WO2012168342A1 - Biopassivierende membranstabilisation mittels nitrocarbonsäuren-enthaltenden phospholipiden in zubereitungen und beschichtungen - Google Patents
Biopassivierende membranstabilisation mittels nitrocarbonsäuren-enthaltenden phospholipiden in zubereitungen und beschichtungen Download PDFInfo
- Publication number
- WO2012168342A1 WO2012168342A1 PCT/EP2012/060773 EP2012060773W WO2012168342A1 WO 2012168342 A1 WO2012168342 A1 WO 2012168342A1 EP 2012060773 W EP2012060773 W EP 2012060773W WO 2012168342 A1 WO2012168342 A1 WO 2012168342A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- nitro
- dinitro
- cyclo
- hydroxy
- Prior art date
Links
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 355
- LJDZFAPLPVPTBD-UHFFFAOYSA-N nitroformic acid Chemical compound OC(=O)[N+]([O-])=O LJDZFAPLPVPTBD-UHFFFAOYSA-N 0.000 title claims abstract description 227
- 238000000576 coating method Methods 0.000 title claims abstract description 134
- 238000002360 preparation method Methods 0.000 title description 53
- 239000012528 membrane Substances 0.000 title description 31
- 230000006641 stabilisation Effects 0.000 title description 9
- 238000011105 stabilization Methods 0.000 title description 9
- -1 stents Chemical class 0.000 claims abstract description 1172
- 239000000203 mixture Substances 0.000 claims abstract description 296
- 239000000243 solution Substances 0.000 claims abstract description 131
- 239000011248 coating agent Substances 0.000 claims abstract description 88
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000002872 contrast media Substances 0.000 claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 claims abstract description 22
- 239000012487 rinsing solution Substances 0.000 claims abstract description 12
- 230000010412 perfusion Effects 0.000 claims abstract description 11
- 229940127554 medical product Drugs 0.000 claims abstract description 8
- 239000003755 preservative agent Substances 0.000 claims abstract description 8
- 230000002335 preservative effect Effects 0.000 claims abstract description 8
- 210000004027 cell Anatomy 0.000 claims description 182
- 210000001519 tissue Anatomy 0.000 claims description 106
- 125000004432 carbon atom Chemical group C* 0.000 claims description 99
- 239000002253 acid Substances 0.000 claims description 78
- 239000007943 implant Substances 0.000 claims description 55
- 239000000126 substance Substances 0.000 claims description 51
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 48
- 239000000463 material Substances 0.000 claims description 35
- 208000027418 Wounds and injury Diseases 0.000 claims description 30
- 206010052428 Wound Diseases 0.000 claims description 29
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 27
- 210000000056 organ Anatomy 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 claims description 17
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 16
- 206010021143 Hypoxia Diseases 0.000 claims description 16
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 230000006378 damage Effects 0.000 claims description 12
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 claims description 11
- 208000014674 injury Diseases 0.000 claims description 11
- 239000002356 single layer Substances 0.000 claims description 11
- 230000007954 hypoxia Effects 0.000 claims description 10
- 235000021313 oleic acid Nutrition 0.000 claims description 10
- 230000008733 trauma Effects 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 9
- 150000007942 carboxylates Chemical group 0.000 claims description 9
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 claims description 9
- 210000004204 blood vessel Anatomy 0.000 claims description 8
- MBMBGCFOFBJSGT-KUBAVDMBSA-N docosahexaenoic acid Natural products CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 claims description 8
- 230000001976 improved effect Effects 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
- 239000003053 toxin Substances 0.000 claims description 8
- 231100000765 toxin Toxicity 0.000 claims description 8
- 108700012359 toxins Proteins 0.000 claims description 8
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 claims description 7
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 7
- 229940108623 eicosenoic acid Drugs 0.000 claims description 7
- 239000012595 freezing medium Substances 0.000 claims description 7
- LQJBNNIYVWPHFW-QXMHVHEDSA-N gadoleic acid Chemical compound CCCCCCCCCC\C=C/CCCCCCCC(O)=O LQJBNNIYVWPHFW-QXMHVHEDSA-N 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 230000002769 anti-restenotic effect Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 claims description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims description 6
- 230000003204 osmotic effect Effects 0.000 claims description 6
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 claims description 6
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 6
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 claims description 6
- 210000000481 breast Anatomy 0.000 claims description 5
- 238000005138 cryopreservation Methods 0.000 claims description 5
- 239000008150 cryoprotective solution Substances 0.000 claims description 5
- CNVZJPUDSLNTQU-SEYXRHQNSA-N petroselinic acid Chemical compound CCCCCCCCCCC\C=C/CCCCC(O)=O CNVZJPUDSLNTQU-SEYXRHQNSA-N 0.000 claims description 5
- 210000004872 soft tissue Anatomy 0.000 claims description 5
- DTOSIQBPPRVQHS-UHFFFAOYSA-N α-Linolenic acid Chemical compound CCC=CCC=CCC=CCCCCCCCC(O)=O DTOSIQBPPRVQHS-UHFFFAOYSA-N 0.000 claims description 5
- YUFFSWGQGVEMMI-UHFFFAOYSA-N (7Z,10Z,13Z,16Z,19Z)-7,10,13,16,19-docosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCCCC(O)=O YUFFSWGQGVEMMI-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 claims description 4
- 206010061688 Barotrauma Diseases 0.000 claims description 4
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 claims description 4
- CQXMAMUUWHYSIY-UHFFFAOYSA-N Lignoceric acid Natural products CCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 CQXMAMUUWHYSIY-UHFFFAOYSA-N 0.000 claims description 4
- CNVZJPUDSLNTQU-UHFFFAOYSA-N Petroselaidic acid Natural products CCCCCCCCCCCC=CCCCCC(O)=O CNVZJPUDSLNTQU-UHFFFAOYSA-N 0.000 claims description 4
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 4
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- WBHHMMIMDMUBKC-QJWNTBNXSA-N ricinoleic acid Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(O)=O WBHHMMIMDMUBKC-QJWNTBNXSA-N 0.000 claims description 4
- FEUQNCSVHBHROZ-UHFFFAOYSA-N ricinoleic acid Natural products CCCCCCC(O[Si](C)(C)C)CC=CCCCCCCCC(=O)OC FEUQNCSVHBHROZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- JIWBIWFOSCKQMA-UHFFFAOYSA-N stearidonic acid Natural products CCC=CCC=CCC=CCC=CCCCCC(O)=O JIWBIWFOSCKQMA-UHFFFAOYSA-N 0.000 claims description 4
- HXQHFNIKBKZGRP-URPRIDOGSA-N (5Z,9Z,12Z)-octadecatrienoic acid Chemical compound CCCCC\C=C/C\C=C/CC\C=C/CCCC(O)=O HXQHFNIKBKZGRP-URPRIDOGSA-N 0.000 claims description 3
- YUFFSWGQGVEMMI-RCHUDCCISA-N (7e,10e,13e,16e,19e)-docosa-7,10,13,16,19-pentaenoic acid Chemical compound CC\C=C\C\C=C\C\C=C\C\C=C\C\C=C\CCCCCC(O)=O YUFFSWGQGVEMMI-RCHUDCCISA-N 0.000 claims description 3
- ZONJATNKKGGVSU-UHFFFAOYSA-N 14-methylpentadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCC(O)=O ZONJATNKKGGVSU-UHFFFAOYSA-N 0.000 claims description 3
- NGYPZWVLQXBEJM-UHFFFAOYSA-N 2,4-bis(methylsulfanyl)butanoic acid Chemical compound CSCCC(SC)C(O)=O NGYPZWVLQXBEJM-UHFFFAOYSA-N 0.000 claims description 3
- YNCBLMJCJJLPEK-UHFFFAOYSA-N 4,6-bis(methylsulfanyl)hexanoic acid Chemical compound CSCCC(SC)CCC(O)=O YNCBLMJCJJLPEK-UHFFFAOYSA-N 0.000 claims description 3
- AVKOENOBFIYBSA-GUTOPQIJSA-N 4,7,10,13,16-Docosapentaenoic acid Chemical compound CCCCC\C=C\C\C=C\C\C=C\C\C=C\C\C=C\CCC(O)=O AVKOENOBFIYBSA-GUTOPQIJSA-N 0.000 claims description 3
- AVKOENOBFIYBSA-UHFFFAOYSA-N 4,7,10,13,16-Docosapentaenoic acid Natural products CCCCCC=CCC=CCC=CCC=CCC=CCCC(O)=O AVKOENOBFIYBSA-UHFFFAOYSA-N 0.000 claims description 3
- MUZYOAHCGSIXJH-UHFFFAOYSA-N 8-(2-hexylcyclopropyl)octanoic acid Chemical compound CCCCCCC1CC1CCCCCCCC(O)=O MUZYOAHCGSIXJH-UHFFFAOYSA-N 0.000 claims description 3
- YDYPHWDFKZRIHX-UHFFFAOYSA-N 8-methylsulfanyloctanoic acid Chemical compound CSCCCCCCCC(O)=O YDYPHWDFKZRIHX-UHFFFAOYSA-N 0.000 claims description 3
- FBUKMFOXMZRGRB-YFHOEESVSA-N 9(10)-EpOME Chemical compound CCCCC\C=C/CC1OC1CCCCCCCC(O)=O FBUKMFOXMZRGRB-YFHOEESVSA-N 0.000 claims description 3
- HQPCSDADVLFHHO-UHFFFAOYSA-N Cis-8,11,14,17-Eicosatetraenoic acid Chemical compound CCC=CCC=CCC=CCC=CCCCCCCC(O)=O HQPCSDADVLFHHO-UHFFFAOYSA-N 0.000 claims description 3
- FBUKMFOXMZRGRB-UHFFFAOYSA-N Coronaric acid Natural products CCCCCC=CCC1OC1CCCCCCCC(O)=O FBUKMFOXMZRGRB-UHFFFAOYSA-N 0.000 claims description 3
- 235000021353 Lignoceric acid Nutrition 0.000 claims description 3
- 235000021314 Palmitic acid Nutrition 0.000 claims description 3
- HXQHFNIKBKZGRP-UHFFFAOYSA-N Ranuncelin-saeure-methylester Natural products CCCCCC=CCC=CCCC=CCCCC(O)=O HXQHFNIKBKZGRP-UHFFFAOYSA-N 0.000 claims description 3
- TWSWSIQAPQLDBP-UHFFFAOYSA-N adrenic acid Natural products CCCCCC=CCC=CCC=CCC=CCCCCCC(O)=O TWSWSIQAPQLDBP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- TWSWSIQAPQLDBP-DOFZRALJSA-N all-cis-docosa-7,10,13,16-tetraenoic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O TWSWSIQAPQLDBP-DOFZRALJSA-N 0.000 claims description 3
- JIWBIWFOSCKQMA-LTKCOYKYSA-N all-cis-octadeca-6,9,12,15-tetraenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/CCCCC(O)=O JIWBIWFOSCKQMA-LTKCOYKYSA-N 0.000 claims description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 3
- MSUOLNSQHLHDAS-UHFFFAOYSA-N cerebronic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCC(O)C(O)=O MSUOLNSQHLHDAS-UHFFFAOYSA-N 0.000 claims description 3
- 239000004020 conductor Substances 0.000 claims description 3
- HOBAELRKJCKHQD-UHFFFAOYSA-N dihomo-γ-linolenic acid Chemical compound CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 claims description 3
- SHMXLCRUTGTGGS-UHFFFAOYSA-N dithiolane-3-carboxylic acid Chemical compound OC(=O)C1CCSS1 SHMXLCRUTGTGGS-UHFFFAOYSA-N 0.000 claims description 3
- MBMBGCFOFBJSGT-SFGLVEFQSA-N docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C\C\C=C\C\C=C\C\C=C\C\C=C\C\C=C\CCC(O)=O MBMBGCFOFBJSGT-SFGLVEFQSA-N 0.000 claims description 3
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 3
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 claims description 3
- QQHJDPROMQRDLA-UHFFFAOYSA-N hexadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCC(O)=O QQHJDPROMQRDLA-UHFFFAOYSA-N 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims description 3
- YWWVWXASSLXJHU-WAYWQWQTSA-N myristoleic acid Chemical compound CCCC\C=C/CCCCCCCC(O)=O YWWVWXASSLXJHU-WAYWQWQTSA-N 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- 229930002330 retinoic acid Natural products 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- QZZGJDVWLFXDLK-UHFFFAOYSA-N tetracosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(O)=O QZZGJDVWLFXDLK-UHFFFAOYSA-N 0.000 claims description 3
- 229960001727 tretinoin Drugs 0.000 claims description 3
- DXNCZXXFRKPEPY-UHFFFAOYSA-N tridecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCC(O)=O DXNCZXXFRKPEPY-UHFFFAOYSA-N 0.000 claims description 3
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 claims description 2
- 239000013566 allergen Substances 0.000 claims description 2
- 238000000502 dialysis Methods 0.000 claims description 2
- 230000001815 facial effect Effects 0.000 claims description 2
- 210000003709 heart valve Anatomy 0.000 claims description 2
- 230000010410 reperfusion Effects 0.000 claims description 2
- 238000002271 resection Methods 0.000 claims description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 claims 4
- KEMQGTRYUADPNZ-UHFFFAOYSA-N heptadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(O)=O KEMQGTRYUADPNZ-UHFFFAOYSA-N 0.000 claims 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 4
- PAHGJZDQXIOYTH-UHFFFAOYSA-N pristanic acid Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C(O)=O PAHGJZDQXIOYTH-UHFFFAOYSA-N 0.000 claims 4
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 claims 2
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 claims 2
- RKQDHVGICBPMIZ-UHFFFAOYSA-N 2-methylideneoctadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(=C)C(O)=O RKQDHVGICBPMIZ-UHFFFAOYSA-N 0.000 claims 2
- 235000021357 Behenic acid Nutrition 0.000 claims 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims 2
- 206010020843 Hyperthermia Diseases 0.000 claims 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims 2
- 235000021355 Stearic acid Nutrition 0.000 claims 2
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims 2
- 229940116226 behenic acid Drugs 0.000 claims 2
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 claims 2
- KFEVDPWXEVUUMW-UHFFFAOYSA-N docosanoic acid Natural products CCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 KFEVDPWXEVUUMW-UHFFFAOYSA-N 0.000 claims 2
- 230000036031 hyperthermia Effects 0.000 claims 2
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 claims 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims 2
- SBHCLVQMTBWHCD-METXMMQOSA-N (2e,4e,6e,8e,10e)-icosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C(O)=O SBHCLVQMTBWHCD-METXMMQOSA-N 0.000 claims 1
- PRHHYVQTPBEDFE-URZBRJKDSA-N (5Z,11Z,14Z)-icosatrienoic acid Chemical compound CCCCC\C=C/C\C=C/CCCC\C=C/CCCC(O)=O PRHHYVQTPBEDFE-URZBRJKDSA-N 0.000 claims 1
- DFJAXEWDHVOILU-UHFFFAOYSA-N (5Z,9E)-5,9-Octadecadienoic acid Natural products CCCCCCCCC=CCCC=CCCCC(O)=O DFJAXEWDHVOILU-UHFFFAOYSA-N 0.000 claims 1
- UNSRRHDPHVZAHH-UHFFFAOYSA-N 5,8,11-eicosatrienoic acid Chemical compound CCCCCCCCC=CCC=CCC=CCCCC(O)=O UNSRRHDPHVZAHH-UHFFFAOYSA-N 0.000 claims 1
- OYHQOLUKZRVURQ-UHFFFAOYSA-N 9,12-Octadecadienoic Acid Chemical compound CCCCCC=CCC=CCCCCCCCC(O)=O OYHQOLUKZRVURQ-UHFFFAOYSA-N 0.000 claims 1
- DFJAXEWDHVOILU-KWUOUXIESA-N Taxoleic acid Chemical compound CCCCCCCC\C=C/CC\C=C/CCCC(O)=O DFJAXEWDHVOILU-KWUOUXIESA-N 0.000 claims 1
- 238000002224 dissection Methods 0.000 claims 1
- PRHHYVQTPBEDFE-UHFFFAOYSA-N eicosatrienoic acid Natural products CCCCCC=CCC=CCCCCC=CCCCC(O)=O PRHHYVQTPBEDFE-UHFFFAOYSA-N 0.000 claims 1
- 230000004927 fusion Effects 0.000 claims 1
- YZXBAPSDXZZRGB-UHFFFAOYSA-N icosa-5,8,11,14-tetraenoic acid Chemical compound CCCCCC=CCC=CCC=CCC=CCCCC(O)=O YZXBAPSDXZZRGB-UHFFFAOYSA-N 0.000 claims 1
- 230000001717 pathogenic effect Effects 0.000 claims 1
- 239000002831 pharmacologic agent Substances 0.000 claims 1
- 239000002577 cryoprotective agent Substances 0.000 abstract description 5
- 238000005470 impregnation Methods 0.000 abstract description 5
- 239000003356 suture material Substances 0.000 abstract description 4
- 230000002338 cryopreservative effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
- 229960004956 glycerylphosphorylcholine Drugs 0.000 description 143
- 238000000034 method Methods 0.000 description 95
- 238000006243 chemical reaction Methods 0.000 description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- 238000004128 high performance liquid chromatography Methods 0.000 description 66
- 230000000694 effects Effects 0.000 description 64
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 59
- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
- 230000015572 biosynthetic process Effects 0.000 description 59
- 230000032050 esterification Effects 0.000 description 57
- 238000005886 esterification reaction Methods 0.000 description 57
- 239000010410 layer Substances 0.000 description 51
- 238000006396 nitration reaction Methods 0.000 description 51
- 150000003254 radicals Chemical class 0.000 description 49
- 239000000047 product Substances 0.000 description 42
- 238000003786 synthesis reaction Methods 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 29
- 230000004075 alteration Effects 0.000 description 29
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 27
- 238000000746 purification Methods 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 210000000170 cell membrane Anatomy 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 238000002953 preparative HPLC Methods 0.000 description 25
- 150000004665 fatty acids Chemical class 0.000 description 24
- 238000005755 formation reaction Methods 0.000 description 24
- 235000014113 dietary fatty acids Nutrition 0.000 description 23
- 238000002474 experimental method Methods 0.000 description 23
- 229930195729 fatty acid Natural products 0.000 description 23
- 239000000194 fatty acid Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 229920000642 polymer Polymers 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 150000001735 carboxylic acids Chemical class 0.000 description 20
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 230000004663 cell proliferation Effects 0.000 description 19
- 239000013545 self-assembled monolayer Substances 0.000 description 19
- 230000002792 vascular Effects 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 17
- 230000006907 apoptotic process Effects 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 16
- 230000012292 cell migration Effects 0.000 description 16
- 235000020778 linoleic acid Nutrition 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000969 carrier Substances 0.000 description 15
- 229940042880 natural phospholipid Drugs 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 229960004488 linolenic acid Drugs 0.000 description 14
- 230000017074 necrotic cell death Effects 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 108060003393 Granulin Proteins 0.000 description 13
- 206010028851 Necrosis Diseases 0.000 description 13
- 229920001577 copolymer Polymers 0.000 description 13
- 230000001965 increasing effect Effects 0.000 description 13
- 230000035755 proliferation Effects 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- JLPULHDHAOZNQI-AKMCNLDWSA-N [3-hexadecanoyloxy-2-[(9z,12z)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-AKMCNLDWSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 210000002889 endothelial cell Anatomy 0.000 description 12
- 239000011859 microparticle Substances 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- NJRMERHPSVGZHK-LZOINSICSA-N (9e,12z)-9-nitrooctadeca-9,12-dienoic acid Chemical compound CCCCC\C=C/C\C=C([N+]([O-])=O)/CCCCCCCC(O)=O NJRMERHPSVGZHK-LZOINSICSA-N 0.000 description 11
- WTJKGGKOPKCXLL-VYOBOKEXSA-N 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC WTJKGGKOPKCXLL-VYOBOKEXSA-N 0.000 description 11
- 108090000695 Cytokines Proteins 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 239000001963 growth medium Substances 0.000 description 11
- 238000011835 investigation Methods 0.000 description 11
- 150000002632 lipids Chemical group 0.000 description 11
- 125000004971 nitroalkyl group Chemical group 0.000 description 11
- 238000000039 preparative column chromatography Methods 0.000 description 11
- 108010088751 Albumins Proteins 0.000 description 10
- 102000009027 Albumins Human genes 0.000 description 10
- 150000007513 acids Chemical class 0.000 description 10
- 230000007246 mechanism Effects 0.000 description 10
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 10
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 10
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 9
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 9
- 108010052285 Membrane Proteins Proteins 0.000 description 9
- 239000005642 Oleic acid Substances 0.000 description 9
- 230000036755 cellular response Effects 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 238000007598 dipping method Methods 0.000 description 9
- 230000035876 healing Effects 0.000 description 9
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 9
- 210000002540 macrophage Anatomy 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000001179 sorption measurement Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- CQOAKBVRRVHWKV-SAPNQHFASA-N (9E)-9-nitrooctadecenoic acid Chemical compound CCCCCCCC\C=C([N+]([O-])=O)/CCCCCCCC(O)=O CQOAKBVRRVHWKV-SAPNQHFASA-N 0.000 description 8
- LELVHAQTWXTCLY-XYWKCAQWSA-N 10-Nitro-9Z,12Z-octadecadienoic acid Chemical compound CCCCC\C=C/C\C([N+]([O-])=O)=C/CCCCCCCC(O)=O LELVHAQTWXTCLY-XYWKCAQWSA-N 0.000 description 8
- VUWNNVXIDWRCNO-UHFFFAOYSA-N 10-hydroxy-9-nitrooctadecanoic acid Chemical compound CCCCCCCCC(O)C([N+]([O-])=O)CCCCCCCC(O)=O VUWNNVXIDWRCNO-UHFFFAOYSA-N 0.000 description 8
- 108010035532 Collagen Proteins 0.000 description 8
- 102000008186 Collagen Human genes 0.000 description 8
- 102000016359 Fibronectins Human genes 0.000 description 8
- 108010067306 Fibronectins Proteins 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 229920001436 collagen Polymers 0.000 description 8
- 229960005188 collagen Drugs 0.000 description 8
- 238000002591 computed tomography Methods 0.000 description 8
- 239000002537 cosmetic Substances 0.000 description 8
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 230000002209 hydrophobic effect Effects 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 8
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 102000007547 Laminin Human genes 0.000 description 7
- 108010085895 Laminin Proteins 0.000 description 7
- 208000007536 Thrombosis Diseases 0.000 description 7
- 230000001464 adherent effect Effects 0.000 description 7
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 230000000875 corresponding effect Effects 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 230000007794 irritation Effects 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 230000005012 migration Effects 0.000 description 7
- 238000013508 migration Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 230000000704 physical effect Effects 0.000 description 7
- 238000010186 staining Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 102000004506 Blood Proteins Human genes 0.000 description 6
- 108010017384 Blood Proteins Proteins 0.000 description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 229920000954 Polyglycolide Polymers 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 6
- 230000021164 cell adhesion Effects 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 210000003743 erythrocyte Anatomy 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000007710 freezing Methods 0.000 description 6
- 230000008014 freezing Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000001146 hypoxic effect Effects 0.000 description 6
- 150000008105 phosphatidylcholines Chemical class 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000004753 textile Substances 0.000 description 6
- RRCUDWCPORMMDJ-XDHUAGTDSA-N (9z,12z,15e)-15-nitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C=C([N+]([O-])=O)/C\C=C/C\C=C/CCCCCCCC(O)=O RRCUDWCPORMMDJ-XDHUAGTDSA-N 0.000 description 5
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 229920001661 Chitosan Polymers 0.000 description 5
- 206010063837 Reperfusion injury Diseases 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000007257 deesterification reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 235000021588 free fatty acids Nutrition 0.000 description 5
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 5
- 238000002513 implantation Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000010348 incorporation Methods 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229920002521 macromolecule Polymers 0.000 description 5
- 238000002595 magnetic resonance imaging Methods 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 229920000747 poly(lactic acid) Polymers 0.000 description 5
- 229920000728 polyester Polymers 0.000 description 5
- 239000004814 polyurethane Substances 0.000 description 5
- 230000036647 reaction Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 5
- NRLWAKOZMVJDSJ-KABLSXSFSA-N (5e,8z,11z,14z)-5-nitroicosa-5,8,11,14-tetraenoic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C([N+]([O-])=O)/CCCC(O)=O NRLWAKOZMVJDSJ-KABLSXSFSA-N 0.000 description 4
- MHYIFXTWQBVNFA-YDBMBEKPSA-N (5e,8z,11z,14z)-6-nitroicosa-5,8,11,14-tetraenoic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C([N+]([O-])=O)=C/CCCC(O)=O MHYIFXTWQBVNFA-YDBMBEKPSA-N 0.000 description 4
- QGXVYQKXZZRRKQ-MJXBFTTASA-N (5z,8z,11z,14e)-14-nitroicosa-5,8,11,14-tetraenoic acid Chemical compound CCCCC\C=C([N+]([O-])=O)/C\C=C/C\C=C/C\C=C/CCCC(O)=O QGXVYQKXZZRRKQ-MJXBFTTASA-N 0.000 description 4
- KBDYBVRMSBDCBQ-UNZYHPAISA-N (9e,12e)-10,12-dinitrooctadeca-9,12-dienoic acid Chemical compound CCCCC\C=C([N+]([O-])=O)/C\C([N+]([O-])=O)=C/CCCCCCCC(O)=O KBDYBVRMSBDCBQ-UNZYHPAISA-N 0.000 description 4
