor-loaded osteotropic Pluronic hydrogel effectively mitigates periodontal tissue damage associated with experimental periodontitis | |
US10729810B2 (en) | Methods, systems, and compositions for promoting bone growth | |
JP2023181185A (ja) | ビスホスホネート・キノロン複合体及びそれらの用途 | |
Houghton et al. | Linking bisphosphonates to the free amino groups in fluoroquinolones: preparation of osteotropic prodrugs for the prevention of osteomyelitis | |
JPWO2006016695A1 (ja) | Ep4アゴニストを含有してなる高カリウム血症の予防および/または治療剤 | |
JP6010196B2 (ja) | オキサゾリジノン含有二量体化合物、組成物、ならびに作製および使用方法 | |
Sedghizadeh et al. | Bisphosphonates in dentistry: Historical perspectives, adverse effects, and novel applications | |
JP7501960B2 (ja) | ビスホスホネート・キノロン複合体及びそれらの用途 | |
JP2011518169A (ja) | 骨増殖を変化させるための化合物及び方法 | |
CN109641003A (zh) | 甲状腺β-激动剂的应用 | |
JP2021528499A (ja) | 骨標的抗菌オキサゾリジノン関連化合物、その製剤及び用途 | |
US11400104B2 (en) | Skeletal removal of bisphosphonates | |
Musolino et al. | Bisphosphonates (BPs) are drugs made up of two phosphonic acids joined to a car-bon plus two side chains designated R and R 2 (Fig. 1). They have wide use as antiscaling agents because of their physical-chemical property of complexing with divalent cations (eg, calcium and magnesium). The P–C–P structure acts as a bone | |
Almoshari | Development of Local Drug Delivery Systems for Periodontal Disease | |
KR20080093343A (ko) | 골대사성 질환의 예방 및 치료를 위한 조성물 | |
RU2271822C1 (ru) | Композиция для профилактики и лечения болезней, вызываемых дефицитом кальция (варианты) | |
Musolino et al. | Osteonecrosis | |
Daoudi | H istological A nalysisof M icrobial C olonizationand O steoclastic A ctivityin B isphosphonate-T reated R ats |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220602 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220602 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230418 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230413 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230710 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230915 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231018 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231107 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240207 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240507 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240603 |