- JIGLUBHCFCGZJG-VKESVQGDSA-N (9e,12e)-10,13-dinitrooctadeca-9,12-dienoic acid Chemical compound CCCCC\C([N+]([O-])=O)=C/C\C([N+]([O-])=O)=C/CCCCCCCC(O)=O JIGLUBHCFCGZJG-VKESVQGDSA-N 0.000 description 4
- ZDXIWLDBWUTRBU-HQJKSCAWSA-N (9e,12e)-9,12-dinitrooctadeca-9,12-dienoic acid Chemical compound CCCCC\C=C([N+]([O-])=O)/C\C=C([N+]([O-])=O)/CCCCCCCC(O)=O ZDXIWLDBWUTRBU-HQJKSCAWSA-N 0.000 description 4
- JJWNWESTVSXZDQ-AEFYIPPFSA-N (9e,12z,15z)-10-nitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C=C/C\C=C/C\C([N+]([O-])=O)=C/CCCCCCCC(O)=O JJWNWESTVSXZDQ-AEFYIPPFSA-N 0.000 description 4
- WZWPBDQYCAJWSX-FYWRMAATSA-N (e)-10-nitrohexadec-9-enoic acid Chemical compound CCCCCC\C([N+]([O-])=O)=C/CCCCCCCC(O)=O WZWPBDQYCAJWSX-FYWRMAATSA-N 0.000 description 4
- YZNSJIAWRWPQGX-NTCAYCPXSA-N (e)-9-nitrohexadec-9-enoic acid Chemical compound CCCCCC\C=C([N+]([O-])=O)/CCCCCCCC(O)=O YZNSJIAWRWPQGX-NTCAYCPXSA-N 0.000 description 4
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 4
- WZCLAXMADUBPSG-RIXBAXMTSA-N 1-stearoyl-2-(alpha-linolenoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/C\C=C/CC WZCLAXMADUBPSG-RIXBAXMTSA-N 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VFTOHJFKIJLYKN-UHFFFAOYSA-N 7-nitro-9h-fluoren-2-ol Chemical group [O-][N+](=O)C1=CC=C2C3=CC=C(O)C=C3CC2=C1 VFTOHJFKIJLYKN-UHFFFAOYSA-N 0.000 description 4
- HTHBLMOFSNPJLE-UHFFFAOYSA-N 9-hydroxy-10-nitrooctadecanoic acid Chemical compound CCCCCCCCC([N+]([O-])=O)C(O)CCCCCCCC(O)=O HTHBLMOFSNPJLE-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Citronensaeure-tributylester Natural products CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 4
- 108090000862 Ion Channels Proteins 0.000 description 4
- 102000004310 Ion Channels Human genes 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000004809 Teflon Substances 0.000 description 4
- 229920006362 Teflon® Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000016396 cytokine production Effects 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 4
- 239000012894 fetal calf serum Substances 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 229920002674 hyaluronan Polymers 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000035987 intoxication Effects 0.000 description 4
- 231100000566 intoxication Toxicity 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- JMLYDLZRFNYHHO-UHFFFAOYSA-N methyl ester of azelaic acid aldehyde Natural products COC(=O)CCCCCCCC=O JMLYDLZRFNYHHO-UHFFFAOYSA-N 0.000 description 4
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 4
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 4
- 229920001610 polycaprolactone Polymers 0.000 description 4
- 239000003761 preservation solution Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003248 quinolines Chemical group 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 4
- 238000000682 scanning probe acoustic microscopy Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005507 spraying Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 230000009772 tissue formation Effects 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 235000008979 vitamin B4 Nutrition 0.000 description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
- TZPZMVZGJVYAML-REOHCLBHSA-N (2s)-2-(oxaloamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)C(O)=O TZPZMVZGJVYAML-REOHCLBHSA-N 0.000 description 3
- AUZAKLJUNATYMZ-DISAMGIASA-N (9e,12e)-9,13-dinitrooctadeca-9,12-dienoic acid Chemical compound CCCCC\C([N+]([O-])=O)=C/C\C=C([N+]([O-])=O)/CCCCCCCC(O)=O AUZAKLJUNATYMZ-DISAMGIASA-N 0.000 description 3
- NECRATKYNLUQPY-VHRJKPHESA-N (9e,12z,15z)-9-nitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C=C/C\C=C/C\C=C([N+]([O-])=O)/CCCCCCCC(O)=O NECRATKYNLUQPY-VHRJKPHESA-N 0.000 description 3
- XIUNPAFIOWRAIO-HZJYTTRNSA-N (9z,12z)-2-nitrooctadeca-9,12-dienoic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCC(C(O)=O)[N+]([O-])=O XIUNPAFIOWRAIO-HZJYTTRNSA-N 0.000 description 3
- OQDQEPYVQZCDQG-SUOWLAJFSA-N (9z,12z,15z)-10-hydroxy-9-nitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C=C/C\C=C/C\C(O)=C([N+]([O-])=O)/CCCCCCCC(O)=O OQDQEPYVQZCDQG-SUOWLAJFSA-N 0.000 description 3
- OHAPVAYWVHQKQV-DQEXKGTLSA-N (9z,12z,15z)-9-hydroxy-10-nitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C=C/C\C=C/C\C([N+]([O-])=O)=C(\O)CCCCCCCC(O)=O OHAPVAYWVHQKQV-DQEXKGTLSA-N 0.000 description 3
- UODZGUWUVVAESS-HTXNQAPBSA-N (e)-10-nitroicos-9-enoic acid Chemical compound CCCCCCCCCC\C([N+]([O-])=O)=C/CCCCCCCC(O)=O UODZGUWUVVAESS-HTXNQAPBSA-N 0.000 description 3
- BLWBXXNMNNRCTM-KNTRCKAVSA-N (e)-9-nitroicos-9-enoic acid Chemical compound CCCCCCCCCC\C=C([N+]([O-])=O)/CCCCCCCC(O)=O BLWBXXNMNNRCTM-KNTRCKAVSA-N 0.000 description 3
- WZWPBDQYCAJWSX-SQFISAMPSA-N (z)-10-nitrohexadec-9-enoic acid Chemical compound CCCCCC\C([N+]([O-])=O)=C\CCCCCCCC(O)=O WZWPBDQYCAJWSX-SQFISAMPSA-N 0.000 description 3
- YZNSJIAWRWPQGX-QINSGFPZSA-N (z)-9-nitrohexadec-9-enoic acid Chemical compound CCCCCC\C=C([N+]([O-])=O)\CCCCCCCC(O)=O YZNSJIAWRWPQGX-QINSGFPZSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 206010018910 Haemolysis Diseases 0.000 description 3
- 238000006842 Henry reaction Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 241001585714 Nola Species 0.000 description 3
- 235000021319 Palmitoleic acid Nutrition 0.000 description 3
- 102000015439 Phospholipases Human genes 0.000 description 3
- 108010064785 Phospholipases Proteins 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000001994 activation Methods 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000020411 cell activation Effects 0.000 description 3
- 230000032677 cell aging Effects 0.000 description 3
- 230000005779 cell damage Effects 0.000 description 3
- 238000005229 chemical vapour deposition Methods 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 238000006471 dimerization reaction Methods 0.000 description 3
- 238000003618 dip coating Methods 0.000 description 3
- 150000002016 disaccharides Chemical class 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 3
- IZOOGPBRAOKZFK-UHFFFAOYSA-K gadopentetate Chemical compound [Gd+3].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O IZOOGPBRAOKZFK-UHFFFAOYSA-K 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 150000002327 glycerophospholipids Chemical class 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 229960001340 histamine Drugs 0.000 description 3
- 229960003160 hyaluronic acid Drugs 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229920001477 hydrophilic polymer Polymers 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 210000000287 oocyte Anatomy 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 3
- 239000004632 polycaprolactone Substances 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 229920002635 polyurethane Polymers 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 3
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 3
- BITHHVVYSMSWAG-KTKRTIGZSA-N (11Z)-icos-11-enoic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCC(O)=O BITHHVVYSMSWAG-KTKRTIGZSA-N 0.000 description 2
- WRADPCFZZWXOTI-BMRADRMJSA-N (9E)-10-nitrooctadecenoic acid Chemical compound CCCCCCCC\C([N+]([O-])=O)=C/CCCCCCCC(O)=O WRADPCFZZWXOTI-BMRADRMJSA-N 0.000 description 2
- YWWVWXASSLXJHU-AATRIKPKSA-N (9E)-tetradecenoic acid Chemical compound CCCC\C=C\CCCCCCCC(O)=O YWWVWXASSLXJHU-AATRIKPKSA-N 0.000 description 2
- RBQLBHYURYFOOK-GSPUAMIQSA-N (9e,12z,15e)-10,16-dinitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C([N+]([O-])=O)=C/C\C=C/C\C([N+]([O-])=O)=C/CCCCCCCC(O)=O RBQLBHYURYFOOK-GSPUAMIQSA-N 0.000 description 2
- FBWMYSQUTZRHAT-HZJYTTRNSA-N (9z,12z)-octadeca-9,12-dienoyl chloride Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(Cl)=O FBWMYSQUTZRHAT-HZJYTTRNSA-N 0.000 description 2
- CFPNFQFBGZRFDE-IHUXPXEUSA-N (9z,12z,15e)-16-nitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C([N+]([O-])=O)=C/C\C=C/C\C=C/CCCCCCCC(O)=O CFPNFQFBGZRFDE-IHUXPXEUSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- MLQBTMWHIOYKKC-KTKRTIGZSA-N (z)-octadec-9-enoyl chloride Chemical compound CCCCCCCC\C=C/CCCCCCCC(Cl)=O MLQBTMWHIOYKKC-KTKRTIGZSA-N 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- UZONFOPDCXAZND-UHFFFAOYSA-N 1-nitroheptane Chemical compound CCCCCCC[N+]([O-])=O UZONFOPDCXAZND-UHFFFAOYSA-N 0.000 description 2
- RMBLICPYYUUDOM-UHFFFAOYSA-N 10-hydroxy-9-nitrooctadec-12-enoic acid Chemical compound CCCCCC=CCC(O)C([N+]([O-])=O)CCCCCCCC(O)=O RMBLICPYYUUDOM-UHFFFAOYSA-N 0.000 description 2
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 2
- NJNWCIAPVGRBHO-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[(oxo-$l^{5}-phosphanylidyne)methyl]azanium Chemical class OCC[N+](C)(C)C#P=O NJNWCIAPVGRBHO-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QZKYMSWXSDQFMS-UHFFFAOYSA-N 6-hydroxy-5-nitroicosa-8,11,14,17-tetraenoic acid Chemical compound CCC=CCC=CCC=CCC=CCC(O)C([N+]([O-])=O)CCCC(O)=O QZKYMSWXSDQFMS-UHFFFAOYSA-N 0.000 description 2
- DIJCILWNOLHJCG-UHFFFAOYSA-N 7-amino-2',7'-difluoro-3',6'-dihydroxy-6-(methylamino)spiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound C12=CC(F)=C(O)C=C2OC2=CC(O)=C(F)C=C2C21OC(=O)C1=C(N)C(NC)=CC=C21 DIJCILWNOLHJCG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- YORHESWLEQGOBU-UHFFFAOYSA-N 9-hydroxy-10-nitrooctadec-12-enoic acid Chemical compound CCCCCC=CCC([N+]([O-])=O)C(O)CCCCCCCC(O)=O YORHESWLEQGOBU-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- YEBDWAHEIMUJQT-XVSDJDOKSA-N CCCCCC=CCC=CCC=CCC=CCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O Chemical compound CCCCCC=CCC=CCC=CCC=CCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YEBDWAHEIMUJQT-XVSDJDOKSA-N 0.000 description 2
- XSNPCADVCQDLAN-ZVMXUFIRSA-N CCCCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCCCC\C=C/CCCCCCCC(O)=O Chemical compound CCCCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCCCC\C=C/CCCCCCCC(O)=O XSNPCADVCQDLAN-ZVMXUFIRSA-N 0.000 description 2
- 229920002101 Chitin Polymers 0.000 description 2
- 229910000684 Cobalt-chrome Inorganic materials 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- 244000303965 Cyamopsis psoralioides Species 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 229910052692 Dysprosium Inorganic materials 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 229910052689 Holmium Inorganic materials 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 2
- 208000034693 Laceration Diseases 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000012868 Overgrowth Diseases 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- WAIPAZQMEIHHTJ-UHFFFAOYSA-N [Cr].[Co] Chemical compound [Cr].[Co] WAIPAZQMEIHHTJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 230000000181 anti-adherent effect Effects 0.000 description 2
- 230000003510 anti-fibrotic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002473 artificial blood Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000000231 atomic layer deposition Methods 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 238000006065 biodegradation reaction Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000012888 bovine serum Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001723 carbon free-radicals Chemical class 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 230000036978 cell physiology Effects 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 229940045110 chitosan Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 239000010952 cobalt-chrome Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000002316 cosmetic surgery Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 210000004292 cytoskeleton Anatomy 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 229960001378 dequalinium chloride Drugs 0.000 description 2
- LTNZEXKYNRNOGT-UHFFFAOYSA-N dequalinium chloride Chemical compound [Cl-].[Cl-].C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 LTNZEXKYNRNOGT-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000001083 documented effect Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 125000004050 enoyl group Chemical group 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229960003460 gadopentetic acid Drugs 0.000 description 2
- 108060003196 globin Proteins 0.000 description 2
- 102000018146 globin Human genes 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- FXHGMKSSBGDXIY-UHFFFAOYSA-N heptanal Chemical compound CCCCCCC=O FXHGMKSSBGDXIY-UHFFFAOYSA-N 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- RSKGMYDENCAJEN-UHFFFAOYSA-N hexadecyl(trimethoxy)silane Chemical compound CCCCCCCCCCCCCCCC[Si](OC)(OC)OC RSKGMYDENCAJEN-UHFFFAOYSA-N 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 230000001744 histochemical effect Effects 0.000 description 2
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960000367 inositol Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 230000002262 irrigation Effects 0.000 description 2
- 238000003973 irrigation Methods 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- MASXKPLGZRMBJF-MVSGICTGSA-N mastoparan Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(N)=O MASXKPLGZRMBJF-MVSGICTGSA-N 0.000 description 2
- 108010019084 mastoparan Proteins 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000000936 membranestabilizing effect Effects 0.000 description 2
- GDAXBYSNPSRHEN-OBGWFSINSA-N methyl (e)-9-nitrooctadec-9-enoate Chemical compound CCCCCCCC\C=C([N+]([O-])=O)/CCCCCCCC(=O)OC GDAXBYSNPSRHEN-OBGWFSINSA-N 0.000 description 2
- SCJDSHHBXQHWFY-UHFFFAOYSA-N methyl 15-nitropentadeca-9,12-dienoate Chemical compound COC(=O)CCCCCCCC=CCC=CCC[N+]([O-])=O SCJDSHHBXQHWFY-UHFFFAOYSA-N 0.000 description 2
- VHPWFGUENFPGML-UHFFFAOYSA-N methyl 15-oxopentadeca-9,12-dienoate Chemical compound COC(=O)CCCCCCCC=CCC=CCC=O VHPWFGUENFPGML-UHFFFAOYSA-N 0.000 description 2
- 238000010232 migration assay Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- GYHFUZHODSMOHU-UHFFFAOYSA-N nonanal Chemical compound CCCCCCCCC=O GYHFUZHODSMOHU-UHFFFAOYSA-N 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 229960001774 octenidine Drugs 0.000 description 2
- SMGTYJPMKXNQFY-UHFFFAOYSA-N octenidine dihydrochloride Chemical compound Cl.Cl.C1=CC(=NCCCCCCCC)C=CN1CCCCCCCCCCN1C=CC(=NCCCCCCCC)C=C1 SMGTYJPMKXNQFY-UHFFFAOYSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- LCEFEIBEOBPPSJ-UHFFFAOYSA-N phenyl selenohypobromite Chemical compound Br[Se]C1=CC=CC=C1 LCEFEIBEOBPPSJ-UHFFFAOYSA-N 0.000 description 2
- 150000008103 phosphatidic acids Chemical class 0.000 description 2
- 238000004375 physisorption Methods 0.000 description 2
- 229920001308 poly(aminoacid) Polymers 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 238000004528 spin coating Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- RGTIBVZDHOMOKC-UHFFFAOYSA-N stearolic acid Chemical compound CCCCCCCCC#CCCCCCCCC(O)=O RGTIBVZDHOMOKC-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- NSNZHQVMWJPBPI-QMMMGPOBSA-N tert-butyl (2s)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC(C)(C)C NSNZHQVMWJPBPI-QMMMGPOBSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000010692 trans-unsaturated fatty acids Nutrition 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 238000007740 vapor deposition Methods 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- GWHCXVQVJPWHRF-KTKRTIGZSA-N (15Z)-tetracosenoic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCCCC(O)=O GWHCXVQVJPWHRF-KTKRTIGZSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- ZUUFLXSNVWQOJW-MBIXAETLSA-N (2e,4e,6e)-octadeca-2,4,6-trienoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C=C\C(O)=O ZUUFLXSNVWQOJW-MBIXAETLSA-N 0.000 description 1
- RLCKHJSFHOZMDR-UHFFFAOYSA-N (3R, 7R, 11R)-1-Phytanoid acid Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)CC(O)=O RLCKHJSFHOZMDR-UHFFFAOYSA-N 0.000 description 1
- XVEIGUQEXNENQF-LNMUMINZSA-N (6Z,9Z,12Z)-octadeca-6,9,12-trienoic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O XVEIGUQEXNENQF-LNMUMINZSA-N 0.000 description 1
- BKRHMHFUTUUCEK-DPRXULCUSA-N (6z,9z,12z)-5-nitrooctadeca-6,9,12-trienoic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C([N+]([O-])=O)CCCC(O)=O BKRHMHFUTUUCEK-DPRXULCUSA-N 0.000 description 1
- GLTSCLVTJOAFAI-YEUYUGHHSA-N (9e,12z,15e)-9,16-dinitrooctadeca-9,12,15-trienoic acid Chemical compound CC\C([N+]([O-])=O)=C/C\C=C/C\C=C([N+]([O-])=O)/CCCCCCCC(O)=O GLTSCLVTJOAFAI-YEUYUGHHSA-N 0.000 description 1
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- AGBQKNBQESQNJD-ZETCQYMHSA-N (S)-lipoic acid Chemical compound OC(=O)CCCC[C@H]1CCSS1 AGBQKNBQESQNJD-ZETCQYMHSA-N 0.000 description 1
- JNKSXSJNLXMTSV-KTKRTIGZSA-N (z)-docos-13-enoyl chloride Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(Cl)=O JNKSXSJNLXMTSV-KTKRTIGZSA-N 0.000 description 1
- LRMDXTVKVHKWEK-UHFFFAOYSA-N 1,2-diaminoanthracene-9,10-dione Chemical compound C1=CC=C2C(=O)C3=C(N)C(N)=CC=C3C(=O)C2=C1 LRMDXTVKVHKWEK-UHFFFAOYSA-N 0.000 description 1
- ZNLAHAOCFKBYRH-UHFFFAOYSA-N 1,4-dioxane-2,3-dione Chemical class O=C1OCCOC1=O ZNLAHAOCFKBYRH-UHFFFAOYSA-N 0.000 description 1
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- DAIRUATTZJOIQO-UHFFFAOYSA-N 1-nitrononane Chemical compound CCCCCCCCC[N+]([O-])=O DAIRUATTZJOIQO-UHFFFAOYSA-N 0.000 description 1
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- RPARJORFDYXUJJ-UHFFFAOYSA-N 10,13-dinitrooctadecane-1,9,12-triol Chemical compound OC(CCCCCCCCO)C(CC(C(CCCCC)[N+](=O)[O-])O)[N+](=O)[O-] RPARJORFDYXUJJ-UHFFFAOYSA-N 0.000 description 1
- HYPNWNPGVKMDKV-UHFFFAOYSA-N 10-hydroxy-9-nitroicosanoic acid Chemical compound CCCCCCCCCCC(O)C([N+]([O-])=O)CCCCCCCC(O)=O HYPNWNPGVKMDKV-UHFFFAOYSA-N 0.000 description 1
- ZYFTUIURWQWFKQ-QIAGQCQHSA-N 12-Nitro-9Z,12Z-octadecadienoic acid Chemical compound CCCCC\C=C([N+]([O-])=O)/C\C=C/CCCCCCCC(O)=O ZYFTUIURWQWFKQ-QIAGQCQHSA-N 0.000 description 1
- OXEDXHIBHVMDST-UHFFFAOYSA-N 12Z-octadecenoic acid Natural products CCCCCC=CCCCCCCCCCCC(O)=O OXEDXHIBHVMDST-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- HRBGUGQWTMBDTR-UHFFFAOYSA-N 2,3,4-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC=C(S(Cl)(=O)=O)C(C(C)C)=C1C(C)C HRBGUGQWTMBDTR-UHFFFAOYSA-N 0.000 description 1
- KHEDIYCQDPMFKF-UHFFFAOYSA-N 2-(sulfooxy)acetic acid Chemical compound OC(=O)COS(O)(=O)=O KHEDIYCQDPMFKF-UHFFFAOYSA-N 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethyl hydrogen phosphate Chemical compound C[N+](C)(C)CCOP(O)([O-])=O YHHSONZFOIEMCP-UHFFFAOYSA-N 0.000 description 1
- NFPWGFSRWDHFFT-UHFFFAOYSA-N 2-[bis[2-[carboxymethyl-[2-(methylamino)-2-oxoethyl]amino]ethyl]amino]acetic acid gadolinium Chemical compound [Gd].CNC(=O)CN(CCN(CCN(CC(O)=O)CC(=O)NC)CC(O)=O)CC(O)=O NFPWGFSRWDHFFT-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- RLCKHJSFHOZMDR-PWCSWUJKSA-N 3,7R,11R,15-tetramethyl-hexadecanoic acid Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCC(C)CC(O)=O RLCKHJSFHOZMDR-PWCSWUJKSA-N 0.000 description 1
- WSQZNZLOZXSBHA-UHFFFAOYSA-N 3,8-dioxabicyclo[8.2.2]tetradeca-1(12),10,13-triene-2,9-dione Chemical compound O=C1OCCCCOC(=O)C2=CC=C1C=C2 WSQZNZLOZXSBHA-UHFFFAOYSA-N 0.000 description 1
- 229910000619 316 stainless steel Inorganic materials 0.000 description 1
- ZXVONLUNISGICL-UHFFFAOYSA-N 4,6-dinitro-o-cresol Chemical group CC1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1O ZXVONLUNISGICL-UHFFFAOYSA-N 0.000 description 1
- AXDJCCTWPBKUKL-UHFFFAOYSA-N 4-[(4-aminophenyl)-(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]aniline;hydron;chloride Chemical compound Cl.C1=CC(=N)C(C)=CC1=C(C=1C=CC(N)=CC=1)C1=CC=C(N)C=C1 AXDJCCTWPBKUKL-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 description 1
- GFXNUAAEPXXRPH-UHFFFAOYSA-N 9-hydroxy-10-nitroicosanoic acid Chemical compound CCCCCCCCCCC([N+]([O-])=O)C(O)CCCCCCCC(O)=O GFXNUAAEPXXRPH-UHFFFAOYSA-N 0.000 description 1
- IPCZHGACNSBKMU-UHFFFAOYSA-N 9-nitrononanoic acid Chemical compound OC(=O)CCCCCCCC[N+]([O-])=O IPCZHGACNSBKMU-UHFFFAOYSA-N 0.000 description 1
- 229920005789 ACRONAL® acrylic binder Polymers 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 208000002102 Atrial Premature Complexes Diseases 0.000 description 1
- 206010003662 Atrial flutter Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930185605 Bisphenol Natural products 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010005908 Body temperature conditions Diseases 0.000 description 1
- 101100273064 Brassica oleracea var. botrytis CAL-B gene Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 108010031797 Candida antarctica lipase B Proteins 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 108700027941 Celsior Proteins 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- OONXYOAWMIVMCI-UHFFFAOYSA-N D-Lesquerolinsaeure Natural products CCCCCCC(O)CC=CCCCCCCCCCC(O)=O OONXYOAWMIVMCI-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 101100394030 Dictyostelium discoideum gxcB gene Proteins 0.000 description 1
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229910052691 Erbium Inorganic materials 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-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
- 108010019393 Fibrin Foam Proteins 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000001034 Frostbite Diseases 0.000 description 1
- OPGOLNDOMSBSCW-CLNHMMGSSA-N Fursultiamine hydrochloride Chemical compound Cl.C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N OPGOLNDOMSBSCW-CLNHMMGSSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 206010019909 Hernia Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 101000764872 Homo sapiens Transient receptor potential cation channel subfamily A member 1 Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- XUHXFSYUBXNTHU-UHFFFAOYSA-N Iotrolan Chemical compound IC=1C(C(=O)NC(CO)C(O)CO)=C(I)C(C(=O)NC(CO)C(O)CO)=C(I)C=1N(C)C(=O)CC(=O)N(C)C1=C(I)C(C(=O)NC(CO)C(O)CO)=C(I)C(C(=O)NC(CO)C(O)CO)=C1I XUHXFSYUBXNTHU-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl tetradecanoate Chemical class CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 1
- 241001125831 Istiophoridae Species 0.000 description 1
- 108010093008 Kinins Proteins 0.000 description 1
- 102000002397 Kinins Human genes 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229910052765 Lutetium Inorganic materials 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000235395 Mucor Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229910052779 Neodymium Inorganic materials 0.000 description 1
- 208000034827 Neointima Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- XJXROGWVRIJYMO-SJDLZYGOSA-N Nervonic acid Natural products O=C(O)[C@@H](/C=C/CCCCCCCC)CCCCCCCCCCCC XJXROGWVRIJYMO-SJDLZYGOSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 229920002201 Oxidized cellulose Polymers 0.000 description 1
- BVGQXSCOKWJBFV-UHFFFAOYSA-N P(=O)(OC(C)(C)C)(OC(C)(C)C)OCC(O)CO Chemical compound P(=O)(OC(C)(C)C)(OC(C)(C)C)OCC(O)CO BVGQXSCOKWJBFV-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- 231100000742 Plant toxin Toxicity 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920002413 Polyhexanide Polymers 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 229910052777 Praseodymium Inorganic materials 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- LRDHPEKBQXDTLO-BQYQJAHWSA-N Pyrulic acid Chemical compound CCCCCC\C=C\C#CCCCCCCC(O)=O LRDHPEKBQXDTLO-BQYQJAHWSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- 241000566107 Scolopax Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 102000003563 TRPV Human genes 0.000 description 1
- 108060008564 TRPV Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 229910052771 Terbium Inorganic materials 0.000 description 1
- 229910052775 Thulium Inorganic materials 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102100026186 Transient receptor potential cation channel subfamily A member 1 Human genes 0.000 description 1
- 229920004935 Trevira® Polymers 0.000 description 1
- 235000021322 Vaccenic acid Nutrition 0.000 description 1
- UWHZIFQPPBDJPM-FPLPWBNLSA-M Vaccenic acid Natural products CCCCCC\C=C/CCCCCCCCCC([O-])=O UWHZIFQPPBDJPM-FPLPWBNLSA-M 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000009729 Ventricular Premature Complexes Diseases 0.000 description 1
- 206010047289 Ventricular extrasystoles Diseases 0.000 description 1
- VENIIVIRETXKSV-BQYQJAHWSA-N Ximenynic acid Chemical compound CCCCCC\C=C\C#CCCCCCCCC(O)=O VENIIVIRETXKSV-BQYQJAHWSA-N 0.000 description 1
- VENIIVIRETXKSV-UHFFFAOYSA-N Xionenynic acid Natural products CCCCCCC=CC#CCCCCCCCC(O)=O VENIIVIRETXKSV-UHFFFAOYSA-N 0.000 description 1
- 229910052769 Ytterbium Inorganic materials 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- FHQVHHIBKUMWTI-JPPWSRCLSA-N [(2r)-1-[2-aminoethoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (e)-octadec-9-enoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C\CCCCCCCC FHQVHHIBKUMWTI-JPPWSRCLSA-N 0.000 description 1
- FJWGYAHXMCUOOM-QHOUIDNNSA-N [(2s,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6s)-4,5-dinitrooxy-2-(nitrooxymethyl)-6-[(2r,3r,4s,5r,6s)-4,5,6-trinitrooxy-2-(nitrooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-3,5-dinitrooxy-6-(nitrooxymethyl)oxan-4-yl] nitrate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O)O[C@H]1[C@@H]([C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@@H](CO[N+]([O-])=O)O1)O[N+]([O-])=O)CO[N+](=O)[O-])[C@@H]1[C@@H](CO[N+]([O-])=O)O[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O FJWGYAHXMCUOOM-QHOUIDNNSA-N 0.000 description 1
- TYVWBCMQECJNSK-UHFFFAOYSA-N [2-methyl-3-(2-methylprop-2-enoyloxy)butan-2-yl]azanium;chloride Chemical compound [Cl-].CC([NH3+])(C)C(C)OC(=O)C(C)=C TYVWBCMQECJNSK-UHFFFAOYSA-N 0.000 description 1
- XQAXGZLFSSPBMK-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride;trihydrate Chemical compound O.O.O.[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 XQAXGZLFSSPBMK-UHFFFAOYSA-M 0.000 description 1
- CRBMRKFEXOVWIU-UHFFFAOYSA-N [N+](=O)([O-])C(C=CCCCCCCCCC)CCCCCC Chemical compound [N+](=O)([O-])C(C=CCCCCCCCCC)CCCCCC CRBMRKFEXOVWIU-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 231100000659 animal toxin Toxicity 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002095 anti-migrative effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical class CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- UTOVMEACOLCUCK-PLNGDYQASA-N butyl maleate Chemical compound CCCCOC(=O)\C=C/C(O)=O UTOVMEACOLCUCK-PLNGDYQASA-N 0.000 description 1
- SXPLZNMUBFBFIA-UHFFFAOYSA-N butyl(trimethoxy)silane Chemical compound CCCC[Si](OC)(OC)OC SXPLZNMUBFBFIA-UHFFFAOYSA-N 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002729 catgut Substances 0.000 description 1
- 230000007348 cell dedifferentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 1
- 229940117916 cinnamic aldehyde Drugs 0.000 description 1
- GWHCXVQVJPWHRF-UHFFFAOYSA-N cis-tetracosenoic acid Natural products CCCCCCCCC=CCCCCCCCCCCCCCC(O)=O GWHCXVQVJPWHRF-UHFFFAOYSA-N 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000002016 colloidosmotic effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 230000008473 connective tissue growth Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 1
- HABLENUWIZGESP-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O HABLENUWIZGESP-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- BAAAEEDPKUHLID-UHFFFAOYSA-N decyl(triethoxy)silane Chemical compound CCCCCCCCCC[Si](OCC)(OCC)OCC BAAAEEDPKUHLID-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000004053 dental implant Substances 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- JWCYDYZLEAQGJJ-UHFFFAOYSA-N dicyclopentyl(dimethoxy)silane Chemical compound C1CCCC1[Si](OC)(OC)C1CCCC1 JWCYDYZLEAQGJJ-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- DXAPNHFOXAMIIR-UHFFFAOYSA-N docosa-2,4,6,8,10,12-hexaenoyl chloride Chemical compound CCCCCCCCCC=CC=CC=CC=CC=CC=CC(Cl)=O DXAPNHFOXAMIIR-UHFFFAOYSA-N 0.000 description 1
- AGDANEVFLMAYGL-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCCCCCC(O)=O AGDANEVFLMAYGL-UHFFFAOYSA-N 0.000 description 1
- QTHQYNCAWSGBCE-UHFFFAOYSA-N docosanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCCCCCC(Cl)=O QTHQYNCAWSGBCE-UHFFFAOYSA-N 0.000 description 1
- GMSCBRSQMRDRCD-UHFFFAOYSA-N dodecyl 2-methylprop-2-enoate Chemical compound CCCCCCCCCCCCOC(=O)C(C)=C GMSCBRSQMRDRCD-UHFFFAOYSA-N 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- MGLDCXPLYOWQRP-UHFFFAOYSA-N eicosa-5,8,11,14-tetraynoic acid Chemical compound CCCCCC#CCC#CCC#CCC#CCCCC(O)=O MGLDCXPLYOWQRP-UHFFFAOYSA-N 0.000 description 1
- BITHHVVYSMSWAG-UHFFFAOYSA-N eicosenoic acid Natural products CCCCCCCCC=CCCCCCCCCCC(O)=O BITHHVVYSMSWAG-UHFFFAOYSA-N 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002674 endoscopic surgery Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- TVFJAZCVMOXQRK-UHFFFAOYSA-N ethenyl 7,7-dimethyloctanoate Chemical compound CC(C)(C)CCCCCC(=O)OC=C TVFJAZCVMOXQRK-UHFFFAOYSA-N 0.000 description 1
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
- WYZIWOFFABWKJN-UHFFFAOYSA-N ethyl 4,5-dimethoxy-2-[(3,4,5-trimethoxybenzoyl)amino]benzoate Chemical compound CCOC(=O)C1=CC(OC)=C(OC)C=C1NC(=O)C1=CC(OC)=C(OC)C(OC)=C1 WYZIWOFFABWKJN-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 210000001650 focal adhesion Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 229960005063 gadodiamide Drugs 0.000 description 1
- RYHQMKVRYNEBNJ-BMWGJIJESA-K gadoterate meglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 RYHQMKVRYNEBNJ-BMWGJIJESA-K 0.000 description 1
- 229960005451 gadoteridol Drugs 0.000 description 1
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 description 1
- VZCCETWTMQHEPK-UHFFFAOYSA-N gamma-Linolensaeure Natural products CCCCCC=CCC=CCC=CCCCCC(O)=O VZCCETWTMQHEPK-UHFFFAOYSA-N 0.000 description 1
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 1
- 229960002733 gamolenic acid Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000021299 gondoic acid Nutrition 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- NSEXTLCTTCFJCT-UHFFFAOYSA-N heptadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCC(O)=O NSEXTLCTTCFJCT-UHFFFAOYSA-N 0.000 description 1
- NIDYWHLDTIVRJT-UJPOAAIJSA-N heptyl-β-d-glucopyranoside Chemical compound CCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O NIDYWHLDTIVRJT-UJPOAAIJSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- KYYWBEYKBLQSFW-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O KYYWBEYKBLQSFW-UHFFFAOYSA-N 0.000 description 1
- ZILMEHNWSRQIEH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O.CCCCCC(O)=O ZILMEHNWSRQIEH-UHFFFAOYSA-N 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229940099552 hyaluronan Drugs 0.000 description 1
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000013115 immunohistochemical detection Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000000193 iodinated contrast media Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
- 229960004647 iopamidol Drugs 0.000 description 1
- 229960003182 iotrolan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- OONXYOAWMIVMCI-KWRJMZDGSA-N lesquerolic acid Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCCCC(O)=O OONXYOAWMIVMCI-KWRJMZDGSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000010872 live dead assay kit Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 1
- 206010025226 lymphangitis Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002052 molecular layer Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- WUFHQGLVNNOXMP-UHFFFAOYSA-N n-(triethoxysilylmethyl)cyclohexanamine Chemical compound CCO[Si](OCC)(OCC)CNC1CCCCC1 WUFHQGLVNNOXMP-UHFFFAOYSA-N 0.000 description 1
- VNBLTKHUCJLFSB-UHFFFAOYSA-N n-(trimethoxysilylmethyl)aniline Chemical compound CO[Si](OC)(OC)CNC1=CC=CC=C1 VNBLTKHUCJLFSB-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- AAAUMZZBNYAFHL-UHFFFAOYSA-N nitro nitroformate Chemical compound [O-][N+](=O)OC(=O)[N+]([O-])=O AAAUMZZBNYAFHL-UHFFFAOYSA-N 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- AOZJRUUQFPERPD-UHFFFAOYSA-N nitromethaneperoxoic acid Chemical class OOC(=O)[N+]([O-])=O AOZJRUUQFPERPD-UHFFFAOYSA-N 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QZGIOJSVUOCUMC-UHFFFAOYSA-N octa-2,4-dienoic acid Chemical compound CCCC=CC=CC(O)=O QZGIOJSVUOCUMC-UHFFFAOYSA-N 0.000 description 1
- XVEIGUQEXNENQF-HPFCUAHCSA-N octadeca-6,9,12-trienoic acid;(6z,9z,12z)-octadeca-6,9,12-trienoic acid Chemical compound CCCCCC=CCC=CCC=CCCCCC(O)=O.CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O XVEIGUQEXNENQF-HPFCUAHCSA-N 0.000 description 1
- VJZWIFWPGRIJSN-NBTZWHCOSA-N octadeca-9,12-dienoic acid;(9z,12z)-octadeca-9,12-dienoic acid Chemical compound CCCCCC=CCC=CCCCCCCCC(O)=O.CCCCC\C=C/C\C=C/CCCCCCCC(O)=O VJZWIFWPGRIJSN-NBTZWHCOSA-N 0.000 description 1
- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 1
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- MSRJTTSHWYDFIU-UHFFFAOYSA-N octyltriethoxysilane Chemical compound CCCCCCCC[Si](OCC)(OCC)OCC MSRJTTSHWYDFIU-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940107304 oxidized cellulose Drugs 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000004796 pathophysiological change Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 229920003175 pectinic acid Polymers 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003123 plant toxin Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000117 poly(dioxanone) Polymers 0.000 description 1
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 1
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920000141 poly(maleic anhydride) Polymers 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920002037 poly(vinyl butyral) polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229940093158 polyhexanide Drugs 0.000 description 1
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- LRDHPEKBQXDTLO-UHFFFAOYSA-N pyrulic acid Natural products CCCCCCC=CC#CCCCCCCC(O)=O LRDHPEKBQXDTLO-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008263 repair mechanism Effects 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 229960003656 ricinoleic acid Drugs 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- GVZXZHWIIXHZOB-UHFFFAOYSA-N tariric acid Chemical compound CCCCCCCCCCCC#CCCCCC(O)=O GVZXZHWIIXHZOB-UHFFFAOYSA-N 0.000 description 1
- GDBJCCBRRCYCEG-UHFFFAOYSA-N tariric acid Natural products CCCCCCCCCCCCC#CCCCC(O)=O GDBJCCBRRCYCEG-UHFFFAOYSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- 229920006027 ternary co-polymer Polymers 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- ZTUXEFFFLOVXQE-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCC(O)=O ZTUXEFFFLOVXQE-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound 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 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- AQWHMKSIVLSRNY-UHFFFAOYSA-N trans-Octadec-5-ensaeure Natural products CCCCCCCCCCCCC=CCCCC(O)=O AQWHMKSIVLSRNY-UHFFFAOYSA-N 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- UWHZIFQPPBDJPM-BQYQJAHWSA-N trans-vaccenic acid Chemical compound CCCCCC\C=C\CCCCCCCCCC(O)=O UWHZIFQPPBDJPM-BQYQJAHWSA-N 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
- ZKLMUSUAPQLNQB-UHFFFAOYSA-N trichloro(2-dodecylhexadecyl)silane Chemical compound CCCCCCCCCCCCCCC(C[Si](Cl)(Cl)Cl)CCCCCCCCCCCC ZKLMUSUAPQLNQB-UHFFFAOYSA-N 0.000 description 1
- HXOGQBSDPSMHJK-UHFFFAOYSA-N triethoxy(6-methylheptyl)silane Chemical compound CCO[Si](OCC)(OCC)CCCCCC(C)C HXOGQBSDPSMHJK-UHFFFAOYSA-N 0.000 description 1
- JCVQKRGIASEUKR-UHFFFAOYSA-N triethoxy(phenyl)silane Chemical compound CCO[Si](OCC)(OCC)C1=CC=CC=C1 JCVQKRGIASEUKR-UHFFFAOYSA-N 0.000 description 1
- UWSYCPWEBZRZNJ-UHFFFAOYSA-N trimethoxy(2,4,4-trimethylpentyl)silane Chemical compound CO[Si](OC)(OC)CC(C)CC(C)(C)C UWSYCPWEBZRZNJ-UHFFFAOYSA-N 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical class O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- 206010044697 tropical sprue Diseases 0.000 description 1
- 238000013042 tunel staining Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 210000000685 uterine artery Anatomy 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000002348 vinylic group Chemical group 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000000207 volumetry Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
- 150000007964 xanthones Chemical class 0.000 description 1
- RQIDQEBURXNDKG-MDZDMXLPSA-N ximenic acid Chemical compound CCCCCCCC\C=C\CCCCCCCCCCCCCCCC(O)=O RQIDQEBURXNDKG-MDZDMXLPSA-N 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
-
- 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
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
- A01N1/0215—Disinfecting agents, e.g. antimicrobials for preserving living parts
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having alternatively specified atoms bound to the phosphorus atom and not covered by a single one of groups A01N57/10, A01N57/18, A01N57/26, A01N57/34
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/10—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-oxygen bonds or phosphorus-to-sulfur bonds
- A01N57/12—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-oxygen bonds or phosphorus-to-sulfur bonds containing acyclic or cycloaliphatic radicals
-
- 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
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
-
- 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
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/14—Post-treatment to improve physical properties
- A61L17/145—Coating
-
- 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
- A61L27/28—Materials for coating prostheses
-
- 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
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
Definitions
- the present invention relates to nitrocarboxylic acid-containing phospholipids, medical devices coated with said compounds, such as stents, catheter balloons, implants, wound inserts or surgical sutures, and biopassivant compositions, rinse solutions, impregnation solutions, coating solutions, cryoprotective solutions, cryopreservation media, lyoprotective solutions, contrast agent solutions, preservative solutions, and perfusion solutions containing these compounds and the preparation of these solutions and the coated medical devices and their uses.
- medical devices coated with said compounds such as stents, catheter balloons, implants, wound inserts or surgical sutures, and biopassivant compositions, rinse solutions, impregnation solutions, coating solutions, cryoprotective solutions, cryopreservation media, lyoprotective solutions, contrast agent solutions, preservative solutions, and perfusion solutions containing these compounds and the preparation of these solutions and the coated medical devices and their uses.
- Any physical, chemical or hypoxic cell alteration will result in a response of the affected cells which may cause migration, proliferation, matrix and cytokine production, apoptosis or necrosis.
- the extent of the cell reaction depends essentially on the severity of the alteration, whereby the effects of cell alterations can be potentiated in simultaneous presence.
- the type of cell aging is of minor importance because the cellular reaction patterns are basically the same.
- the cellular response to alteration may be different under different conditions.
- the willingness to mast cell degranulation increases with increased adrenergic stimulation or there is an increased mechanical fragility of erythrocytes in the presence of hypoosmolarity and cell toxins.
- membrane proteins By dimerization, many membrane proteins first acquire their functionally active form. A such can be achieved by a translocation of the protein subunits, eg by the cytoskeleton.
- the membrane conductivity has a considerable influence on the translocation of membrane proteins.
- the physical properties of cell membranes cause the conformation of membrane proteins and thus their functionality.
- the physical cell membrane properties are essentially due to hydrophobic alternating forces of the alkyl chains of the membrane phospholipids.
- the physical membrane properties are, however, also by physiologically interponêt Arthur molecules, or nonspecific and transient by physiosorbed molecules such as fatty acids changed.
- the magnitude of potentiating alteration mechanisms is virtually unpredictable, but crucial to the on-going repair and healing process.
- the repair mechanisms can take on an unphysiological scale if significantly more cells or matrix proteins are formed than are needed to stabilize a defect.
- the result is connective tissue growth (eg fibrosis, capsule formation, celloid), which leads to a functional impairment of the tissue / organ / body part or causes cosmetic / esthetic problems.
- Of prime importance are cell alterations caused by contact with non-cellular foreign materials.
- Percutaneous transluminal balloon angioplasty of arterial stenoses leads to a barotrauma of the cells of the affected vessel wall and to a rupture of vessel wall structures.
- a large wound surface that is in direct contact with blood is generated.
- the consequence is rapid attachment of plasma proteins and subsequently of platelets.
- the extent of this aggregate formation causes the secretion of cytokines that stimulate vascular cell proliferation as well as enhance thrombus formation.
- the latter condition can lead to a closure thrombosis in the treated vessel section.
- similar mechanisms are found after implantation of a vascular stent.
- stents and catheter balloons have been coated with antiproliferative agents, such as paclitaxel and rapamycin, to inhibit stent-associated cell proliferation. These agents are released spontaneously over a longer period from the stent strut coating. Due to the dense contact of the stent and / or balloon surface with the vessel wall, these substances are taken up by the vascular smooth muscle cells and effectively inhibit their further proliferation.
- antiproliferative agents such as paclitaxel and rapamycin
- microparticles comprising phospholipids and proteins
- Platelets may release phospholipid membranes from the cells that are delivered as microparticles into the blood or surrounding tissue fluid.
- the ability to deliver microparticles has also been described for other cell types.Microparticles have a local and systemic effect that enhances or reduces them Tissue responses (Meziani et al., Pharmacol Rep 2008, 60, 75-84), this information is passed on to the cells directly surrounding it, but can also lead to the recruitment of remote cells, ie the bone marrow
- microparticles have a significant influence on the pathophysiological changes in e in sepsis
- biocompatibility of an artificial surface that is in direct contact with cells is a crucial determinant for subsequent cell responses. While less biocompatible surfaces can induce cell dedifferentiation, migration, proliferation or apoptosis, the ideal biocompatible surface would not result in such a cellular response and would rather retain the physiological status and metabolism of the adherent cells. Furthermore, biocompatibility is inversely proportional to the rate and amount of biomolecules, such as albumin, fibronectin, or complement factors that attach to the artificial surface. This is also true for the amount of extracellular matrix proteins produced by adherent cells on the artificial surfaces. Furthermore, the quantity and quality of serum proteins adhering to an artificial surface will determine which cells will attach to such surface as well as their rates of proliferation.
- Biocompatibility is not the same for the different mammalian cell types.
- Cells react to incompatibilities in their chemical environment (eg pH), surface geometry (eg roughness of the surface), fluidity of the interface (such as determined by water content) and quality and quantity of cell contacts with the artificial surface.
- chemical environment eg pH
- surface geometry eg roughness of the surface
- fluidity of the interface such as determined by water content
- phospholipids have similar physicochemical properties at the interface with the adherent cell as the cell membranes themselves.
- Phospholipids have the property of spontaneously forming membrane-like structures, resulting in a homogeneous surface which, in the event that the head group carries a choline residue, resulting in a high density of bound water molecules.
- Another advantage of a boundary layer that is not firmly anchored to the support material is the free lateral mobility of the phospholipids.
- the melting point of natural phospholipids found in human cell membranes is low, so that the high degree of mobility under body temperature conditions facilitates mechanical or thermodynamically driven detachment.
- phosphorylcholines were polymerized with a co-polymer (eg, lauryl methacrylate); Such phospholipid compounds are not found in nature and have fundamentally different physicochemical properties than natural phospholipids, which is why a coating with polymerized phosphorylcholines must be named as a synthetic phospholipid layer. Since a covalent anchoring to the support material was not intended, the resistance to shear forces was achieved by a polymerization process, which resulted in a coating with a thickness of 50 ⁇ .
- a co-polymer eg, lauryl methacrylate
- Biopassivant coatings are not only beneficial on cardiovascular implants, but are also desirable for wound materials, wound inserts, surgical sutures, or other implants such as face and breast implants because they are expected to have anti-fibrotic properties. It has surprisingly been found that nitrocarboxylic acid-containing phospholipids have such biopassivating properties.
- biopassivating compounds which are suitable for coating medical devices, in particular for the biopassivative coating of medical devices and for producing biopassivating compositions, rinsing solutions, impregnating solutions, coating solutions, Cryoprotektionsaten, cryopreservation media, Lyoprotektions55en, contrast agent solutions, preservative solutions and perfusion solutions are suitable and the provision of such solutions and such coated medical devices.
- the medical devices are preferably those which come into direct contact with cells / tissues and lead to a cell / tissue alteration, which without a surface coating leads to an increased production of matrix proteins / fibrosis and / or cell migration / cell proliferation and / or apoptosis / Lead to necrosis.
- Solutions or biopassivating compositions in the form of rinse solutions, impregnation solutions, coating solutions, cryoprotective solutions, cryopreservation media, lyoprotective solutions, contrast agent solutions, preservative solutions and perfusion solutions are a suitable application if trauma / intoxication as well as medical / cosmetic interventions involving similar cell / tissue alterations and cell / tissue reactions go hand in hand, are expansive and difficult to reach, so that a coating of the cells / tissues can be ensured or an immediate treatment of medical devices that come into contact with tissues can be made.
- X is O or S
- R 1 and R 2 are independently selected from the group consisting of or consisting of: linear nitroalkyl radicals having 5 to 30 carbon atoms, branched nitroalkyl radicals having 5 to 30 carbon atoms, linear nitroalkenyl radicals having 5 to 30 carbon atoms, branched nitroalkenyl radicals having 5 to 30 carbon atoms, linear nitroalkynyl radicals having 5 to 30 carbon atoms, branched nitroalkynyl radicals having 5 to 30 carbon atoms, nitroalkyl radicals 5 to 30 carbon atoms, wherein the nitroalkyl radical contains a cycloalkyl radical or a heterocycloalkyl radical or a carbonyl group,
- alkyl radical, alkenyl radical and alkynyl radical having one, two or three hydroxyl groups, thiol groups, halogen radicals, carboxylate groups, C 1 -C 5 -alkoxycarbonyl groups, C 1 -C 5 -alkylcarbonyloxy groups, C 1 -C 5 -alkoxy groups, C 1 -C 5 -alkylamino groups, C 1 -C 4 -alkyl 5 -dialkylamino and / or amino groups may be substituted and wherein the nitroalkyl, Nitroalkenylrest and Nitroalkinylrest with one, two or three hydroxy groups, thiol groups, halogen radicals, carboxylate groups, Ci-C5 alkoxycarbonyl, C1-C5 alkylcarbonyloxy groups, Ci-C 5 - Alkoxy groups, C 1 -C 5 -alkylamino groups, C 1 -C 5 -dialkylamino groups and
- R 1 and R 2 must contain at least one nitro group
- R 3 is one of the following radicals: -H, -CH 2 -CH (COO " ) - NH 3 + ,
- R 4 - R 14 are independently
- Another aspect of the present invention relates to the use of the nitrocarboxylic acid (s) -containing phospholipids of the invention for the preparation of medical compositions and for coating medical devices.
- the medical compositions are preferably biopassivating compositions such as e.g. Rinsing solutions for medical devices, rinsing solutions for wounds, impregnation solutions for dressings, wound and suture materials, coating solutions for medical devices, cryoprotection solutions, cold preservation media, lyoprotection solutions, contrast agent solutions, preservation solutions and perfusion solutions for cells, tissues and organs.
- biopassivating compositions such as e.g. Rinsing solutions for medical devices, rinsing solutions for wounds, impregnation solutions for dressings, wound and suture materials, coating solutions for medical devices, cryoprotection solutions, cold preservation media, lyoprotection solutions, contrast agent solutions, preservation solutions and perfusion solutions for cells, tissues and organs.
- the terms “medical device” or “medical device” are used herein as generic terms that include any implants, natural and artificial grafts, suture and bandage materials, as well as parts of medical devices such as catheters.
- the medical products which also include cosmetic or partially cosmetic and partially medical implants, are preferably medical devices, more preferably implants that are temporarily or permanently introduced into the organism and medical articles that come into contact with cells / tissues, such as Wound materials, suture materials, wound and body oil closure systems, biological grafts, artificial grafts, biological implants, artificial implants, artificial blood vessels, natural blood vessels, blood conductors, blood pumps, dialyzers, dialysis machines, vascular prostheses, vascular supports, heart valves, artificial hearts, vascular clamps, autologous implants, Bone implants, intraocular lenses, shunts, dental implants, infusion tubes, medical cuffs, bandages, medical clamps, pumps, pacemakers, laboratory gloves, medical scissors, medical cutlery, needles, cannulas, endoprostheses
- the surface coatings according to the invention are thus suitable for all medical devices or medical devices that come into contact with cells / tissues / organs temporarily or permanently and that this contact can lead to irritation of the coming in contact cells / tissues / organs that are undesirable Reaction (as described below or on page 8 above) of said structures leads.
- Vital cells can respond to external stimuli by altering their metabolism and / or phenotype and / or genotype. The reaction behavior depends on the type and intensity of the irritation as well as on the affected cell species and preconditioning factors such. The integrity of a cell network or the presence of mediators.
- the cell reaction is dependent on the abovementioned determinants and may result in formation of mediators or extracellular matrix, cell migartion or cell proliferation as well as necrosis or apoptosis. Therefore, the reaction to a cell irritation is not exactly predictable. The quantification of a change in the response to a cell / tissue irritation must therefore be done by comparing the reaction behavior under the same starting conditions.
- biopassivation or “biopassivating” is understood to mean the following.
- a biopassivation according to the invention is when the cell / tissue response to a physical, chemical or hypoxic cell or tissue alteration is limited to a level as would be expected under the same conditions but without additional cell / tissue alteration.
- the cell / tissue alteration may be due to introduction of foreign material, addition of barotrauma or thermal trauma, hypoxia, toxins and / or radiation.
- a biopassivation of cells / tissues according to the invention is present if the cell / tissue reactions resulting from physical, chemical or hypoxic cell or tissue alterations, consisting of production of mediators or matrix proteins and / or cell migration / proliferation and / or necrosis / Apoptosis, preferably at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, further preferably at least 50%, even more preferably at least 60% and most preferably at least about 70% compared to a similar alteration of Cells and tissues that have not come into contact with the phospholipids according to the invention are reduced.
- biopassivating effects are present when cellular or tissue response, which is the production of mediators and / or matrix proteins, cell migration and / or proliferation, necrosis and / or apoptosis due to physical, chemical or hypoxic cell or tissue alterations, in their Scope to preferably at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, further preferably at least 50%, even more preferably at least 60% and most preferably at least reduced by 70%.
- the present invention relates to biopassivierende compounds of general formula (I), biopassivierende compositions containing at least one of the biopassivierenden compounds of the general formula (I) and biopassivierende coatings of or containing the biopassivierenden compounds of the general formula (I).
- biopassivating compounds, compositions and coatings are particularly suitable for direct or indirect contact with living cells, tissues and organs.
- biopassivating means that the cells and / or tissues which have come into contact or have been treated with the biopassivating compounds, coatings or compositions, compared to comparable cells and / or or tissues which have not been contacted or treated with the biopassivating compounds, coatings or compositions, at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, even more preferably at least 50%, more preferably at least 60%, and most preferably at least 70%, less cell reactions and / or tissue reactions due to physical, chemical or hypoxic cell or tissue alterations, wherein the cell responses and / or tissue reactions are the production of mediators and / or Ma trix proteins, cell migration and / or cell proliferation as well as necrosis and / or apoptosis.
- Biopassivation therefore preferably does not mean the at least 10% lower production of mediators or the at least 10% lower production of matrix proteins or the at least 10% lower cell migration or the at least 10% lower cell proliferation or at least 10% lower necrosis or at least 10% lower apoptosis; Biopassivation preferably means at least 10% lower production of mediators and / or matrix proteins and at least 10% less cell migration and / or cell proliferation and at least 10% less necrosis and / or apoptosis.
- the aforementioned effects production of mediators / matrix proteins, cell migration / proliferation, necrosis / apoptosis
- the reduction by at least 10% or more refers only to the effects that actually occur in the considered biological process.
- the expression "at least 50% lower” or at least 10% / at least 20% / at least 30% / at least 40% / at least 60% / at least 70%) not that all the aforementioned effects must be reduced by this percentage. It is sufficient if one of the actually occurring effects is reduced by this percentage, whereby the other occurring effects can be reduced by the same, the same or a lower percentage but preferably there is a measurable reduction.
- this reduction is at least 10%, preferably at least 20%, more preferably at least 30%, more preferably at least 40%, even more preferably at least 50%, more preferably at least 60% and most preferably at least 70% by the following experiments.
- biocompatibility is meant also a broad chemical and biological neutrality of a surface coating for cells or tissues in contact with the biopassivating compounds, coatings or compositions Such chemical and biological neutrality is present when the cell / tissue reactions occur
- Contact with a biopassivating surface of the present invention with or without simultaneous physical, chemical or hypoxic cell or tissue alterations, exhibits cell and / or tissue reactions that are no more pronounced than 30%, more preferably no more pronounced than 10% and no more attenuated than 10 % in comparison to cell and / or tissue reactions of cells which have not come into contact with a biopassivating surface according to the invention, wherein the cell and / or tissue reactions are the production of mediators and / or matrix proteins, cell migration and / or Cell proliferation as well as necrosis and / or apoptosis.
- a biocompatibility of a coating or medical preparation according to the invention is present if, under the same in vitro / ex vivo / in vivo conditions, the cell and / or tissue reactions take the form of a production of mediators and / or matrix proteins Cell migration and / or cell proliferation and necrosis and / or apoptosis are not more pronounced than 30%, more preferably not more pronounced than 10% and no more attenuated than 10% compared to a similar cell / tissue alteration without contact of the coated material or a medical Preparation under otherwise identical conditions.
- antiproliferative an inhibitory effect on the migration, proliferation, and formation of extracellular matrix of cells / tissues in contact with the compounds of the invention, such as when the cell / tissue response to a physical, chemically or hypoxically induced cell or tissue alteration consisting of production of matrix proteins and / or cell migration and / or cell proliferation between 55% and 100% are reduced, preferably by 60% -65% and more preferably by 75% -85% in comparison to the cell or tissue reactions with a similar alteration of comparable cells and tissues, with comparable surfaces or medical preparations that were not coated with the compounds of the invention or in which the compounds of the invention were not included in the medical preparations in Konakt came.
- a proliferation reduction according to the invention of a coating or medical preparation is then present if, under the same in vitro / ex vivo / in vivo conditions, the cell and / or tissue reactions take the form of a production of matrix proteins, cell migration and / or cell proliferation between 55% and 100%, preferably by 60% -65% and more preferably by 75% -85%, compared to a similar cell / tissue alteration in the case of a material or medical preparation coated or uncoated with the compounds according to the invention does not contain compounds according to the invention.
- nitrocarboxylic acid-containing phospholipid or “nitrocarboxylic acid-containing phospholipid” or “nitrocarboxylic acid-containing phospholipid”, which are used synonymously, it is meant that at least one of the two lipid residues R 1 and / or R 2 is a nitro group Contains (-NO2).
- the carboxylic acid radical R 1 COO- or the carboxylic acid radical R 2 COO- has at least one nitro group or both carboxylic acid radicals R 1 COO- and R 2 COO- each have at least one nitro group.
- R 1 denotes the carbon radical or the carbon chain of the carboxylic acid radical R 1 COO-
- the corresponding carboxylic acid is R 1 COOH.
- R 2 denotes the carbon radical or the carbon chain of the carboxylic acid radical
- Phospholipid are included, this means the radicals R 1 COO- and R 2 COO-, which are derived from the corresponding carboxylic acids R 1 COOH and R 2 COOH and are bound via an ester bond to the glycerol.
- Phosphoglycerides with glycerol as a backbone are also called glycerophospholipids or phosphatides.
- phospholipids are referred to as phospholipids and preferably glycerophospholipids whose lipid residues carry no nitro groups.
- the compounds according to the invention are called nitrocarboxylic acid (s) -containing phospholipids in order to express that at least one of the two carbon chains R 1 or R 2 carries at least one nitro group.
- Phospholipids containing unsaturated nitrocarboxylic acid residues are preferred.
- the nitro group in R 1 and / or R 2 has no specific position. It can be located at any of the carbon atoms (a to co), ie at any point in the carbon chain. If several nitro groups are present at R 1 and / or R 2 , these may be located at any position in the carbon chains R 1 and R 2 .
- the at least one nitro group is preferably located on a vinyl group of an unsaturated carbon chain. Accordingly, the at least one nitro group is preferably located on a double bond of the unsaturated carbon chain. It is possible that the carbon chain contains more than one nitro group. It is further preferred if the nitro group or nitro groups are in allylic position to the double bond.
- the carbon chain can also double It may contain a carbocycle or a heterocycle or an aromatic ring or a heteroaromatic ring or a carbonyl group, it may be linear or branched and may carry further substituents.
- the term "carbon chain” refers not only to linear and saturated alkyl groups but also to monounsaturated, polyunsaturated, cyclic, branched, and higher substituted alkyl, alkenyl, or alkynyl groups.
- the mono-, di- or polyunsaturated carbon chains of the unsaturated carboxylic acids are preferred. Most preferred are double bonds in the carbon chain of the carboxylic acid, whereas triple bonds and saturated carbon chains are less preferred.
- the term "nitrated carbon chain” means a carbon chain having at least one nitro group and consisting of 5 to 30 carbon atoms, which carbon chain may contain one or more double bonds and / or one or more triple bonds, may be cyclic Carbocyclic, heterocyclic, aromatic ring or heteroaromatic ring, may be substituted by one or more further nitro groups and having one, two or three hydroxyl groups, thiol groups, halogen radicals, carboxylate groups, C 1 -C 5 -alkoxycarbonyl groups, C 1 -C 5 -alkylcarbonyloxy groups, C 1 -C 5 -alkoxy groups, C 1 -C 5 -alkylamino groups, C 1 -C 5 -dialkylamino groups and / or amino groups may be substituted.
- branched means that the carbon chain of the carboxylic acid moiety has at least one branch, i. no linear carbon chain is present.
- nitroalkyl refers to a linear or branched and saturated carbon chain of 5 to 30 carbon atoms and at least one nitro group. At most, the nitroalkyl radical can carry 10 nitro groups. Preferably, the nitroalkyl radical carries 1, 2 or 3 nitro groups if it has 5 to 10 carbon atoms and preferably 1, 2, 3, 4 or 5 nitro groups if it has 1 1 to 20 carbon atoms and preferably 1, 2, 3, 4, 5 , 6 or 7 nitro groups if it has 21-30 carbon atoms.
- the nitroalkyl radical also preferably contains between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- nitroalkenyl radical or “nitrated alkenyl radical” refers to a 5-30 linear or branched and double bond unsaturated carbon chain Carbon atoms and at least one nitro group. At most, the nitroalkenyl radical can carry 10 nitro groups. Preferably, the nitroalkenyl radical carries 1, 2 or 3 nitro groups if it has 5-10 carbon atoms, and preferably
- the nitroalkenyl group contains one, two or three nitro groups.
- the nitroalkenyl radical contains at least one and a maximum of 15 double bonds. Preference is given to one, two or three double bonds, further preferred are one or two double bonds and particularly preferred is a double bond.
- the double bonds may each independently be E (opposite, sometimes also referred to as "trans") or Z (together, sometimes also referred to as "ice"). Preference is given to Z double bonds.
- the nitroalkenyl radical also preferably contains between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- nitroalkynyl or “nitrated alkynyl” refers to a linear or branched and triply unsaturated carbon chain of 5 to 30 carbon atoms and at least one nitro group. At most, the nitroalkynyl radical can carry 10 nitro groups. Preferably, the nitroalkynyl moiety carries 1, 2 or 3 nitro groups if it has 5-10 carbon atoms and preferably 1,
- the nitroalkynyl moiety contains one, two or three nitro groups.
- the nitroalkynyl radical contains at least one and a maximum of ten triple bonds. Preference is given to one, two or three triple bonds, more preferred are one or two triple bonds and particularly preferred is a triple bonds.
- the nitroalkynyl moiety also preferably contains between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- nitrogenalkyl radicals having 5 to 30 carbon atoms containing a cycloalkyl radical or a heterocycloalkyl radical or a carbonyl group refers to a linear or branched carbon chain having 5 to 30 carbon atoms, in which carbon chain is a cycloalkyl radical or a heterocycloalkyl radical or a carbonyl group.
- the carbon atoms of the cycloalkyl radical or the heterocycloalkyl radical or the carbonyl group are contained in the total number of carbon atoms, that is contained in the 5-30 carbon atoms.
- the A nitroalkyl radical having 5 to 30 carbon atoms containing a cycloalkyl radical or a heterocycloalkyl radical or a carbonyl group carries a maximum of 10 nitro groups and preferably carries 1, 2 or 3 nitro groups if it has 5 to 10 carbon atoms and preferably 1, 2, 3, 4 or 5 nitro groups, when it has 1 1 - 20 carbon atoms and preferably 1, 2, 3, 4, 5, 6 or 7 nitro groups, if it has 21 - 30 carbon atoms. Most preferably, this nitroalkyl radical contains one, two or three nitro groups.
- the nitroalkyl radical containing a cycloalkyl radical or a heterocycloalkyl radical or a carbonyl group preferably has between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- alkyl refers to a linear or branched and saturated carbon chain of 5 to 30 carbon atoms and no nitro group.
- the alkyl group further preferably contains between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- alkenyl refers to a linear or branched and double bond unsaturated carbon chain of 5 to 30 carbon atoms and no nitro group.
- the alkenyl radical contains at least one and a maximum of 15 double bonds. Preference is given to one, two or three double bonds, further preferred are one or two double bonds and particularly preferred is a double bond.
- the double bonds may each independently be E (opposite, sometimes also referred to as “trans”) or Z (together, sometimes also referred to as "ice”). Preference is given to Z double bonds.
- the alkenyl group further preferably contains between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- alkynyl refers to a linear or branched and triply unsaturated carbon chain of 5 to 30 carbon atoms and at least one nitro group.
- the alkynyl radical contains at least one and a maximum of ten triple bonds. Preference is given to one, two or three triple bonds, more preferred are one or two triple bonds and particularly preferred is a triple bonds.
- the alkynyl radical preferably also contains between 8 and 28 carbon atoms, more preferably between 10 and 26 carbon atoms, even more preferably between 12 and 24 carbon atoms, and most preferably between 14 and 22 carbon atoms.
- nitroalkyl radical, nitroalkenyl radical, nitroalkynyl radical, nitroalkyl radicals having from 5 to 30 carbon atoms containing a cycloalkyl radical or a heterocycloalkyl radical or a carbonyl group, alkyl radical, alkenyl radical and alkynyl radical can furthermore be substituted by one, two or three hydroxyl groups, thiol groups, halogen radicals (-F, -Cl, -Br , -I), carboxylate groups, Ci-C5 alkoxycarbonyl, Ci-C 5 oxy groups alkylcarbonyl, Ci-C5 alkoxy groups, Ci-C 5 substituted alkylamino, Ci-C groups and 5 dialkylamino / or amino groups his. Further preferred are hydroxyl and C 1 -C 5 -alkoxy groups and particularly preferred are hydroxyl groups.
- the following carboxylic acids represented as free acid R 1 COOH and R 2 COOH are preferably used as radicals R 1 COO- and R 2 COO- in the nitrocarboxylic acid-containing phospholipids according to formula (I). That is to say that the following carboxylic acids are preferably used in nitrated form, ie with at least one nitro group and optionally further substituents as listed above for the esterification of the glycerol residue in the phospholipids according to the invention: hexanoic acid (caproic acid), octanoic acid (caprylic acid), decanoic acid (capric acid), dodecanoic acid (lauric acid ), Tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), heptadecanoic acid (margaric acid), octadecanoic acid (stearic acid), eicosanoic acid (arachidic acid), docosanoic acid (
- Octadecatrienoic acid ( ⁇ -linolenic acid), 6,9,12,15-octadecatetraenoic acid
- Step 1 (Stearidonic acid), 8,1 1,14,17-eicosatetraenoic acid, 5,8,1,1,14,17-eicosapentaenoic acid (EPA), 7,10,13,16,19-docosapentaenoic acid (DPA), 4,7, 10,13,16,19-docosahexaenoic acid (DHA), 5,8,1-eicosatrienoic acid (meadklare), 9c1 1 t13t-eleostearic acid, 8t10t12c-calendulic acid, 9c1 1113c-catalpinic acid,
- the radicals R 1 COO and R 2 COO- in the nitrocarboxylic acid-containing phospholipids according to the present invention shown as the free acid R 1 COOH and R 2 COOH, may represent a nitrated carboxylic acid, wherein the respective (s) carboxylic acid (n ) are selected from the above group.
- carboxylic acids are preferably used as radicals R 1 COO- or as radical R 2 COO- in the phospholipids according to general formula (I) according to the invention and the nitrated form of these concretely mentioned carboxylic acids preferably as second lipid radical R 2 COO or R 1 COO be used or the nitrated form of these concretely mentioned carboxylic acids are preferably used for both lipid R 1 COO and R 2 COO-.
- Particularly preferred lipid radicals in the phospholipids according to the invention are the following nitrated carboxylic acid radicals R 1 COO- and R 2 COO-:
- trans-9-nitro-9-octadecenoyl and trans-10-nitro-9-octadecenoyl Mixtures of trans-9-nitro-9-octadecenoyl and trans-10-nitro-9-octadecenoyl, trans-9-nitro-10-octadecenoyl, trans -10-nitro-8-octadecenoyl.
- trans-6-nitro-6-octadecenoyl trans-7-nitro-6-octadecenoyl.
- trans-1 1 -nitro-1 1 -octadecenoyl Mixtures of trans-1 1 -nitro-1 1 -octadecenoyl and trans-12-nitro-1 1 -octadecenoyl, trans-1 1 -nitro-12-octadecenoyl, trans-12-nitro-10-octadecenoyl.
- trans-1 1 -nitro-1 1 -eicosenoyl Mixtures of trans-1 1 -nitro-1 1 -eicosenoyl and trans-12-nitro-1 1 -eicosenoyl, trans-1 1 -nitro-12-eicosenoyl, trans-12-nitro-10-eicosenoyl.
- E, Z -6,9-dinitro-5,8,1-eicosathenoyl, (E, Z, E) -5,1 1 -dinitro-5,8,1-eicosathenoyl, (E, Z, E) -5,12-dinitro-5,8,1-eicosathenoyl, (E, Z, E) -6,1 1 -dinitro-5,8,1-eicosathenoyl, (E, Z, E) - 6,12-dinitro-5,8,1-eicosathenoyl, (Z, E, E) -8,1 l -dinitro-5,8,1-eicosatrienoyl, (Z, E, E) -8,12 -Dinitro-5,8,1-eicosatrienoyl, (Z, E, E) -9,1 1 -dinitro-5,8,1-eicosathenoyl, (Z, E, E)
- nitration reactions and in particular the acid or free-radical nitration can often not be carried out selectively and the nitrated carboxylic acids are sometimes difficult to separate
- mixtures of nitrated carboxylic acids are also preferred. These mixtures are preferably regioisomers, in particular of carboxylic acids having a plurality of double bonds, as well as mixtures of mono-, di-, di- or poly-nitrated carboxylic acids.
- Nitrated carboxylic acids as pure (i.e., no mixtures) are best prepared by a substitution reaction, as shown below:
- Non-selective nitration reactions are described in Gorczynski, Michael J .; Huang, Jinming; King, S. Bruce; Organic Letters, 2006, 8, 11, 2305-2308 and shown in the following overview:
- the unselective nitration of a double bond of the carboxylic acid can also proceed in an acidic medium, as shown below (Scheme 2):
- Scheme 3 Another possibility of nitration (Scheme 3) of unsaturated carboxylic acid is shown in the following reaction diagram and uses PhSeBr.
- the nitrocarboxylic acid-containing phospholipids of the invention can be obtained by esterifying the two OH groups of the glycerol unit with the same nitrocarboxylic acid.
- R 1 COOH is identical to R 2 COOH and R 1 is identical to R 2 (see Scheme 4).
- the esterifications must be carried out successively, preferably first selectively esterifying the primary OH group and then the secondary OH group.
- a nitrocarboxylic acid can be used in the first esterification and a non-nitrated carboxylic acid in the second esterification or a non-nitrated carboxylic acid in the first esterification and a nitrocarboxylic acid in the second esterification or a different nitrocarboxylic acid in both esterifications (see Scheme 4).
- the esterifications are carried out according to standard reactions known to the person skilled in the art.
- nitrocarboxylic acid (s) -containing phospholipids Another possibility for the preparation of the nitrocarboxylic acid (s) -containing phospholipids according to the invention is shown in Scheme 5.
- PL results primarily with different radicals in positions 1 and 2, ie R 1 COO- ⁇ R 2 COO-
- the reaction sequence according to Scheme 5 allows the introduction of non-nitrated carboxylic acid residues (R 1 COO-) Position 1 and a nitrated carboxylic acid residue (R 2 COO-) at position 2.
- the reaction sequence shown in Scheme 5 is also applicable when R 1 represents COO- a nitrated saturated carboxylic acid residue.
- R 2 COO may mean any nitrated or non-nitrated as well as saturated or unsaturated carboxylic acid residues.
- the reaction sequence shown in Scheme 5 is not or only poorly applicable when R 1 is COO- a nitrated unsaturated carboxylic acid radical and above all a vinylated (ie at the double bond) nitrated unsaturated carboxylic acid radical. The further esterification with R 2 COO then takes place only under drastic yield losses. For such a case, a new synthesis was developed, which is shown in Scheme 6.
- both positions 1 and 2 are esterified with non-nitrated carboxylic acid residues or with nitrated saturated carboxylic acid residues and then saponified enzymatically by means of phospholipase selectively position 1, so that then at position 1, a nitrated unsaturated carboxylic acid residue can be introduced.
- General as well as concrete reaction instructions are given in the experimental part.
- the radicals R 1 COO- and R 2 COO- in the nitrocarboxylic acid (s) -containing phospholipids can be varied widely, at least one of the radicals R 1 COO- and R 2 COO- represents one of the aforementioned nitrocarboxylic ,
- the radical R 3 may be, for example, hydrogen, serine, choline, a sugar such as inositol or colamine (ethanolamine). If it is an esterification with cholines, then lecithins (also phosphatidylcholines) are formed, in the esterification with ethanolamine cephalins are formed. The phosphatidylcholines are preferred.
- Phosphatidylethanolamine also cephalin, short PE
- Phosphatidylcholine also lecithin, short PC
- the nitrocarboxylic acid-containing phospholipids can be used as pure substances, diastereomer mixtures, regioisomer mixtures or mixtures of different nitrocarboxylic acid-containing phospholipids for the preferably biopassivating compositions according to the invention and the preferably biopassivating coatings according to the invention.
- product mixtures of nitrocarboxylic acids which are regioisomers as well as mono- or poly-nitrated carboxylic acids.
- Such product mixtures of different nitrated carboxylic acids obtained in the nitration reaction can thus be used as a mixture for the esterification with the Phospholipidrest such as sn-glycero-3-phosphocholine are used and the resulting mixtures of differently nitrated carboxylic acid - containing phospholipids can be used without being a separation into pure substances, as a mixture for the uses of the invention.
- the pure nitrocarboxylic acid (s) -containing phospholipids and the mixtures of nitrocarboxylic acid-containing phospholipids can be used in combination with or as a mixture with non-nitrated PL.
- all layers also consist of mixtures of nitrated phospholipids with phospholipids which do not contain a nitro group.
- the advantage of a high proportion of nitrated phospholipids is the improved physico-chemical properties of phospholipid mixtures on surfaces compared to non-nitrated phospholipids, and a high degree of coverage and a low rate of multiple layer formation.
- residual phospholipid vacancies close spontaneously when phospholipid mixtures with a high content of nitrated phospholipids are used and moderate heat (up to 50 ° C) and high humidity are used (Example 1).
- SAMs with a significant proportion of nitro-phospholipids were more resistant to mechanical and chemical changes than SAMs, which consist of comparable non-nitrated phospholipids.
- the lateral mobility of SAM with nitrated phospholipids is lower than that of SAM from non-nitrated phospholipids, but the lateral mobility in monolayers of pure nitrated phospholipids is still measurable.
- Hydrophilic polymers such as PEG were physisorbed onto phospholipid coatings in the presence of electrolytes such as calcium. An overcoat of hydrophilic polymers extended the shelf life of a closed formation of the phospholipid layer. The physisorbed polymers could be quickly removed by rinsing. When such a combined coating was used on catheter balloons, no defect of the phospholipid monolayer after balloon expansion could be observed.
- nitrated phospholipids exhibit a low dissociation rate from a monolayer assembly than comparable non-nitrated phospholipids. This effect can be attributed to the denser packing of nitrated phospholipids and the stronger hydrophobic adhesion forces (Example 3). About a relevant effect of a nitrogen oxide is not known in this context. The number of nitro groups before and after cell experiments was almost the same. It is still unlikely that one pharmacologically relevant concentration of nitrated phospholipids in the cell membranes of the adherent cells was inserted, as shown by experiments with radioactively labeled nitrated phospholipids (Example 4).
- endothelial cells adhering to a SAM with nitrated phospholipids expressed significantly fewer cell adhesion molecules than cells adhering to phospholipid-coated surfaces without nitrated carboxyl chains.
- vascular smooth muscle cells VSMC
- SAM nitrocarboxylic acid Phospholipids contained
- the biopassivating properties of the nitrated phospholipids cause an increased survival of cells (eg macrophages) by a lower apoptosis induction compared to a coating of non-nitrated phospholipids.
- the higher survival rate causes a lower cytokine production, whereby the possible immune reactions at the site of the implant are lower and thereby a tissue-proliferating stimulus by the implant is absent (Example 7).
- the results surprisingly and unexpectedly show that coatings of SAM with nitrated phospholipids enhance the cell homing of cells such as VSMC and endothelial cells, while cell responses to one cell Artificial surface can be reduced by providing a highly biocompatible surface without pharmacological effects.
- Naturally occurring and synthetic phospholipids have been proposed for coating implant materials.
- free nitrated fatty acids have been suggested for inhibiting an aggressive healing pattern.
- an improvement in biocompatibility over the use of the uncoated materials has been assumed.
- biopassivating effects as disclosed herein, have neither been proven nor have been expected by a person skilled in the art.
- an interaction between the phospholipids according to the invention and the cell / tissue structures is required, for which purpose these molecules should or must be present in unbound form.
- nitrocarboxylic acid-containing phospholipids according to the invention were investigated in direct comparison with comparable natural phospholipids and fatty acids with or without nitration. The main results are summarized below:
- the free fatty acids are absorbed by cells to a much greater extent than phospholipids, whereby intracellular vesicles are formed. This is associated with a significantly lower toxicity limit and a significant increase in apoptosis rate. But native phospholipids are also taken up by cells in the cell membrane, causing them to enlarge. This can subsequently promote the willingness to cell division. Such behavior was not present in the phospholipids containing nitrocarboxylic acid (s) (Example 8, 16).
- nitrocarboxylic acid (s) -containing phospholipids differ significantly from the corresponding non-nitrated phospholipids (PL) but also compared to the free nitrofatty acids. It could thus be shown that in the case of a coating with nitrocarboxylic acid-containing phospholipids, these have a significantly higher adherence to the coating material, whereby the retention of lubricity is significantly stronger and longer lasting than with the comparable substances (Experiment 10) , 12).
- microparticles require a partial protuberance of the cell membrane and is therefore highly dependent on the physico-chemical membrane properties. Also for the deposition of microparticles clearly different values between nitrocarboxylic acid (s) -containing phospholipids, natural PL and the free nitrofatty acids were found, which are consistent with the aforementioned changes in membrane properties (experiment 10, 14, 15).
- the noception and transmembrane signal transduction is significantly influenced by the physicochemical properties of the cell membrane.
- the opening of ion channels plays an outstanding role here. It has been shown that the transmembrane ion channel opening observed under different conditions, e.g. in the context of a hypoxia, a mechanical cell aging or a receptor excitation, to a considerable extent by the nitrocarboxylic acid (s) -containing phospholipids is reduced (Experimental O, 1 1, 13, 16, 17, 19, 20).
- nitrocarboxylic acid (s) -containing phospholipids Studies on the long-term stability of the natural and the nitrocarboxylic acid (s) -containing phospholipids showed a significantly lower in the nitrocarboxylic acid (s) -containing phospholipids Tendency to Transisomehe the nitrated fatty acids on (experiment 12). Since adverse biological effects have been described for cellular uptake of trans fatty acids, avoidance of the provision of trans fatty acids is advantageous.
- the nitrocarboxylic acid-containing phospholipids according to the invention have shown biocompatible, biopassivating but also proliferation-reducing effects under various conditions. It can therefore be assumed that these effects are also transferable to other cell types and clinical situations, where in particular a biopassivating effect is desired.
- Biopassivation preferably causes no or almost no pathologically altered response in the cells or tissues that come in contact with the coated surface. As a result, for example, there is a healing of the foreign surface, which is characterized by a lower tissue proliferation. This results in endothelialization / healing of the thus coated material, with a physiologically required amount of cells / matrix proteins.
- an anti-restenotic effect is indirectly achieved such that the biopassivating properties of such coated vascular grafts provide them with the ability to passively prevent, inhibit, or arrest symptoms of restenosis, ie, overgrowth of the implanted stent and stent-stabilized site ,
- phospholipids containing nitrocarboxylic acids by their properties for coatings of medical devices are suitable because they counteract passive mechanisms of restenosis or overgrowth of the medical device and blood clotting and cell damage at the site of implantation of the medical device.
- Another aspect of the effects of phospholipids with nitrocarboxylic acids is their effect on the release and composition of microparticles secreted by traumatized cells. This may result in uptake / incorporation of nitrocarboxylic acid-containing phospholipids into cell membranes, which could have a passive effect on the local as well as systemic tissue responses. In this case, an influence of the proteins enclosed in the microparticles can also be assumed. This particularly concerns glycoprotein tissue factors whose biological activity is passively inhibited by nitrocarboxylic acid-containing phospholipids.
- Another effect is the stabilization of cell membrane properties (resistance to mechanical, chemical, osmotic or electrical irritations as well as against mechanical, chemical, osmotic or electrical trauma) and functionality (membrane potential, regulation of ion channels, signal membrane transduction).
- Tissue hypoxia rapidly leads to changes in the cell membranes. This activates phospholipases that release fatty acids from the phospholipids. A consequent increase in the concentration of lysophospholipids is associated with a reperfusion injury. While a saturation of cell membranes with natural phospholipid (PL) prior to ischemia had no relevant influence on ischemia tolerance and reperfusion damage, surprisingly a significant reduction in hypoxia-related cell damage could be demonstrated by the compounds according to the invention. The analysis carried out for the evaluation of the reperfusion damage is limited due to the experiments carried out under ex-vivo conditions. Nonetheless, it has been demonstrated in the literature that the extent of reperfusion damage is correlated with the loss of NAD + in the cytoplasm as well as intramitochondrially.
- nitrocarboxylic acid (s) -containing phospholipids according to the invention have advantageous properties on phospholipid membranes which can be summarized as cell-protective, biocompatible, and biopassivating, the common inventive concept being summarized under the term biopassivation.
- nitrocarboxylic acid (s) -containing phospholipids of the invention are useful in biopassivating or biocompatible uses, e.g. for the production of medical compositions and for the coating of medical devices.
- the phospholipids containing nitrocarboxylic acid (s) are particularly suitable for bi-neutral monolayers or bilayer coatings of medical implants.
- the present invention is also directed to medical devices coated with at least one nitrocarboxylic acid-containing phospholipid.
- a coating is preferably present as a monolayer, bilayer or multilayer and has biopassivierende properties.
- coatings may also contain active ingredients, such as anti-restenotic agents, which is advantageous in catheter balloons and cardiovascular implants and will be discussed in more detail below.
- Preferred implant materials are stents that are inserted into hollow organs to keep them open.
- stents are made in tube form and classically consist of a framework of struts.
- Stents are used for vascular stabilization, especially to keep them open, which is especially important for blood vessels, especially coronary arteries, to keep them open or to prevent re-occlusion (restenosis) after expansion by balloon catheters.
- Stents can also be used to stabilize the airways, the esophagus or the bile ducts.
- the coating of stents is preferred according to the invention.
- stents which are introduced into blood vessels are particularly preferred.
- Balloon catheters are also preferred medical products according to the invention.
- implants particularly, but not exclusively, include soft tissue implants, in particular breast implants.
- Joint and cartilage implants include soft tissue implants, in particular breast implants.
- grafts of biological or artificial origin include intraocular lenses, surgical nets and adhesion barriers, nerve regeneration suite, shunts, biological or artificial vessel vessels, catheters, probes, ports, drains, stoma junctions, endoluminal tubes, sutures, ligatures, implantable devices such as defibrillators, surgical instruments such as hooks and tweezers.
- a further field of application is the provision of nitrocarboxylic acid-containing phospholipids for tissue / organ systems which, by incorporation of these phospholipids or the phospholipids containing their surface with nitrocarboxylic acid-containing phospholipids, have improved tolerance to metabolic, physical and chemical alterations demonstrate. This leads to a passivation of these cells to the body's own (eg cytokines, growth factors) or foreign (eg toxins) substances that otherwise lead to cell proliferation or apoptosis / necrosis. These documented effects differ substantially from the effects of naturally occurring phospholipids as well as the effects of nitrated fatty acids.
- tissue / organ trauma is caused by physical (e.g., mechanical, thermal), chemical, or electrical mechanisms. Examples include: cuts and sores, burns, frostbite, burns, ulcerations, radiation, and allergen and toxin exposures.
- This relates to wound care preparations which are applied to carrier materials or are contained in pharmaceutical preparations and applied superficially to a tissue or introduced into the organism.
- the physical properties of the nitrocarboxylic acid (s) -containing phospholipids can also be used to effect a delayed dissolution / release of substances from a mixture, as well as to effect their physical stabilization.
- Particularly preferred fields of application include surgical treatment methods in which tissue is separated or connected, in particular if this separation / connection occurs in connection with a trauma or other chemical or physical irritation of the tissue, and includes in particular plastic-reconstructive and cosmetic procedures.
- Preferred wound care materials are: wound dressings in the form of gels, tablets, colloids, adhesives, aglinates, foams, adsorbents, gauzes, cotton swabs and bandages. 3. Preparations for tissue / organ protection
- nitrocarboxylic acid (s) -containing phospholipids causes a Prolongation of the ischemia tolerance, so that a pretreatment of such tissue makes sense. This can be done in the form of a previous perfusion of the tissue / organ but also an installation or placement in a solution with nitrocarboxylic acid (s) - containing phospholipids, since the phospholipids are rapidly absorbed from the surrounding medium or on the cell and / or tissue surface supports.
- nitrocarboxylic acid (s) - containing phospholipids are also suitable for cryopreservation of tissues / organs via the previously reported preparatory measures.
- Cell membranes have a variety of functions and tasks. Many of these functions are conditioned by the physical properties of cell membranes. These include mechanical stability to physical and chemical alterations. But also interactions between the alkyl chains and membrane proteins have an influence on the functionality of ion channels and receptor proteins.
- nitrocarboxylic acid-containing phospholipids By including nitrocarboxylic acid-containing phospholipids and the resulting change in membrane properties, it is possible to influence some of these membrane functions. Thus it could be proven that changes which lead to a disruption of the membrane potential can be reduced, whereby nitrocarboxylic acid-containing phospholipids have antiarrhythmic properties. Furthermore, it has been demonstrated that, in principle, cell-toxic substances which are absorbed by an intact cell membrane via different mechanisms by a prior uptake of nitrocarboxylic acid (s) -containing phospholipids into the cell membrane, the uptake / action of such toxins can be significantly reduced.
- nitrocarboxylic acid (s) -containing phospholipids By including nitrocarboxylic acid (s) -containing phospholipids and the resulting change in membrane properties, it is possible to influence some of these membrane functions. Thus it could be proven that changes which lead to a disruption of the membrane potential can be reduced, whereby nitrocarboxylic acid-containing phospho
- nitrocarboxylic acid-containing phospholipids results in greater resistance to an osmotic gradient.
- stabilization of the cell membrane has a significant effect on ionic nodules, especially those that undergo a change in intracellular Calcium concentrations cause, which also z. B. cause antiarrhythmic effects and inhibition of degranulation of eosin cells.
- the investigations show that the above-mentioned changes in the membrane properties by the nitrocarboxylic acid-containing phospholipids also influence the cell reactivity / noumption on endogenous or exogenous stimulators and inhibitors. So z.
- the diminished nociception of TNF alpha or TGF-beta has an antifibrotic effect.
- biodegradable medical devices according to the invention are thus selectable from the group comprising or consisting of: medical pulp, dressing materials, wound inserts, surgical sutures, compresses, sponges, medical textiles, ointments, gels or film-forming sprays.
- the medical pulp and medical textiles preferably are two-dimensional structures of small thickness impregnated with the nitrocarboxylic acid-containing phospholipids.
- the Nitrocarboxylic acid-containing phospholipids attach themselves to the fibrous structures of these medical devices, which can be used in dry or pre-moistened form.
- a preferred form of medical device according to the invention are sponges or generally biodegradable porous three-dimensional structures which may contain the nitrocarboxylic acid-containing phospholipids both on the surface and in the interior of the porous structure in the cavities.
- These sponges can e.g. after an operation are placed in the wound and fill the operating room largely or only partially. From these sponge-like structures, the nitrocarboxylic acid-containing phospholipids can be released, but the nitrocarboxylic acid-containing phospholipids can also be present in firmly bound form. The release can be effected both by diffusion of only loosely bound nitrocarboxylic acid (s) -containing phospholipids from the cavities of the porous structure and by biodegradation of the sponge structure.
- a carrier having the nitrocarboxylic acid-containing phospholipids and serving as a "carrier", among others.
- the tissues, pulps, gels, film-forming compositions, etc. described in detail herein, which may be biodegradable or biostable.
- the carriers may also be made of living matter and may contain x-ray markers or contrast agents.
- tissue refers to any medically used textile or pulp from which dressing materials, dressings, dressings, or other medical wipes or fabrics are made.
- Polyhydroxybutyrates and cellulose derivatives, chitosan derivatives as well as collagen, polyethylene glycol, polyethylene oxide and polylactides are preferred materials for medical pulps and textiles.
- alginates When alginates are used as the wound dressing, it is preferred to use calcium alginate with sodium carboxymethylcellulose interwoven products.
- the SeaSorb Soft from Coloplast is an example.
- Surgical sutures may be subdivided into monofilament and polyfile filaments in terms of their construction. Polyfile threads can show a so-called wicking effect. That is, by capillary action tissue fluid migrates along the thread. This can also be associated with a migration of microbial germs, so that can propagate along the thread material infections. It is therefore desirable to provide surgical suture material in such a way that germ colonization on the thread surface and thus migration of germs along the thread are effectively prevented.
- the suture is wetted with a homogeneous methanolic solution containing at least one nitrocarboxylic acid-containing phospholipid, and then the methanol is evaporated, forming a coating on the thread surface.
- a homogeneous methanolic solution containing at least one nitrocarboxylic acid-containing phospholipid
- the methanol is evaporated, forming a coating on the thread surface.
- other lower alcohols such as ethanol, propanol and isopropanol or mixtures thereof with methanol instead of methanol.
- the nitrocarboxylic acid-containing phospholipids disinfectant solutions are added, such as octenidine dichloride solutions (eg, sold under the name OcteniseptB by the company Schüle & Mayr) or added to dequalinium chloride solutions.
- the weight ratio of octenidine dichloride or dequalinium chloride to nitrocarboxylic acid-containing phospholipids is preferably 1 to 0.1 to 1 to 5, and more preferably 1 to 1.
- sutures are preferably used which are preferably polyglycolic acid, polycaprolactone-co-glycolide, or poly-p-dioxanone. Examples include the products Marlin ® , PCL and Marisorb ® Catgut GmbH called.
- nitrocarboxylic acid-containing phospholipids I particularly sterile 100% cotton gauze compresses are to be used here.
- Examples include the product lines Stericomp ® and Askina ® .
- the medical textiles and pulps are sprayed or dipped therein with a solution of the nitrocarboxylic acid-containing phospholipids in water, organic solvents such as ethanol or mixtures thereof, the dipping or spraying process after drying the medical device can be repeated several times.
- Per cm 2 surface of the medical device 10 g to 100 mg of nitrocarboxylic acid (s) -containing phospholipids are applied.
- the medical sponges are bioresorbable implants with a sponge-like, porous structure. Preferred materials for the medical sponges are collagen, oxidized cellulose, chitosan, thrombin, fibrin, chitin, alginates, hyaluronic acid, PLGA, PGA, PLA, polysaccharides and globin. If medical sponges are used, those having a proportion of more than 90% of collagen are preferred.
- an ointment base containing or consisting of purified water may be used in an amount of preferably 5 to 50% by weight, more preferably 10 to 40% by weight, and most preferably from 20-30% by weight.
- the ointment also preferably contains Vaseline in an amount of 40-90% by weight, more preferably 50-80% by weight and most preferably 20-60% by weight.
- the ointment may still contain thick liquid paraffin in an amount of 5-50% by weight, more preferably 10-40% by weight, and most preferably 20-30% by weight.
- gel formers and / or film formers may be added in an amount of up to 30% by weight.
- polymers such as cellulose, chitosan, thrombin, fibrinogen, chitin, alginates, albumin, hyaluronic acid, hyaluronan, polysaccharides, globin, polylactide, polyglycolide, polylactide-co-glycolide, polyhydroxybutyrates, cellulose derivatives, chitosan derivatives, polyethylene glycol and polyethylene oxide in amounts up to 30 wt .-% are used.
- the phospholipids according to the invention containing nitrocarboxylic acids can also be incorporated into spray solutions or be constituents of film-forming sprays.
- the phospholipids containing nitrocarboxylic acids described herein can be combined with gel or film formers.
- Film-forming sprays contain at least one or more film formers.
- Suitable film formers are preferably cellulose-based substances such as cellulose nitrate or ethylcellulose or physiologically acceptable polymers thereof, polyvinyl acetate, partially saponified polyvinyl acetate, copolymers of vinyl acetate and acrylic acid or crotonic acid or monoalkyl maleate, ternary copolymers of vinyl acetate and crotonic acid and vinyl neodecanoate, or crotonic acid and vinyl propionate, copolymers of methyl vinyl ether and monoalkyl maleate, in particular monobutyl maleate, copolymers of fatty acid vinyl ester and acrylic acid or methacrylic acid, copolymers of N-vinylpyrrolidone, methacrylic acid and methacrylic acid, copolymers of acrylic acid and methacrylic acid or alkyl acrylates or methacrylates, in particular containing quaternary ammonium groups , or polymers, copolymers or mixtures containing e
- the film formers also include water-soluble polymers such as ionic polyamides, polyurethanes and polyesters and homo- and copolymers of ethylenically unsaturated monomers.
- water-soluble polymers such as ionic polyamides, polyurethanes and polyesters and homo- and copolymers of ethylenically unsaturated monomers.
- Such materials are, for example, under the trade names Acronal ®, Acudyne ®, Amerhold ®, Amphome ®, Eastman AQ ®, Ladival ®, Lovocryl ®, Luviflex VBM ®, Luvimer ®, Luviset PU R ®, Luviskol ®, Luviskol ® Plus, Stepanhold ® , Ultrahold ® , Ultrahold Strong ® or Versatyl ® .
- Luvimer ® is developed by the company BASF AG is a polyacrylate as a hair styling polymer.
- nitrocarboxylic acid (s) -containing phospholipid-coated implants by means of dipping or spraying.
- the products to be implanted are immersed in a solution or suspension of the nitrocarboxylic acid-containing phospholipids or sprayed with an appropriate solution. Thereafter, the implants are dried and packaged sterile.
- the gels, ointments, solutions and sprays are obtained by preparing the desired pharmaceutical preparation according to standard methods and preferably in a last step adding the desired amount of phospholipids containing nitrocarboxylic acids. Also part of the present invention are the medical devices of the invention obtainable thereby.
- the rinsing solutions according to the invention for medical devices containing at least one nitrocarboxylic acid-containing phospholipid according to the invention can be used for rinsing u. Cleaning instruments and. Accessories, for moistening Wundtamponaden, towels u. Bandages, filling of the respiratory humidification equipment, to check the permeability of catheters - nasal rinsing and intra- u. postoperative irrigation during endoscopic surgery, rinsing and cleaning of wound drainage catheters.
- the rinsing solutions according to the invention for wounds containing at least one nitrocarboxylic acid-containing phospholipid according to the invention comprise rinsing solutions for rinsing and cleaning during surgical interventions, rinsing and cleaning in the case of stoma care, for rinsing wounds and burns and for mechanical eye rinsing.
- Woundwash solutions are generally used to remove cell debris, necroses, blood and pus remnants but also residues of wound dressings.
- the phospholipids containing nitrocarboxylic acids according to the invention can form a coating or a film on the rinsed surfaces and thus cause biopassivation of the surfaces.
- Suitable basic solutions or formulations which nitro carboxylic acid of the invention (s) -containing phospholipids may be added and which are used as flushing solution such as physiological saline, Ringer's or lactated Ringer's solution, solutions containing polyhexanide or polyethylene glycol, and commercially available irrigation solutions like Prontosan ® or Lavanid ®.
- biological samples includes cells, both eukaryotic and prokaryotic, organs and tissues, and biologically active molecules, eg, macromolecules, such as nucleic acids or proteins, Especially preferred is cryopreservation of human embryos and embryos of other mammals.
- biological samples includes cells, both eukaryotic and prokaryotic, organs and tissues, and biologically active molecules, eg, macromolecules, such as nucleic acids or proteins, Especially preferred is cryopreservation of human embryos and embryos of other mammals.
- One preferred embodiment of the present invention consists of a cryoprotective solution or a cryopreservation medium containing at least one nitrocarboxylic acid (s) according to the present invention.
- the nitrocarboxylic acid-containing phospholipids according to the invention have a positive effect on the survival rate of the cells / microorganisms.
- Cryoprotective solutions or cryopreservation media generally comprise a cryoprotectant which is ensured by cryoprotectants, for example glycerol, dimethyl sulfoxide (DMSO) amorphous solidifying disaccharides and polymers.
- cryoprotectants for example glycerol, dimethyl sulfoxide (DMSO) amorphous solidifying disaccharides and polymers.
- Cryoprotection solutions or cryopreservation media which should be suitable for freezing cells, organs and tissues, have as base a corresponding culture medium.
- As culture medium all common culture media for the culture of microorganisms, cells and tissues can be used. In addition, it may also contain: buffer substances, indicators, dyes, inhibitors (for example antibiotics) or growth aids (hormones, vitamins and the like).
- Cryoprotection solutions for freezing macromolecules contain no nutrient media as base, but preferably aqueous buffer solutions.
- the cryoprotectants used for macromolecules are preferably amorphous solidifying disaccharides and polymers.
- lycoprotective solutions according to the invention differ from the above-described Cryoprotektionslosungen only by the stabilizing additives used. While the cryoprotectants ensure stability during freezing, lyoprotectors are used during drying. Lyoprotectors form a matrix by means of hydrogen bonds to functional polar groups of macromolecules and act as a water substitute. For this reason, molecules which have hydrophilic groups and, due to their structure, are sufficiently flexible to be able to form hydrogen bonds to the surface of the macromolecules are particularly suitable for this purpose. Preference is given here to call disaccharides and mannitol.
- the present invention also encompasses solutions comprising at least one nitrocarboxylic acid-containing phospholipid according to the invention and both a cryoprotector and a lyoprotector.
- inventive contrast agent solutions which contain at least one nitrocarboxylic acid-containing phospholipid according to the invention and a contrast agent or contrast agent analogues.
- a contrast agent or contrast agent analogues such Barium, iodine, manganese, iron, lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium and / or lutetium are preferred as contrast agents and / or contrast agents / or complexed form.
- Preferred X-ray contrast agents are those used for joint imaging (arthrography) and CT (computed tomography).
- X-rays, computed tomography (CT), magnetic resonance imaging, magnetic resonance imaging (MRI) and ultrasound are used as imaging methods, with magnetic resonance imaging and magnetic resonance imaging (MRI) being preferred.
- iodine-containing contrast agents are preferred, which are used in angiography and venography (CT) and CT (computed tomography).
- CT computed tomography
- MRI magnetic resonance imaging
- MRI magnetic resonance imaging
- iodine-containing contrast agents are preferred, which are used in angiography and venography (CT) and CT (computed tomography).
- CT venography
- iodinated contrast media the following examples can be mentioned: amidotrizoic, iotrolan, iopamidol, lodoxaminklare, iodine-Lipiodol ® and amidotrizoate.
- Another class of preferred contrast agents are the paramagnetic contrast agents, which usually contain a lanthanide such as gadolinium (Gd 3+ ), europium (Eu 2+ , Eu 3+ ), dysprosium (Dy 3+ ) or holmium (Ho 3+ ) ,
- gadolinium-containing contrast agents are gadolinium diethylenetriaminepentaacetic acid, gadopentetic acid (GaDPTA), gadodiamide, meglumine gadoterate and gadoteridol.
- the term "medicinal composition” or “solution” as used herein means the mixture of at least one nitrocarboxylic acid-containing phospholipid according to the invention and a solvent and / or excipient and / or carrier, ie an actual solution, dispersion, suspension or An emulsion of a nitrocarboxylic acid-containing phospholipid or a mixture of different phospholipids containing nitrocarboxylic acids and at least one further constituent selected from the solvents, oils, fatty acids, fatty acid esters, phospholipids, amino acids, vitamins, contrast agents, salts and / or membrane-forming substances mentioned herein ,
- solution should also clarify that it is a liquid mixture, which, however, may also be gelatinous, viscous or pasty (viscous or highly viscous).
- a perfusion and preservation solution comprising at least one nitrocarboxylic acid-containing phospholipid according to the invention for the preservation of cells in the absence of a blood supply, in particular in the preservation of complex cell systems such as organs or living tissue is provided.
- Organ transplantation is currently available for the kidney, liver, heart, lung, pancreas, intestine, cornea, and skin. Upon removal, the vascular system of a transplant organ is perfused with a preservative solution.
- This solution is designed to facilitate lowering of the temperature of the organ, to prevent swelling of cells, to eliminate oxygen free radicals, to control the pH, to reduce ischemic damage, to prolong the safe time while allowing the organs to be stored outside the body , and to facilitate the recovery of the organ during reperfusion.
- preservative solutions such as Eurocollins solution ® , the University of Wisconsin solution ® , Celsior solution ® and the low-potassium-dextran solution (Perfadex® solution) available.
- a perfusion or preservation solution of the invention is formed by aqueous pH buffer systems, preferably selected from a sodium phosphate buffer and a potassium phosphate buffer having a pH in the range of 6.8 to 7.4, e.g. Krebs-Henseleit buffer (KHB).
- aqueous pH buffer systems preferably selected from a sodium phosphate buffer and a potassium phosphate buffer having a pH in the range of 6.8 to 7.4, e.g. Krebs-Henseleit buffer (KHB).
- a perfusion or preservation solution of the invention may contain, in addition to the nitrocarboxylic acid-containing phospholipids of the invention: water for injection, sucrose, at least one component having pH buffering properties, at least one component having calcium transport blocking properties, calcium ions, blood coagulation inhibitor such as acetylsalicylic acid , Colloid osmotic drugs such as polyethylene glycol (PEG) or chelators such as amino acids.
- PEG polyethylene glycol
- Medical devices which are particularly preferred according to the invention are coated stents for use in blood vessels which are coated with nitrocarboxylic acid-containing phospholipids on one or two layers.
- This embodiment is particularly advantageous because it is easy to manufacture, its small dimensions increase the thickness of the stent only insignificantly and lead to biopassivation of the stent and at the same time to the passive anti-restenotic effect described above.
- a phospholipid coating is preferred as a monolayer (monolayer), where, as the name implies, the layer height is exactly one molecule.
- a monolayer according to the invention preferably corresponds to the complete coverage of the medical device with a layer of nitrocarboxylic acid-containing phospholipids. However, it is also possible that only parts of the medical device are covered with a monolayer.
- stents with a bilayer of nitrocarboxylic acid-containing phospholipids are also preferred.
- stents with a bilayer of nitrocarboxylic acid-containing phospholipids are also preferred.
- Another preferred embodiment is stents with a monolayer or bilayer of nitrocarboxylic acid-containing phospholipids having a superposed layer of at least one bioresorbable polymer.
- coated balloon catheters which have a pure layer of nitrocarboxylic acid-containing phospholipids.
- balloon catheters having a bilayer of nitrocarboxylic acid-containing phospholipids are also preferred.
- balloon catheters and stents that have a pure coating with nitrocarboxylic acid-containing phospholipids and a superposed layer of contrast agent.
- the stents, balloon catheters and other artificial implants may have alternating coatings of nitrocarboxylic acid-containing phospholipid layers and layers of contrast agent and / or comparable substances.
- Embodiments with 2-10 nitrocarboxylic acid-containing phospholipid layers, more preferably 2-6 layers and even more preferably 2-4 layers are preferred.
- implants are suitable for coating with nitrocarboxylic acid-containing phospholipids, since the documented effects lead to an improved healing compared to an uncoated implant material.
- implants for reconstructive and plastic surgery such as surgical nets, implants for tissue replacement or construction, implanted indwelling catheter and ports, and drainage are particularly suitable for a coating according to the invention.
- the phospholipid layers are naturally very thin.
- the thickness of a single phospholipid layer can be given as 2-4 nm. Accordingly, the thickness of a phospholipid bilayer is 4 - 8 nm, and even more layers add up to the corresponding values.
- the stents may have a hemocompatible layer of the hemocompatible substances mentioned below, which is preferably bound to the surface.
- At least one pharmacologically active substance preferably an antiproliferative or antirestenotic active ingredient, is applied to the coating of at least one nitrocarboxylic acid-containing phospholipid layer as a pure active substance layer or together with an adjuvant.
- the active substances are used individually or combined in the same or different concentrations. Particularly preferred are active substances which, in addition to their anti-restenotic action, have further supporting properties, ie antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic.
- the active ingredient (s) is / are preferably contained at a pharmaceutically active concentration of 0.001 -10 mg per cm 2 of stent surface.
- adjuvants may be applied to the nitrocarboxylic acid-containing phospholipid layer or layers together with the drug solution, either to provide visualization of the medical device as a contrast agent or to act as a so-called transport mediator and accelerate uptake of the drug into the cell.
- vasodilators include endogenous substances such as kinins, substances of plant origin such as gingko biloba, DMSO, xanthones, flavonoids, terpenoids, plant and animal dyes, contrast agents and contrast agent analogues, as well as cholesterols also to these tools or are themselves used synergistically as an active ingredient.
- 2-pyrrolidone tributyl and triethyl citrate such as their acteylated derivatives, dibutyl phthalate, benzyl benzoate, diethanolamine, diethyl phthalate, isopropyl myristate and palmitate, triacetin, etc.
- DMSO iodine-containing contrast agents
- PETN tributyl and triethyl citrate
- the nitrocarboxylic acid-containing phospholipid layer may be surrounded by a layer of polymers or polysaccharides with or without an active substance layer.
- the polymer layer can consist of biostable and / or biodegradable polymers.
- the biodegradable polymer layer is preferred.
- the active ingredient can be slowly released into the environment over a first period of time. Thereafter, the biopassivated stent would still have an anti-biopassive long-term effect.
- at least one active substance may be contained in the polymer layer itself.
- biodegradable or resorbable polymers it is possible to use, for example: polyvalerolactones, poly-s-decalactones, polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly-s-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrates,
- Polyhydroxyvalerates polyhydroxybutyrate-co-valerates, poly (1,4-dioxane-2,3-diones), poly (1,3-dioxan-2-ones), poly-para-dioxanones, polyanhydrides such as
- Polymaleic anhydrides polyhydroxymethacrylates, poly (lactate-co-glycolic acid), fibrin, polycyanoacrylates, polycaprolactone dimethyl acrylates, poly-b-maleic acid, polycaprolactone butyl acrylates, multiblock polymers, e.g. from oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers such as e.g.
- Polyhydroxypentanoic acid polyethylene oxide-propylene oxide, soft polyurethanes, polyurethanes with amino acid residues in the backbone, polyether esters such as Polyethylene oxide, polyalkene oxalates, polyorthoesters and their copolymers, carrageenans, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, polyhydroxyalkanoates, pectinic acid, actinic acid, fibrin, casein, carboxymethylsulfate, albumin, hyaluronic acid, heparan sulfate, heparin, chondroitin sulfate , Dextran, ⁇ -cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen, collagen N-hydroxysuccinimide, lipids and lipids, polymerizable oils with low degree of crosslinking, modifications
- the coatings according to the invention for medical products and compositions for medical or cosmetic procedures are particularly suitable for the prevention, reduction or treatment of vascular or restenoses, and in vascular injuries, vascular interventions, bypass supplies, in coronary heart disease or arterial disease, valvular heart disease, varicosis, vasculitis, lymphangitis, Erysipelas, extracorporeal circulation, for keeping open artificial or natural exits (eg stomata).
- the medical devices according to the invention are suitable for the treatment and prophylaxis of restenosis.
- the medical devices according to the invention for treatment with artificial blood conductors or pumps is understood to mean endoprostheses, for example of PTFE, PET, polyester, etc. for use in or instead of a natural blood vessel or pump systems for intracorporeal or extracorporeal circulation and their connections, eg of PU, PTFE , Polyesther, uam.
- This also includes the application to Pachmaterialien which may consist of polyester or allogenic or xenogeneic tissue.
- the medical devices are coated with a viscoelastic layer consisting of the phospholipids according to the invention. It has been found that the lubricity of such coated medical devices in the vascular system is improved.
- nitrocarboxylic acid-containing phospholipids disclosed herein are used to coat medical devices, particularly to improve the lubricity of medical devices.
- lubricity of tissue-contacting medical devices is improved, and more particularly, of catheters, angioplasty catheters, dilatation catheters, catheter balloons, guidewires, guiding catheters, stents and other medical devices for use in blood vessels.
- tissue replacement materials such as artificial tendons, and bone replacement materials.
- a coating to improve lubricity may be advantageous in device implants, but also soft tissue implants such as breast implants.
- lubricity enhancement refers to lubricity of the coated medical device when inserted and advanced into a preformed or non-preformed body cavity that is superior to the lubricity of the uncoated medical device when inserted into tissue layers or cavities.
- the monolayers, bilayer systems or multilayer systems on a stent, a balloon catheter or other implants are preferably applied by spraying, spin-coating, dipping, pipetting, chemical vapor deposition (CVD) and atomic layer deposition (ALD), but more preferably by dipping and vapor deposition.
- CVD chemical vapor deposition
- ALD atomic layer deposition
- the preferably uncoated or covered with a hemocompatible layer surface of the stent or the preferably uncoated surface of the balloon catheter is coated with a nitrocarboxylic acid (s) -containing phospholipid coating solution.
- Phospholipids can form self-assembled monolayers (SAM) by dip coating on suitable surfaces.
- SAM forms spontaneously when immersing surfactants or organic substances in a solution or suspension.
- the film formation can be assisted by a previous coating of the surface with a covalently bonded alkane layer, e.g. in the form of alkanethiols, whereby the physisorbed carbon chains of the phospholipids receive high physical adherence.
- Hydrophobic molecules, such as cholesterol, incorporated into the phospholipid membranes have been described as being suitable for the formation of focal adhesion points necessary for cell adhesion and cell migration on a surface. Cholesterol and related substances can be readily integrated into an artificial phospholipid layer in a known manner.
- cell adhesion proteins such as cell adhesion proteins.
- B. RDG tripeptides RDG tripeptides.
- Physisorption is the general form of adsorption in which an adsorbed molecule is bound by physical forces on a substrate.
- the implant is dipped in a tank or container containing the coating solution. The procedure is repeated until a complete and even distribution of coating on the implant surface is achieved.
- the implant may optionally be immersed in the tank while permanently changing its position, e.g. through a rotation.
- the dipping process is also suitable for polymers. If a polymer layer is applied, the coated implant can be dried by rotary drying after the dipping process.
- Another preferred coating method is vapor deposition. This method is particularly advantageous for the production of very thin layers, in which the layer thickness and uniformity of the coating must be well controlled, such as the individual phospholipid or drug layers.
- a fine nozzle or cannula is attached to the medical device and the coating solution is sprayed onto the medical device.
- This method allows accurate and precise coating of the surface of the medical device.
- This method is equally suitable for the nitrocarboxylic acid-containing phospholipids, the active compounds and the polymers of the invention.
- Particularly preferred is the method for coating the medical device with drug solutions and polymers.
- This method should be carried out with any coating solution which is still so viscous that it is drawn over the medical device within 5 minutes, preferably 2 minutes due to adhesive forces or additionally by utilizing gravity, and covers the medical device largely completely.
- the medical device is immersed in a liquid vertically and slowly pulled out again.
- the so-called Langmuir-Blodgett layer transfers as a monolayer of organic molecules from the surface of the liquid to the medical device.
- the organic molecules used form a film.
- the number of dipping operations can control the number of monolayers and thus the thickness of the coating.
- the hydrophobic end of the organic molecule aligns with the hydrophobic surface of the medical device while the hydrophilic end of the organic molecule orients toward the water. This can be reversed by repeated immersion and withdrawal, since there is once a hydrophobic and once a hydrophilic end on the surface of the medical device. Therefore, in this coating method, organic molecules having both a hydrophilic and a hydrophobic end are preferred. This technique is particularly suitable for coating with phospholipids and long-chain fatty acids.
- nonpolar long-chain molecules such as the said phospholipids
- a detergent solution Suitable detergents for this purpose are, for example, cholate, deoxycholate, octyl-glucoside, heptyl-glucoside and Triton X-100. This solution is then dialyzed to remove the detergent.
- the phospholipids can form in this way liposomes on the surface of the medical device to be coated.
- the medical device is attached by vacuum suction on the bottom of a turntable.
- a metering device above the center of the medical device the desired amount of the solution is applied.
- a uniform coating with a film is achieved.
- Excess coating solution, however, is thrown away by the centrifugal forces acting.
- FIG. 1 shows investigations on the effects of nitrocarboxylic acids
- the first line shows the
- the tested substances are: PC: phosphatidylcholine, SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-PC), DOPC (1, 2-dioleoyl-sn-glycero-3-PC),
- POPC 1-palmitoyl-2-oleoyl-sn-glycero-3-PC
- ONOPC 1-oloyl-2- (E-9-nitrooleoyl) -sn-glycero-3-PC
- PNLPC 1-palmitoyl- 2- (E-9-nitrolinoleoyl-sn-glycero-3-PC) and the free fatty acids OA (oleic acid), LA (linoleic acid), NOOA (E-9-nitrooleic acid) and NOLA (E-9-nitrolinolic acid).
- FIG. 2 shows investigations on the effects of nitrocarboxylic acids
- the tested substances are: SOPC, DOPC, POPC, ONOPC, PNLPC and the free fatty acids OA, LA, NOOA and NOLA.
- the first two lines show the effect of the tested substances on the proliferation of the cells after incubation with concentrations of ⁇ ⁇ and ⁇ ⁇ after 24h, 48h or 72h. Shown are the relative numbers (%) of cells compared to the untreated control. The following two lines show the cell detachment after each 24h and 72h preincubation with the substances 10 and
- Figure 3 shows studies on the stability of nitrocarboxylic acid containing
- Balloon catheter applied by the Langmuir-Schäfer method The table shows the relative (%) change in substance volume after 24 h, after heat treatment and after the slide examination as well as the relative change of the tensile work compared to an uncoated balloon catheter.
- FIG. 4 a shows investigations on long-term erythrocyte stability
- FIG. 4b shows studies on mast cell activation with mastoparan.
- cells were first preincubated with the natural phospholipids SOPC and PLPC and the analog phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC for one hour and then with
- the Ca 2+ influx was determined by normalizing the calcium influx to the respective baseline measurement and expressing it as a percentage increase.
- histamine release from the C2 cells was determined by histamine ELISA and expressed in ng / ml.
- FIG. 4 c shows investigations for the examination of the influence on the mechanical
- Phospholipids SOPC and PLPC as well as the analog phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC.
- erythrocyte samples were treated in an ultrasonic bath at a temperature of 30 ° and 50 ° C for two and five minutes at 10 watts. Subsequently, the samples were centrifuged and the supernatant analyzed. Shown are the hemolysis rates in percent.
- Figure 4d shows examinations for testing the influence on the osmotic
- Phospholipids SOPC and PLPC as well as the analog phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC.
- Purified, resuspended erythrocytes were placed in distilled water and NaCI solutions increasing in concentration from 0.1 to 1.0 g / dl.
- the photometrically determined hemoglobin concentration of a completely lysed reference sample was related to the hemoglobin concentration determined in each case.
- the Y-axis indicates the relative hemolysis fraction.
- Figure 5 shows studies on cell vitality after pretreatment with NaCl solution or the natural phospholipids SOPC and PLPC and the analogous phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC with a concentration of 10 and 50 ⁇ / ⁇ or nitrofatty acids nitrooleate (NOA) and nitrolinolate (NLA) in a concentration of 10 or 30 ⁇ . Subsequently, the cells were washed with
- Cisplatin 25 and 50 ⁇ / ⁇
- cyclosporin 50 and 100 ⁇ / ⁇
- lipopolysaccharide LPS
- the table shows the number of dead cells after treatment with a concentration of 10 / 50 ⁇ for the related PL, as well as 10 / 30 ⁇ for the related fatty acids in relation to the absolute
- Figure 6 shows studies on the vitality of porcine uterine arteries, with the natural phospholipids POPC and SLPC and the analogous Phospholipids with nitration of the unsaturated fatty acids (1-palmitoyl-2- (E-9-nitrooleoyl) -sn-glycero-3-PC and 1-stearoyl-2- (E-9-nitrolinoleoyl) -sn-3-glycero-phosphatidylcholine were pretreated and then incubated for one hour at 15 bar in a pressure chamber. The evaluation was carried out via a TUNEL staining (TUNEL positive cells in%) and the determination of the microparticles in cell culture supernatant (microparticles / ⁇ ).
- TUNEL staining TUNEL positive cells in
- FIG. 6a The values determined were statistically significant
- FIG. 7 shows investigations on the membrane-stabilizing effects of
- the vessel segments were incubated in NaCl solution, a NaCl solution with natural phospholipids SOPC and PLPC and the analogous phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC in a concentration of 200 mmol / l for one hour.
- the isometric force development under noradrenaline (arteries) as well as histamine stimulation (veins) (tensile strength in grams) as well as the vascular dilatation under acetylcholine was investigated.
- a native vessel segment which was not frozen, was similarly examined and the value determined for the treated vessel segments was reproduced as a percentage compared to the native control.
- FIG. 7a The values determined were statistically significant
- Figure 8 shows studies on effects of nitrocarboxylic acid (s) -containing
- the oocytes were previously treated with phospholipids SOPC and PLPC as well as the analog phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC in a concentration of 50 mmol / l, furthermore with the natural fatty acids oleic acid and linoleic acid as well as nitrooleic acid and nitrolinolic acid in each case in a concentration of 30 ⁇ incubated for 10 and for 60 minutes.
- Non-pretreated oocytes served as control, the measurement results of which were assumed to be the reference value. After pretreatment there was an increase and decrease in the inducible inone stream, which is expressed as a percentage of the reference.
- FIG. 8a The values determined were statistically significant
- Soft tissue implant material with phospholipids containing nitrocarboxylic acids on the tissue reaction in vivo Soft tissue implant material with phospholipids containing nitrocarboxylic acids on the tissue reaction in vivo.
- sterile silicone pads were used as the implant material, which by spray coating in two layers with the natural phospholipids SOPC and PLPC as well as the analogous phospholipids with nitration of the unsaturated fatty acids SNOPC and PNLPC were coated or left untreated.
- the silicone pads were inserted into Wistar rats and the cellular response and fibrous tissue formation after implantation evaluated according to the following key.
- A) Cellular reaction A1: none; A2: isolated monocytic cells or lymphocytes; A3: moderate number or groups of monocytic cells or lymphocytes; A4: Dense infiltrate of monocytes, eosinophils or giant cells.
- FIG. 10a shows investigations on the effects of phospholipids containing nitrocarboxylic acids on the dimerization properties of a
- FIG. 10b shows the effect of phospholipids containing nitrocarboxylic acids on the anisotropy in vesicles as a function of the temperature.
- the anisotropy is plotted on the y-axis and the temperature on the x-axis.
- PNOPE 1 Palmitoyl-2- (E-9-nitrooleoyl) -sn-3-glycero-phosphatidylethanolamine
- NPL nitrocarboxylic acid
- acid chloride 4 may be a nitrosol acid chloride or a non-nitrided acid chloride.
- fatty acid 2 a nitrofatty acid or a non-nitrated fatty acid may also be used.
- nitrocarboxylic acid-containing phospholipids wherein R 1 COO- is a non-nitrated carboxylic acid residue and R 2 COO- is a nitrocarboxylic acid residue requires two consecutive regioselective esterifications. Due to the base-sensitive nitrocarboxylic acids, the selective esterification of the sn-1 position must first be carried out with a suitable fatty acid constituent (eg palmitoyl chloride). For this purpose, a method published by Servi was modified.
- a suitable fatty acid constituent eg palmitoyl chloride
- the sn-glycero-3-phosphatidylcholine 1a is converted with dibutyltin oxide into the cyclic dibutyltin diester which is then converted in situ with the acid chloride of the carboxylic acid 4a and triethylamine into the monoester 5a (analogous to Servi, Org , 2974 and Servi, Chem. Phys. Lipids 2007, 147, 1 13).
- This can be worked up and cleaned with standard methods.
- the 1-acyl-2-lyso-sn-3-glycero-phospholipids 5a are subsequently converted into the lipid 6a according to the advanced method of Salomon (Salomon, Biorg. & Med. Chem. 2011, 19, 580) with a nitrocarboxylic acid esterified.
- the sn-1 position can be selectively liberated here to the 1 -lyso compound 10 '(analogous to J. Sakakibara, Tetrahedron Lett. 1993, 34, 2487), a final esterification according to R. Salomon (Biorg. & Med. Chem. 2011, 19, 580) then provides the unsymmetrically substituted 1-nitroacyl-2- (acyl) -sn-3-glycero-phosphatide 10, which, after careful cleaning, used for the coatings becomes.
- Example B Synthesis of 1,2-di- (9-nitrooleoyl) -sn-3-glycero-phosphocholine 3a sn-glycero-3-phosphatidylcholine 1a is commercially available or prepared in a known manner from egg or soy lecithin. 1a could be esterified with nitrooleic acid according to the method developed by RG Salomon (Salomon, Biorg. & Med. Chem. 2011, 19, 580).
- the solvent is removed in vacuo and the oily residue dissolved in 10 ml of EtOH.
- the lyso compound 5a is precipitated by adding 40 ml of acetone at -10 ° C.
- the compound can be purified by HPLC. (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, 95% MeOH / H 2 O). Yield: 0.9 g (1 .8 mmol, 45%) of 5a as a white solid. (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- R 1 COO and R 2 COO- represent a nitrated or non-nitrated and preferably a non-nitrated Carbonklarrest. Since the nitrated carboxylic acid residues R 1 COO- and / or R 2 COO are base-sensitive and can be destroyed by the reaction in pyridine, it is advisable to use for R 1 COO as well as R 2 COO non-nitrated carboxylic acid residues. The non-nitrated carboxylic acid residues R 1 COO- and R 2 COO- can then be re-saponified by NaOMe in methanol and washed with nitrated carboxylic acid residues as described herein reesterify.
- R 3 * herein means one of the protected head groups listed at 8b, 8c, 8d and 8e.
- R 1 COO- and R 2 COO- are palmitoyl radicals.
- Tris-Cl triisopropylbenzenesulfonyl chloride
- N- (BOC) -ethanolamine 137 mg, 0.85 mmol
- Di- (palmitoyl-sn-3-glycerophosphate 7 500 mg, 0.85 mmol) in pyridine added via syringe pump The mixture is stirred for 5 hours at 35 ° C.
- reaction is then terminated by hydrolysis with water, after phase separation
- aqueous phase is extracted with dichloromethane and the organic phases are dried over Na 2 SO 4 and, after the solvent has been removed by evaporation (removal with toluene to remove the pyridine), the residue is purified by preparative column chromatography on silica gel (EtOAc / hexane). Yield 559.2 mg (0.765 mmol, 90%) 9c. (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example E Preparation of 1,2-di- (palmitoyl-sn-3-glycerophosphatidyl- (N-BOC) - (S) -serine-tert-butyl ester 9d:
- Example F Preparation of 1, 2-di-palmitoyl-sn-3-glycerophosphatidyl-penta-O-methoxymethylinositol 9e:
- Example G Preparation of sn-3-glycero-di-tert-butyl phosphate 1 b analogously to J. Brimacombe (J. Chem. Soc. Perkin Trans. I, 1995, 1673) or H. Brockerhoff, M. Yurkowski ⁇ Can. J. Biochem., 1965, 43, 1777).
- the starting material di- (palmitoyl-sn-3-glycero-di-tert-butyl phosphate 9b is prepared according to P. Konradsson, (J. Org. Chem., 2002, 67, 194)
- a solution of di- (palmitoyl-sn-3 Glycerol di-tert-butyl phosphate 9b (600 mg, 0.871 mmol) is dissolved in diethyl ether / methanol (50 ml, 1: 1) and treated with a catalytic amount of sodium methoxide
- Amberlite 1 becomes R120
- the solvents are removed in vacuo and the residue is recrystallized or purified by preparative column chromatography (silica gel, chloroform / MeOH gradient) or preparative HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, 9Gradient MeOH / H 2 O).
- nitrocarboxylic acids can be carried out according to two strategies.
- the direct nitration can be carried out starting from the commercially available carboxylic acid.
- regioisomeric products which must be finally separated, unless they are used as a mixture.
- the polyunsaturated starting materials require carefully elaborated techniques.
- a second strategy starts with selected nitroalkanes and aldehydes, which are then converted into nitroalkene in the sense of a Henry reaction followed by condensation.
- Unsaturated and polyunsaturated carboxylic acids can be radically nitrated analogously to Ishibashi (Org. Lett. 2010, 12, 124).
- the example of linoleic acid [(Z, Z) -9,12-octadecadienoic acid] describes the radical nitration, which leads to regioisomer mixtures. It is usually advisable to replace the gaseous toxic N 2 O 4 with the combination of FeCl3 Fe (NOs) 3.
- Linoleic acid 1 (840 mg, 3 mmol) and FeCb (730 mg, 4.5 mmol) are dissolved in THF (30 mL). Then Fe (NOs) 3-nonahydrate (1.46 mg, 3.6 mmol) is added and the reaction is refluxed for 2 hours. After cooling to room temperature, a mixture of ⁇ -chloro-nitroalkanes 2 and nitroalkenes 3/4 is present. To complete the HCl elimination then dilute with THF (20 mL) N, N-dimethylaminopyridine (550 mg, 4.5 mmol) is added. After stirring overnight at room temperature, the suspension is diluted with diethyl ether and the solid (iron and ammonium salts) is filtered off.
- the solvents are distilled off in vacuo and the residue is pre-purified by preparative column chromatography on silica gel (hexane / ethyl acetate gradient) and pre-separated.
- the fine purification is carried out by preparative HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O).
- Arachidonic acid 9 (100 mg, 0.33 mmol) is treated with a solution of NO 2 in hexane (0.7 mM, density 3.4 g / cm 3 ) and stirred at room temperature for 15 min. Excess NO2 is then purged in the nitrogen stream and the residue is taken up in water and EtOAc (1: 1, 10 mL). The organic phase is extracted several times with water, then the solvent is distilled off. The residue is analyzed by HPLC and separated (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O). There are formed various regioisomer Mononitnanss employment with low yield and other unspecified compounds.
- 6-nitroarachidonic acid 10 (6 mg, 0.017 mmol, 5.2%), 14-nitroarachidonic acid 11 (8 mg, 0.023 mmol, 6.9%), 5-nitroarachidonic acid 12 (3 mg, 0.009 mmol, 2.6%).
- Purity control via HPLC, 1 H and 13 C NMR spectroscopy (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example H2 According to the procedure of Example H2, (Z, Z, Z, Z, Z, Z, Z) -4,7,10,13,16,19-docosahexaenoic acid (DHA) (100 mg, 0.30 mmol) is nitrated. Analysis and separation via HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O). There are formed various regioisomer Mononitn proceedingss occur with low yield and other unspecified compounds. A mixture of 4-nitro-DHA, 5-nitro-DHA, 19-nitro-DHA and 20-nitro-DHA was isolated in a yield of about 7.1%.
- cis-9-hexadecenoic acid (palmitoleic acid) (200 mg, 0.79 mmol) is nitrated. Analysis and separation via HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O). A mixture of 9-nitropalmitoleic acid (68 mg, 0.23 mmol, 29%) and 10-nitropalmitoleic acid (52 mg, 0.17 mmol, 22%) was obtained.
- the electrophilic nitration of linoleic acid 1 is carried out according to M. d'lschia (J. Org. Chem. 2008, 73, 7517).
- the precipitate (AgBr) is removed by filtration through a short celite column (thorough rinsing with diethyl ether). After removal of the solvents in vacuo, the residue was taken up in dichloromethane and washed several times with saturated NaCl solution and dried over Na 2 SO 4 . After renewed removal of the solvent, the residue is purified by preparative HPLC chromatography separated (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeCN / H 2 O). The main fractions are the two regioisomers 9/10-nitro-10/9-phenylselenyl-fatty acid derivatives 17 obtained as diastereomer mixtures. The fractions can be used together or separately in the following eliminations.
- the fractions 17a and / or 17b are dissolved in dichloromethane (10 ml) and treated with vigorous stirring with an excess of aqueous H2O2 (about 8% in H 2 0, at least 4 eq.). After 1 hour at 0 ° C and one hour at room temperature, diluted with ether, the phases are separated and the organic phase is thoroughly washed with saturated NaCl solution and dried over Na 2 SO. 4 After removal of the solvation, the residue is separated by preparative HPLC chromatography (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, MeCN / H 2 O).
- Example 12 Electrophilic nitration of gadoleic acid
- the nitration is carried out as described in Example 11.
- aqueous tetrabutylammonium hydroxide solution and dichloromethane adds the Nitroalkene smooth H 2 O.
- the 9-hydroxy-10-nitro-12-octadecenoic acid 19 is obtained from 10-nitrolinolic acid 4 and the 10-hydroxy-9-nitro-12-octadecenoic acid 18 from the 9-nitrolinolic acid 3rd work-up described in Example 11. Purification via preparative HPLC as in Example 11. The respective separation of the diastereomers is possible, but expensive.
- 9-hydroxy-10-nitro-12-octadecenoic acid 19 we obtained in a yield of 10% and 10-hydroxy-9-nitro-12-octadecenoic acid 18 in a yield of 30%.
- Example J2 Addition of water to nitrated gadoleic acid
- Example J1 -9-eicosenoic acid (gadoleic acid) (150 mg, 0.48 mmol) is reacted with aqueous solution of tetrabutylammonium hydroxide and dichloromethane. It takes place addition of water and there is a product mixture of 10-hydroxy-9-nitroeicosanklare and 9-hydroxy-10-nitroeicosanklare in a ratio of about 5: 2 and a yield of about 30% (54 mg mixture, 0.86 mmol mixture). Analysis and separation via HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O). The diastereomers can be separated, which is complicated and for the purposes of the present invention is not required.
- Example J3 Addition of water to nitrated EPA
- Example J1 According to the procedure of Example J1 nitrated according to Example 13 ( ⁇ , ⁇ , ⁇ , ⁇ , ⁇ ) - 5,8,11,14,17-eicosapentaenoic acid (EPA) (100 mg, 0.33 mmol) with aqueous Implemented tetrabutylammonium hydroxide solution and dichloromethane. It takes place addition of water and there is a product mixture of 6-hydroxy-5-nitro-EPA (14 mg) and 5-hydroxy-6-nitro-EPA (5 mg) in a ratio of about 5: 2 and a yield of about 16% (0.05 mmol). Analysis and separation via HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O). The diastereomers can be separated, which is very expensive and is not required for the purposes of the present invention.
- EPA 5,8,11,14,17-eicosapentaenoic acid
- Example J4 Addition of water to nitrated a-linolenic acid
- Example J1 According to the procedure of Example J1 nitrated according to Example 14 ( ⁇ , ⁇ , ⁇ ) - 9,12,15-Octadecatrien Acid (a-linolenic acid) (150 mg, 0.54 mmol) with aqueous tetrabutylammonium hydroxide solution and dichloromethane. It takes place addition of water and there is a product mixture of 10-hydroxy-9-nitro- ⁇ -linolenic acid and 9-hydroxy-10-nitro- ⁇ -linolenic acid in a ratio of about 2: 1 and a yield of approx 26% (48 mg mixture, 0.14 mmol mixture). Analysis and separation via HPLC (Phenomenex Gemini NX 5 ⁇ C18 1 10 A, gradient MeOH / H 2 O). The diastereomers can be separated, which is complicated and for the purposes of the present invention is not required.
- Example K1 Electrophilic double-nitration of linoleic acid 1
- Example K2 Electrophilic double nitration of gadoleic acid
- Example K3 Electrophilic double nitration of EPA
- Example 13 By repeating the nitration described in Example 13 with the nitration products obtained according to Example 13, a second nitration was carried out. A mixture of 5-nitro-EPA and 6-nitro-EPA (24 mg, 0.07 mmol) was used. A regioisomeric mixture of 5,17-dinitro-EPA, 5,18-dinitro-EPA, 6,17-dinitro-EPA and 6,18-dinitro-EPA was obtained in 10% yield (3 mg, 0.007 mmol).
- Example K4 Electrophilic double-nitration of ⁇ -linolenic acid
- Example 14 By repeating the nitration described in Example 14 with the nitration products obtained according to Example 14, a second nitration was carried out. A mixture of 9-nitro- ⁇ -linolenic acid and 10-nitro- ⁇ -linolenic acid (50 mg, 0.15 mmol) was used. A regioisomer mixture of 9,15-dinitro- ⁇ -linolenic acid, 9,16-dinitro- ⁇ -linolenic acid, 10,15-dinitro- ⁇ -linolenic acid and 10,16-dinitro- ⁇ -linolenic acid was obtained in a yield of 9% (cf. 5 mg, 0.014 mmol).
- Example L1 Henry's reaction of nitroalkanes and aldehydes
- the stereoisomeric E-9-nitroolic acid 25a can be separated off at the methyl ester 24a stage as a minor product (389 mg, 10% yield). Purity control via 1 H and 13 C NMR spectroscopy). A Z / E isomerization of Z-9-nitroolic acid 24a was achieved by Branchaud (1 PhSeSePh, NaBH, then HOAc, 2H2O2) using 1 mmol (207 mg) of acid 24a in 71% yield as Z / E. Mixture of 1: 3, the separation of nitroolefins 24a and 25a by HPLC as above, purity control via 1 H and 13 C NMR spectroscopy).
- Example L1 Reaction according to Example L1 with 9-oxo-nonanoic acid methyl ester 26 (1, 0 g, 5.38 mmol) and 1 -nitroheptane 27b (0.78 g, 5.38 mmol) over the sequence described in Example L1 gives the 10-nitropalmitoleic acid 30b with 38.5% (620 mg, 2.07 mmol) yield over all steps.
- HPLC purification Phenomenex Gemini NX 5 ⁇ C18 1 10 A, MeCN / H 2 O). (Purity control via 1 H and 13 C NMR spectroscopy).
- HPLC purification Phenomenex Gemini NX 5 ⁇ C18 1 10 A, MeCN / H 2 O). (Purity control via 1 H and 13 C NMR spectroscopy).
- Example N1 Synthesis of the mixture of 1,2-di- (9-nitrolinoleoyl) -sn-3-glycero-phosphocholine, 1,2-di- (10-nitrolinoleoyl) -sn-3-glycero-phosphocholine, 1 - ( 9-nitrolinoleoyl) -2- (10-nitrolinoleoyl) -sn-3-glycero-phosphocholine and 1- (10-nitrolinoleoyl) -2- (9-nitrolinoleoyl) -sn-3-glycero-phosphocholine
- Example B sn-glycero-3-phosphatidylcholine 1a (103 mg, 0.4 mmol) was treated with a mixture of 9- Nitrolinolic acid 3 and 10-nitrolinolic acid 4 (mixture in the ratio 1: 1, 0.4 g, 1, 2 mmol) esterified.
- Example N2 nitrolinolic acid ester of sn-glycero-3-phosphatidylcholine 1a
- Example B sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 9-nitrolinolic acid 3, 10-nitrolinolic acid 4, 12-nitolinolic acid and 9- Nitro-10,1 1-octadienoic acid (mixture in the ratio 7: 12: 5: 2, 0.5 g, 1, 5 mmol) esterified. There was obtained a product mixture of differently esterified 1, 2-di (nitrolinoleoyl) -sn-glycero-3-phosphatidylcholinen in a yield of 61% (212 mg, 0.24 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N3 Nitroarachidonic acid ester of sn-glycero-3-phosphatidylcholine 1a
- sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 6- nitroarachidonic acid 10, 14-nitroarachidonic acid 11 and 5-nitroarachidonic acid 12 (mixture in the ratio 8: 6: 3, 0.45 g, 1, 5 mmol) esterified.
- a product mixture of differently esterified 1,2-di (nitroarachidonoyl) -sn-glycero-3-phosphatidylcholines was obtained in a yield of 53% (244 mg, 0.27 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N4 nitroarachidonic acid ester of sn-glycero-3-phosphatidylcholine 1a
- sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 6- nitroarachidonic acid 14, 14-nitroarachidonic acid 15 and 5-nitroarachidonic acid 16 (mixture in the ratio 4: 5: 3, 0.45 g, 1, 5 mmol) esterified.
- a product mixture of differently esterified 1,2-di (nitroarachidonoyl) -sn-glycero-3-phosphatidylcholines was obtained in a yield of 55% (253 mg, 0.28 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N5 Nitro-y-linolenic acid ester of sn-glycero-3-phosphatidylcholine 1a
- Example B sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 6-nitro-1-linolenic acid 14, 12-nitro-Y-linolenic acid obtained according to Example H4 15 and 5-nitro-Y-linolenic acid 16 (mixture in Ratio 4: 4: 1, 485 mg, 1, 5 mmol) esterified. There was obtained a product mixture of differently esterified 1, 2-di (nitro-Y-linolenoyl) -sn-glycero-3-phosphatidylcholinen in a yield of 59% (257 mg, 0.30 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N6 Nitro-DHA-ester of sn-glycero-3-phosphatidylcholine 1a
- Example B sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 4-nitro-DHA, 5-nitro-DHA, 19-nitrobenzene obtained according to Example H5. DHA and 20-nitro-DHA (0.56 g, 1.5 mmol) esterified. There was obtained a product mixture of differently esterified 1, 2-di (nitro-DHA) -sn-glycero-3-phosphatidylcholinen in a yield of 31% (150 mg, 0.16 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N7 Nitropalmitoleic acid ester of sn-glycero-3-phosphatidylcholine Following the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 9-nitropalmitoleic acid obtained according to Example H6 10-Nitropalmitoleic acid (mixture in the ratio 4: 3, 0.45 g, 1, 5 mmol) esterified.
- sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was mixed with a mixture of 10-nitolinolic acid 4 and 9-nitrolinolic acid 3 (mixture in the ratio 1: 3 , 0.49 g, 1, 5 mmol) esterified.
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 9-nitrogadoleic acid and 10-nitrogadoleic acid obtained according to Example 12 (mixture in the ratio 2: 1, 0 , 53 g, 1, 5 mmol) esterified.
- Example N10 Nitro-EPA ester of sn-glycero-3-phosphatidylcholine 1a
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 5-nitro-EPA and 6-nitro-EPA obtained according to Example 13 (mixture in the ratio 5 : 2, 0.46 g, 1.5 mmol) esterified.
- Example N11 Nitro- ⁇ -linolenic acid ester of sn-glycero-3-phosphatidylcholine
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 9-nitro-a-linolenic acid and 10-nitro- ⁇ -linolenic acid (obtained according to Example 14). Mixture in the ratio 1: 2, 485 mg, 1, 5 mmol) esterified.
- Example N12 Dinitrolinolic acid ester of sn-glycero-3-phosphatidylcholine 1a
- sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 9,12-dinitrolinolic acid, 9,13-dinitrolinic acid, 10,12- Dinitrolinolic acid and 10,13-dinitrolinolic acid (0.56 g, 1, 5 mmol) esterified.
- Example N13 Dinitro EPA ester of sn-glycero-3-phosphatidylcholine 1a
- Example B sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was reacted with a mixture of 5,17-dinitro-EPA, 5,18-dinitro-EPA obtained according to Example K2, Esterified 6,17-dinitro-EPA and 6,18-dinitro-EPA (0,59 g, 1, 5 mmol). There was obtained a product mixture of differently esterified 1, 2-di (dinitroeicosapentaenoyl) -sn-glycero-3-phosphatidylcholinen in a yield of 33% (165 mg, 0.17 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N14 Dinitro- ⁇ -linolenic acid ester of sn-glycero-3-phosphatidylcholine
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was treated with a mixture of 9,15-dinitro- ⁇ -linolenic acid, 9,16-dinitro-acid obtained according to Example K4. ⁇ -linolenic acid, 10,15-dinitro- ⁇ -linolenic acid and 10,16-dinitro- ⁇ -linolenic acid (0.55 g, 1, 5 mmol) esterified.
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was esterified with the E-9-nitroolic acid 25a (0.49 g, 1.5 mmol) obtained according to Example L1 , 1,2-Di - ((E) -9-nitrooleoyl) -sn-3-glycerophosphocholine was obtained in 75% yield (328 mg, 0.38 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N16 Synthesis of 1,2-di- (9-nitrooleoyl) -sn-3-glycero-phosphocholine Following the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) esterified with the obtained according to Example L1 Z-9-nitroic acid 24a (0.49 g, 1, 5 mmol). 1,2-Di - ((Z) -9-nitrooleoyl) -sn-3-glycero-phosphocholine was obtained in a yield of 74% (323 mg, 0.37 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N17 Synthesis of 1,2-di- (10-nitrooleoyl) -sn-3-glycerophosphocholine
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was esterified with the 10-nitro-oleic acid 30a (0.49 g, 1.5 mmol) obtained according to Example L2. There was obtained 1, 2-di- (10-nitrooleoyl) -sn-3-glycero-phosphocholine in a yield of 70% (306 mg, 0.35 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example N19 Synthesis of 1,2-di- (Z-10-nitropalmitoleoyl) -sn-3-glycerophospho-choline
- Example B According to the procedure of Example B, sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was esterified with the Z-10-nitropalmitoleic acid 30b (0.45 g, 1.5 mmol) obtained according to Example L4 , There was obtained 1, 2-di (Z-9-nitropalmitoleoyl) -sn-3-glycero-phosphocholine in a yield of 70% (287 mg, 0.35 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example B sn-glycero-3-phosphatidylcholine 1a (0.13 g, 0.5 mmol) was reacted with the Z-15-nitro- ⁇ -linolenic acid obtained according to Example M1 (0.49 g, 1, 5 mmol) esterified. There was obtained 1, 2-di (Z-15-nitro-a-linolenoyl) -sn-3-glycero-phosphocholine in a yield of 65% (282 mg, 0.33 mmol). (Purity control via HPLC, 1 H and 13 C NMR spectroscopy).
- Example 01 Preparation of 1,2-di- (9-nitro-10-hydroxy-stearoyl) -sn-3-glycerophosphocholine ( ⁇ , Y-di (9-nitro-10-hydroxystearoyl) -La-phosphatidylcholine ) 3a1
- the esterification according to R. Salomon (Biorg. & Med. Chem. 2011, 19, 580) can be directly adopted for the incorporation of further functionalized nitroolic acids.
- Example 02 Preparation of 1-palmitoyl-2- (9-nitro-10-hydroxystearoyl) -sn-3-glycero-phosphocholine ( ⁇ - (9-nitro-10-hydroxystearoyl) -Y-palmitoyl-l-phosphatidylcholine ) 6a1
- Example 01 The reaction was carried out according to the procedure of Example 01, but employing racemic but regioisomerically pure 9-nitro-10-hydroxystearic acid the regioisomeric mixture of 9-hydroxy-10-nitrostearic acid and 9-nitro-10-hydroxystearic acid was used.
- Example 04 Example 04:
- Example O2 The reaction was carried out according to the procedure of Example O2, employing racemic but regioisomerically pure 9-nitro-10-hydroxystearic acid the regioisomeric mixture of 9-hydroxy-10-nitrostearic acid and 9-nitro-10-hydroxystearic acid was used.
- Example J3 a mixture of 6-hydroxy-5-nitro-8,1 1, 14,17-eicosatetraenic acid and 5-hydroxy-6-nitro-8,1,1,14,17-eicosatetraenoic acid in a ratio of 5: 2 was prepared , Thereafter, according to Example 03 was the
- Example J4 a mixture of 10-hydroxy-9-nitro- ⁇ -linolenic acid and 9-hydroxy-10-nitro- ⁇ -linolenic acid was prepared in a ratio of about 2: 1. Thereafter, according to Example O4, the regioisomer mixture of 10-hydroxy-9-nitro- ⁇ -linolenic acid and 9-hydroxy-10-nitro- ⁇ -linolenic acid in a ratio of about 2: 1 with 1-palmitoyl-2-lyso-sn 3-glycero-phosphocholine 5a (0.1 g, 0.202 mmol).
- Example P1 Synthesis of the mixture of 1-oloyl-2- (9-nitropalmitoleoyl) -sn-3-glycero-phosphocholine and 1-oloyl-2- (10-nitropalmitoleoyl) -sn-3-glycerophosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1, 0 g, 3.9 mmol) was treated with dibutyltin oxide (1.1 g, 4.3 mmol, 1.1 equivalents (eq)) in 100 ml Isopropanol suspended, heated to reflux and then in a first esterification by adding 0.25 ml of triethylamine (7.8 mmol, 2 eq) with oleic acid chloride (2.35 g, 7.8 mmol, 2 eq). The yield of 1-oloyl-2-lyso-sn-3-glycerophosphocholine was 44% (0.89 g, 1.72 mmol).
- the second esterification was carried out according to Example C by reacting 0.89 g (1.72 mmol) of 1-oloyl-2-lyso-sn-3-glycero-phosphocholine with the mixture of 9-nitropalmitoleic acid and 10-nitropalmitoleic acid obtained according to Example H6 (Mixture in the ratio 4: 3; 1, 03 g, 3.44 mmol) in dry dichloromethane with addition of (5.1 mmol, 3.0 eq) 1-methyl in idazol and 2,6-dichlorobenzoyl chloride (5, 7 mmol, 3.3 eq.).
- Example P2 Synthesis of the mixture of 1-stearoyl-2- (10-nitrolinoleoyl) -sn-3-glycero-phosphocholine and 1-stearoyl-2- (9-nitrolinoleoyl) -sn-3-glycerophosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with stearic acid chloride (2.36g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-stearoyl-2-lyso-sn-3-glycero-phosphocholine was 40% (0.82 g, 1.56 mmol).
- the second esterification was carried out according to Example C by reacting 0.82 g (1, 56 mmol) of 1-stearoyl-2-lyso-sn-3-glycero-phosphocholine with the mixture obtained according to Example 11 from 10-nitrolinolic acid 4 and 9- Nitrolinolic acid 3 (mixture in the ratio 1: 3; 1, 13 g, 3.44 mmol).
- the mixture of 1-stearoyl-2- (10-nitrolinoleoyl) -sn-3-glycero-phosphocholine and 1-stearoyl-2- (9-nitrolinoleoyl) -sn-3-glycero-phosphocholine is obtained in 64% yield (0.78 g, 1.00 mmol).
- Example P3 Synthesis of the mixture of 1-eircinyl-2- (9-nitrogadoleoyl) -sn-3-glycero-phosphocholine and 1-erucinyl-2- (10-nitrogadoleoyl) -sn-3-glycerophosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with erucic acid chloride (2.79g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-erucinyl-2-lyso-sn-3-glycero-phosphocholine was 36% (0.86 g, 1.48 mmol).
- the second esterification was carried out according to Example C by reacting 0.86 g (1, 48 mmol) of 1-erucinyl-2-lyso-sn-3-glycero-phosphocholine with the mixture of 9-nitrogadoleic acid and 10-nitrogadoleic acid obtained according to Example 12 (Mixture in the ratio 5: 2; 1, 58 g, 4.44 mmol).
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with eicosapentaenoic acid chloride (2.50g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-eicosapentaenoyl-2-lyso-sn-3-glycero-phosphocholine was 33% (0.70 g, 1.29 mmol).
- the second esterification was carried out according to Example C by reacting 0.70 g (1, 29 mmol) of 1-eicosapentaenoyl-2-lyso-sn-3-glycero-phosphocholine with the mixture of 5-nitro-EPA and 6 obtained according to Example 13 Nitro-EPA (mixture in the ratio 5: 2; 1, 34 g, 3.87 mmol).
- Example P5 Synthesis of the mixture of 1- (5,8,1-eicosatrienoyl) -2- (9-nitro-a-linolenoyl) -sn-3-glycero-phosphocholine and 1- (5,8,1-eicosatrienoyl) -2- (10-nitro-a-linolenoyl) -sn-3-glycero-phosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1, 0 g, 3.9 mmol) was activated with dibutyltin oxide and then in a first esterification with 5,8,1-eicosatrienoic acid chloride (2.54 g, 7.8 mmol, 2 eq).
- the yield of 1- (5,8,1-eicosatrienoyl) -2-lyso-sn-3-glycero-phosphocholine was 50% (1.06 g, 1.95 mmol).
- the second esterification was carried out according to Example C by reacting 1.06 g (1.95 mmol) of 1- (5.8.1 1 -eicosatrienoyl) -2-lyso-sn-3-glycero-phosphocholine with the product obtained according to Example 14 Mixture of 9-nitro- ⁇ -linolenic acid and 10-nitro- ⁇ -linolenic acid (mixture in the ratio 2: 1, 1, 89 g, 5.85 mmol).
- Example P6 Synthesis of the mixture of 1-linoleoyl-2- (dinitrolinoleoyl) -sn-3-glycero-phosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1.0 g, 3.9 mmol) was activated with dibutyltin oxide and then in a first esterification with linoleic acid chloride (2.33 g, 7.8 mmol, 2 eq ) implemented.
- the yield of 1-linoleoyl-2-lyso-sn-3-glycero-phosphocholine was 57% (1.15 g, 2.22 mmol).
- the second esterification was carried out according to Example C by reacting 1.15 g (2.22 mmol) of 1 -linoleoyl-2-lyso-sn-3-glycero-phosphocholine with the mixture of 9,12-dinitrolinolic acid obtained according to Example K1, 9 , 13-Dinitrolinolic acid, 10,12-dinitrolinolic acid and 10,13-dinitrolinolic acid (2.49 g, 6.66 mmol).
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with palmitic acid chloride (2.14g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-palmitoyl-2-lyso-sn-3-glycero-phosphocholine was 40% (0.77 g, 1.56 mmol).
- the second esterification was carried out according to Example C by reacting 0.77 g (1, 56 mmol) of 1-palmitoyl-2-lyso-sn-3-glycero-phosphocholine with the obtained according to Example 11 (E) -9-nitrolinolic (1 , 19 g, 3.12 mmol).
- the 1-palmitoyl-2- (E-9-nitrolinoleoyl) -sn-3-glycero-phosphocholine is obtained in a yield of 66% (0.83 g, 1.03 mmol).
- Example P8 Synthesis of 1-palmitoyl-2- (Z-9-nitrooleoyl) -sn-3-glycerophosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with palmitic acid chloride (2.14g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-palmitoyl-2-lyso-sn-3-glycero-phosphocholine was 40% (0.77 g, 1.56 mmol).
- the second esterification was carried out according to Example C by reacting 0.77 g (1, 56 mmol) of 1-palmitoyl-2-lyso-sn-3-glycero-phosphocholine with the obtained according to Example L1 Z-9-nitroolic acid 24a (1, 02 g, 3.12 mmol).
- the 1-palmitoyl-2- (Z-9-nitrooleoyl) -sn-3-glycero-phosphocholine is obtained in 63% yield (0.79 g, 0.98 mmol).
- Example P9 Synthesis of 1- (S) -lipoyl-2- (10-nitrooleoyl) -sn-3-glycerophosphocholine According to the procedure of Example P1, sn-glycero-3-phosphatidylcholine 1a (1.0 g, 3.9 mmol) was activated with dibutyltin oxide and then in a first esterification with (S) -liponic acid chloride (1.75 g, 7.8 mmol, 2 eq). The yield of 1- (S) -lipoyl-2-lyso-sn-3-glycero-phosphocholine was 31% (0.54 g, 1.21 mmol).
- the second esterification was carried out according to Example C by reacting 0.54 g (1.21 mmol) of 1- (S) -lipoyl-2-lyso-sn-3-glycero-phosphocholine with the 10-nitroolic acid 30a obtained according to Example L2 ( 0.79 g, 2.24 mmol).
- the 1- (S) -lipoyl-2- (10-nitrooleoyl) -sn-3-glycero-phosphocholine is obtained in 51% yield (0.44 g, 0.62 mmol).
- sn-glycero-3-phosphatidylcholine 1a (1.0 g, 3.9 mmol) was activated with dibutyltin oxide and then in a first esterification with behenic acid chloride (2.80 g, 7.8 mmol, 2 eq ) implemented.
- the yield of 1-behenyl-2-lyso-sn-3-glycero-phosphocholine was 30% (0.68 g, 1.17 mmol).
- the second esterification was carried out according to Example C by reacting 0.68 g (1, 17 mmol) of 1-behenyl-2-lyso-sn-3-glycero-phosphocholine with the obtained according to Example L3 Z-9-Nitropalmitoleic acid 24b (0, 71 g, 2.34 mmol).
- the 1-behenyl-2- (Z-9-nitropalmitoleoyl) -sn-3-glycero-phosphocholine is obtained in 42% yield (0.42 g, 0.49 mmol).
- Example P11 Synthesis of 1-DHA-2- (Z-10-nitropalmitoleoyl) -sn-3-glycerophosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with docosahexaenoic acid chloride (2.71g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-docosahexaenyl-2-lyso-sn-3-glycero-phosphocholine was 25% (0.55 g, 0.98 mmol).
- the second esterification was carried out according to Example C by reacting 0.55 g (0.98 mmol) of 1-docosahexaenyl-2-lyso-sn-3-glycero-phosphocholine with the Z-10-nitropalmitoleic acid 30b obtained according to Example L4 (0, 67 g, 2.2 mmol).
- the 1-docosahexaenyl-2- (Z-10-nitropalmitoleoyl) -sn-3-glycero-phosphocholine is obtained in a yield of 31% (0.26 g, 0.30 mmol).
- Example P12 Synthesis of 1-linolenoyl-2- (Z-15-nitro-a-linolenoyl) -sn-3-glycero-phosphocholine
- sn-glycero-3-phosphatidylcholine 1a (1.0 g, 3.9 mmol) was activated with dibutyltin oxide and then in a first esterification with linoleic acid chloride (2.33 g, 7.8 mmol, 2 eq).
- the yield of 1-linoleoyl-2-lyso-sn-3-glycero-phosphocholine was 60% (1.21 g, 2.34 mmol).
- the second esterification was carried out according to Example C by reacting 1.21 g (2.34 mmol) of 1 -linoleoyl-2-lyso-sn-3-glycero-phosphocholine with the Z-15-nitro- ⁇ -linolenic acid obtained according to Example M1 41 (0.77 g, 2.4 mmol).
- the 1-linoleoyl-2- (Z-15-nitro-a-linolenoyl) -sn-3-glycero-phosphocholine is obtained in 55% yield (0.55 g, 0.67 mmol).
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with stearic acid chloride (2.36g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-stearoyl-2-lyso-sn-3-glycero-phosphocholine was 40% (0.82 g, 1.56 mmol).
- the second esterification was carried out according to Example C by reacting 0.82 g (1, 56 mmol) of 1-stearoyl-2-lyso-sn-3-glycero-phosphocholine with the obtained according to Example 11 (E) -9-nitrolinolic acid (0 , 89 g, 2.34 mmol).
- 1-Stearoyl-2- (E-9-nitrolinoleoyl) -sn-3-glycero-phosphocholine is obtained in a yield of 61% (0.79 g, 0.95 mmol).
- sn-glycero-3-phosphatidylcholine 1a (1.0g, 3.9mmol) was activated with dibutyltin oxide and then in a first esterification with stearic acid chloride (2.36g, 7.8mmol, 2 eq ) implemented.
- the yield of 1-stearoyl-2-lyso-sn-3-glycero-phosphocholine was 40% (0.82 g, 1.56 mmol).
- the second esterification was carried out according to Example C by reacting 0.82 g (1, 56 mmol) of 1-stearoyl-2-lyso-sn-3-glycero-phosphocholine with (E) -9-nitroolic acid (0.77 g, 2 , 34 mmol).
- 1-Stearoyl-2- (E-9-nitrooleoyl) -sn-3-glycero-phosphocholine is obtained in 64% yield (0.83 g, 1.00 mmol).
- sn-glycero-3-phosphatidylcholine 1a (1.0 g, 3.9 mmol) was activated with dibutyltin oxide and then in a first esterification with oleic acid chloride (2.35 g, 7.8 mmol, 2 eq ) implemented.
- the yield of 1-oloyl-2-lyso-sn-3-glycero-phosphocholine was 44% (0.89 g, 1.72 mmol).
- the second esterification was carried out according to Example C by reacting 0.89 g (1.72 mmol) of 1-oloyl-2-lyso-sn-3-glycero-phosphocholine with (E) -9-nitroolic acid (1, 13 g, 3.44 mmol).
- 1-Oleoyl-2- (E-9-nitrooleoyl) -sn-3-glycero-phosphocholine is obtained in 69% yield (0.99 g, 1.19 mmol).
- Example Q 1- (9-nitrooleoyl) -2- (palmitoyl) -sn-3-glycero-phosphatidylcholine
- Example R 1-Stearoyl-2- (E-9-nitrolinoleoyl) -sn-3-glycero-phosphatidylethanolamine
- Example D sn-3-glycerophosphatidyl- (N-BOC) -ethanolamine 1c is prepared.
- the sn-3-glycerophosphatidyl- (N-BOC) -ethanolamine 1c (1, 04 g, 3.3 mmol) is then activated according to Example P1 with dibutyltin oxide and then in a first esterification with stearic acid chloride (2.0 g, 6, 6 mmol, 2 eq) are reacted.
- the yield of 1-stearoyl-2-lyso-sn-3-glycero-phosphatidyl- (N-BOC) -ethanolamine was 48% (0.92 g, 1.58 mmol).
- the second esterification was carried out according to Example C by reacting 0.92 g (1, 58 mmol) of 1-stearoyl-2-lyso-sn-3-glycerophosphatidyl- (N-BOC) -ethanolamine with the product obtained according to Example 11 ( E) -9-Nitrolinolic acid (0.89 g, 2.34 mmol).
- 1-Stearoyl-2- (E-9-nitrolinoleoyl) -sn-3-glycerophosphatidyl- (N-BOC) -ethanolamine is obtained in a yield of 55% (0.78 g, 0.87 mmol).
- the deprotection takes place. There is obtained 1-stearoyl-2- (E-9-nitrolinoleoyl) -sn-3-glycerophosphatidylethanolamine in a yield of 93% (0.64 g, 0.81 mmol).
- Example S 1-Palmitoyl-2- (E-9-nitrooleoyl) -sn-3-glycero-phosphatidylethanolamine
- sn-3-glycerophosphatidyl- (N-BOC) -ethanolamine 1c is prepared.
- the sn-3-glycerophosphatidyl (N-BOC) -ethanolamine 1c (1, 04 g, 3.3 mmol) is then activated according to Example P1 with dibutyltin oxide and then in a first esterification with palmitic acid chloride (1, 81 g, 6, 6 mmol, 2 eq) are reacted.
- the yield of 1-palmitoyl-2-lyso-sn-3-glycero-phosphatidyl- (N-BOC) -ethanolamine was 50% (0.91 g, 1.65 mmol).
- the second esterification was carried out according to Example C by reacting 0.91 g (1.65 mmol) of 1-palmitoyl-2-lyso-sn-3-glycerophosphatidyl- (N-BOC) -ethanolamine (E) -9-nitroolic acid (0.98 g, 3.0 mmol).
- a commercially available LVM 316 stainless steel stent was degreased in an ultrasonic bath with acetone and ethanol (15 minutes) and dried at 100 ° C in a dry box. Thereafter, the stent was gently esterified for 7 minutes in a 1% solution of phosphatidylcholine with 9-nitro-cis-oleic acid (50%) and oleic acid (50%) in a mixture of ethanol / diethyl ether (50/50 (v / v)). ) and then dried at 100 ° C for 10 min. The dipping process and the subsequent drying were repeated two more times. Finally, the stent was washed overnight in ethanol (70%) and dried at 100 ° C for 15 min.
- Nitrocarboxylic acid-containing phospholipids allow rapid and complete coverage of surfaces.
- the blending of nitrated phospholipids with native phospholipids improves coating quality through greater completeness of coverage and by reducing multilayer formation as well as increasing the adhesion of the coating.
- Example 2 Nitrocarboxylic acid-containing phospholipids allow rapid and complete coverage of surfaces. The blending of nitrated phospholipids with native phospholipids improves coating quality through greater completeness of coverage and by reducing multilayer formation as well as increasing the adhesion of the coating.
- Example 2
- tochloroctadecylsilane n-octyltriethoxysilane, n-butyltrimethoxysilane, n-decyltriethoxysilane, hexadecyltrimethoxysilane, isooctyltrimethoxysilane, 13- (trichlorosilylmethyl) -heptacosane, N-phenylaminomethyltrimethoxysilane, N-cyclohexylaminomethyltriethoxysilane, isooctyltriethoxysilane , Hexadecyltrimethoxysilane, phenyltriethoxysilane or dicyclopentyldimethoxysilane.
- the stent was then removed, immersed in a Teflon beaker in chloroform, then immersed in methanol / chloroform (1: 1, v / v volume) and finally in methanol, and sonicated for 5 minutes each.
- silane-coated stent is highly water repellent. If you immerse this stent in water and pull it out quickly and in a straight line, no water droplets stick to its surface.
- silane-coated stent was then immersed in a solution of phosphatidylcholine (0.007 mmol per ml) in which the two fatty acid residues are nitrool acid residues in 5 ml of chloroform for 15 minutes, and dried in a nitrogen stream while rotating the stent.
- the coating process was repeated a further 2 times.
- the coating result is examined by confocal laser microscopy using fluorescein isothiocyanate as a fluorescent marker for the amine group of the choline residue.
- the slides were rinsed several times with alcoholic solutions and finally transferred to a 10% ethanol bath for one hour, which was then replaced with a 0.9% NaCl solution in which the slides remained for an additional 15 minutes. After a final rinse, the slides were placed in a 20% FCS dish. The dishes were continuously agitated at 37 ° C for 1, 3, or 7 days. In a further experimental approach, the prepared slides were placed in culture dishes and 2,500 x 10 5 / ml fibroblasts were suspended in the culture dish where they could grow for 3 and 7 days, respectively. After completion of the cell culture studies, the cells were trypsinized and washed twice carefully. Thereafter, the cells were homogenized and prepared for scintillation measurement.
- Radioactive labeled phospholipids were detected in the serum of samples with nitrated as well as non-nitrated phospholipid coatings. However, the level of samples of nitrated phospholipid coatings tended to be lower compared to samples of phospholipid coatings with native fatty acids. The level of phospholipids released from the coating after 24 hours could be determined to be less than 0.5% and increased to 0.7% on day 3 and to 0.8% on day 7. In the case of non-nitrated phospholipid coatings, the content of released phospholipids was measured correspondingly at 0.8%, 1.0% and 1.2%.
- nitric oxide in the culture medium and in the adherent cells was measured. 1,2-Diaminoanthraquinone (Invitrogen) was used to measure nitric oxide in the culture medium and the DAF-FM nitric oxide indicator (Invitrogen) was used to measure accumulated nitric oxide within cells. Fibroblasts were transferred to a 1% DMSO solution to reach a cell density of 2,500 x 10 5 / ml. Cells were incubated for 30 min with DAF-FM, which was added to a concentration of 5 ⁇ .
- 1,2-Diaminoanthraquinone Invitrogen
- DAF-FM nitric oxide indicator Invitrogen
- nitric oxide intracellularly and in the culture medium was determined by means of a confocal laser-scanning microscope (Fluoview 300, Olympus Europa) and a photomultiplier-based microfluorimetry (Seefelder Messtechnik, Germany).
- nitric oxide production or accumulation was significantly higher in cell culture on uncoated slides than on coated slides, both intracellular and in culture medium. Nitric oxide production or accumulation was both higher intracellular and tend to be higher in culture medium in cultures grown with native fatty acid phospholipid coatings compared to those grown on nitrocarboxylic acid containing phospholipid coatings.
- the higher content of nitric oxide in cultures on uncoated artificial surfaces compared to cultures on biocompatible surfaces can be interpreted as endogenous nitric oxide production as a result of the reaction and proliferation induction of the fibroblasts.
- Example 1 To determine the adsorption of biomolecules on SAM coated with native and nitrocarboxylic acid-containing phospholipids, supports were prepared as in Example 1. Analogously, carriers were also coated with nitrocarboxylic acid-containing phospholipids according to Example N1, namely mixtures of 1,2-di (9-nitrolinoleoyl) -sn-3-glycero-phosphocholine, 1,2-di (10) nitrolinoleoyl) -sn-3-glycero-phosphocholine, 1- (9-nitrolinoleoyl) -2- (10-nitrolinol-oyl) -sn-3-glycero-phosphocholine and 1- (10-nitrolinoleoyl) -2- (9- nitrolinoleoyl) -sn-3-glycero-phosphocholine with nitrocarboxylic acid-containing phospholipids according to Example D (1,2-di- (9-nitrooleoyl) -sn
- Coated and uncoated carriers were placed in Petri dishes. Solutions of 2% bovine albumin or bovine serum with or without the addition of fibronectin or laminin, as well as a 0.9% NaCl solution as a control, were added to the Petri dishes. These were moved slightly for 24 or 72 hours. After the end of the exposure time, the slides were gently rinsed twice with 0.9% NaCl solution. The surfaces were examined for protein absorption by an antibody staining method. Results: The surfaces of the native supports showed a homogeneous layer of albumin except slides incubated in NaCl solution. The addition of fibronectin or laminin resulted in denser protein layers. Complement factors were present on the surface of control slides, as shown by selective staining.
- Carriers coated with native phosphatidylcholine showed negligible amounts of albumin, laminin, fibronectin or complement.
- Carriers coated with a combination of 80% native phosphatidylcholine and 20% phosphatidylserine showed comparable albumin adhesion to uncoated supports and increased adsorption of fibronectin and laminin. The level of complement that adhered to these supports was higher than native supports. All carriers coated with nitrocarboxylic acid-containing phosphohydidylcholine showed significantly lower adsorption of albumin than native carriers. However, the content of albumin, fibronectin and laminin was slightly higher than on carriers with native phosphatidylcholine, while the level of complement was the same.
- Coatings containing a combination of nitrocarboxylic acid-containing phosphatidylcholine (80%) and phosphatidylserine (20%) showed significantly lower absorption of albumin, laminin, fibronectin, and complement than a comparable combination of native phospholipids. The content was also lower than on uncoated carriers. The results were stable over both observation periods.
- Example 2 To study cell homing of endothelial cells on phospholipid-coated artificial surfaces, a cobalt-chromium metal grid was coated as described in Example 2. Similarly, metal lattices were coated with nitrocarboxylic acid-containing phosphatidylcholine according to Examples N2-N6 and O6.
- An uncoated metal grid served as a control.
- the lattices were placed in a culture dish containing a gel matrix in which human umbilical venous endothelial cells (HUVEC) had grown to confluency.
- the culture medium consisted of 5% FCS, which was replaced every two days. The cultivation was carried out according to the standard conditions.
- the culture dishes were rinsed several times superficially with NaCl solution after 3, 7 and 14 days. Thereafter, the surface was stained with methylene blue. Using a reflected light microscope, the samples were investigated immediately after the following measurement parameters: propagation of the cells from the lattice edge to the lattice center, cell density, multilayer formation, and cell shape.
- Glass supports were coated with nitrocarboxylic acid-containing and native phosphatidylcholine, and a mixture of 50% each of phosphatidylcholine and phosphatidyletholamine was applied as described in Example 2. Furthermore, carriers were coated with mixtures of nitrocarboxylic acid-containing phosphatidylcholines according to Examples N12-N14, E, 02, 06, Q and P3-P7. The glass slides covered the bottom of a teflon dish into which the coated and control uncoated carriers were placed. Murine macrophages (RAW 264.7) were cultured to a cell density of 5x10 5 .
- the vitality was significantly higher than in the case of coatings with native phospholipids, namely phosphatidylcholines containing 95% after 48 h for nitrocarboxylic acids and 90% after 48 h for nitrocarboxylic acid-containing phospholipid mixtures.
- the values lay between 85% and 95% after 48 h, with no tendency for individual product mixtures to be recognized.
- the values were between 90% and 95% after 48 h and for the cholines according to Q, O6 and P3 the values were between 95% and 98% after 48 h.
- Physiologically occurring phospholipids can be taken up by virtually all cell lines in large quantities. It is known that phospholipids containing non-physiologically occurring fatty acid residues can cause cell lysis or death.
- Three cell lines (HUVEC, HeLa and L929 fibroblasts) were cultured in an adequate culture medium with 5% FCS at 37 ° C and 5% CO2 content to a subconfluent concentration of 1.5 * 10 5 cells.
- SOPC SOPC
- DOPC DOPC
- POPC POPC
- ONOPC PNLPC
- the free fatty acids OA, LA, NOOA, and NOLA were dissolved in 0.5% DMSO.
- Nile red staining a 1 ⁇ Nile red solution in PBS was added to the cell suspension for 15 minutes. The solution was then decanted and the cell suspension washed twice with PBS. The fat accumulation was quantified by fluorescence microscopy after 1 h, 12 h and 24 h, respectively.
- phenol red was added to the resuspended cells. After 4 h, the medium was renewed and 10 ⁇ of the MTT solution was added. The cells were cultured for 4 h, then a 10% SDS solution was pipetted. After 24 h, the absorption of the dissolved formazan crystals at 500 nm was determined by means of a Power Wave X (Bio-Tek Instruments, Inc., USA). The EC50 was determined for the quantitative comparison.
- the cells were resuspended in a HistoDenz (Sigma) solution with an effective 0.9% NaCl concentration (about 290 mOsm), heated to 37 ° C and sonicated for 2 minutes. The measurement was carried out with a Coulter Counter Z2.
- the free fatty acids had a significantly stronger effect on the vitality in the MTT assay, the EC50 was 48 hours for the different cell lines between 180 - 260 ⁇ for oleic acid, 240 - 260 ⁇ for linoleic acid, 10 - 50 ⁇ for nitroolic acid and 50 - 100 ⁇ for nitrolinolic acid.
- Determination of the cell volume showed that cells incubated with the natural phospholipids DOPC, POCP and SOPC showed a time-dependent increase in size to 180%, 160% and 150% respectively and for pretreated cells with the fatty acids oleic acid 200%, linoleic acid 170% , Nitrooleic acid 140% and nitro-linoleic acid 120%. Cells incubated with the nitrated phospholipids had a non-significant increase in cell volume to 1 10-120%.
- Phospholipids containing nitrocarboxylic acids have similar effects in the assay assays, whereby no significant differences between the various nitrocarboxylic acid (s) -containing phospholipids could be detected.
- Phospholipids with a nitrated fatty acid were taken up in a smaller amount of cells compared to naturally occurring phospholipids and compared to native or nitrated free fatty acids.
- the cellular uptake of nitrofatty acid-containing phospholipids causes a reduction in cell metabolism activity.
- Nitrated free fatty acids also lead to a decrease in cell metabolism activity, with this effect overlapping with the toxic effects.
- the cells remain predominantly vital after intake of nitrocarboxylic acid-containing phospholipids despite a reduced metabolic activity.
- nitrocarboxylic acid-containing phospholipids are not toxic in a much larger concentration range, in contrast to free native or nitrated fatty acids. Despite apparently only a small amount of nitrated phospholipids absorbed, a significant reduction of the metabolism is effected (in contrast to native phospholipids), whereby antiproliferative effects can be derived.
- Phospholipids can be directly absorbed by cells into their outer membrane and thereby alter the properties of the cell membrane. Therefore, it should be investigated whether phospholipids containing at least one nitrocarboxylic acid lead to different effects on cells that ingest them.
- nitrocarboxylic acid-containing phospholipids were tested according to the examples N7-N9, F, O2-O4, P1, P2, P5, P6, P8-P10, P15 and Q.
- the three cell lines were cultured in 5% FCS and 5% CO2 at 37 ° C.
- the cell suspensions were divided into the incubation vessels when a cell density of 1.5 ⁇ 10 5 in a 4-fold batch was obtained and POPC, DOPC, POPE, ONOPC, PNLPC, PNOPE or one of the nitrocarboxylic acid-containing phospholipids or phospholipid mixtures according to the examples N7 - N9, F, 02 - 04, P1, P2, P5, P6, P8 - added P10, P15 and Q, so that final concentrations of 10 ⁇ and 100 ⁇ resulted. In one approach, only a 0.5% DMSO solution was added.
- the cells were then washed twice with PBS and cultured under the above standard conditions for 24h, 48h and 96h.
- the cells were detached with trypsin-ethylenediaminetetraacetate solution.
- the detached cells were separated and the activity of trypsin stopped by adding culture medium. Aliquots were taken to determine the cell number and analyzed in a CASY 1 cell counter and analyzer system, model TTC (Schärfe System, Reutlingen), whereby not only cell concentration but also cell diameter and volume were determined.
- 6-well plates were completely coated with collagen XXII.
- Cell suspensions pretreated with 10 ⁇ and 100 ⁇ of said phospholipids and native fatty acids were cultured with a cell number of 2.5 - 3.5 * 10 5 in the 6-well plates for 24 h and 72 h in fresh nutrient medium under standard conditions , Thereafter, the culture medium was withdrawn and replaced with a 0.05% trypsin-EDTA solution. Under cultivation conditions and on a shaking plate, 2 wells were withdrawn after 10, 30 and 60 minutes and refilled with PBS. Finally, a 2% trypsin solution was added and incubated for a further hour and the suspension was stripped off. The withdrawn cell suspensions were analyzed with an automatic cell counter (see above) in terms of cell number and cell volume.
- Cell migration was performed using a standardized wound healing assay.
- the three cell lines were incubated with phospholipids and fatty acids as described above. After washing twice with PBS, 2 - 3 * 10 5 cells were placed in Ibidi culture inserts overlaying the agar plate and cultured for 24 h under standard conditions. Thereafter, the culture surface interrupting stamp was removed with a width of ⁇ . This was followed by further cultivation for three days. Every eight hours there was a photo documentation of the cultural area. The pictures were evaluated with a software for the automatic detection of cell-covered areas.
- nitrocarboxylic acid-containing phospholipids and phospholipid mixtures according to the examples N7-N9, F, 02-04, P1, P2, P5, P6, P8-P10, P15 and Q showed overall very homogeneous results, not far from the Deviated effects of the other tested nitrocarboxylic acid (s) -containing phospholipids ONOPC, PNLPC or PNOPE. It can thus be stated that the mixtures of nitrocarboxylic acid-containing phospholipids also exhibit a uniform action which does not differ from the effects of individual nitrocarboxylic acid-containing phospholipids used.
- the incorporation of phospholipids into a cell membrane can lead to a change in their physicochemical properties. It should therefore be investigated what effect nitrated alkyl chains in phospholipids have on the membrane properties.
- the membrane pressure, the degree of anisotropy and the phase transition temperature can be estimated in model membranes of unilaminar vesicles via the reporter molecule Laurdan.
- membrane proteins only become functional after a subunit interaction has been established.
- the folding process of membrane proteins is mediated, among other things, by the lateral interaction of adjacent transmembrane helices.
- FRET Förster resonance energy transfer
- the change in Förster resonance energy transfer (FRET) of fluorescently labeled peptides with ⁇ -helical transmembrane structures in a lipid bilayer can be used to determine the concentration of monomeric and dimeric transmembrane helices and thus to quantify helix-helix interactions.
- FRET Förster resonance energy transfer
- the FRET measurements were performed with fluorescently labeled glycophorin A peptides (GpA).
- GpA fluorescently labeled glycophorin A peptides
- the transmembrane GpA forms dimers, whereby an energy transfer is measurable.
- 5-carboxyfluorescein and tetramethyl-6-carboxy rhodamine were used as chromophores.
- the native phospholipids SOPC and SLPC and the analogous phospholipids SNOPC and SNPLC were each mixed alone and in each case with the phospholipid DSPC 1: 1 (w / w).
- the phospholipids according to the examples N1 - N5, N15 - N20, O1, O2, P1 - P4, D, F, Q, R and S were investigated in further mixtures.
- the determination of the degree of dimerization of the model protein was carried out in a direct comparison between native phospholipids and the corresponding phospholipids with a nitrated Alcylkette for the investigated concentrations of phospholipids (10 - 50%, mol / mol) in DSPC vesicles.
- the phospholipids were dissolved in a CHCIs / MeOH mixture (1: 1), the total concentration of phospholipids was always 1 mM.
- Laurdan (in EtOH) in the ratio 1: 500 (2 ⁇ ) was added to the lipid mixtures and the mixture was homogenized.
- the samples were freed of solvent and dried under vacuum. It was then hydrated with 250 ⁇ M HEPES buffer (10 mM HEPES, 150 mM NaCl, pH 7.4) and incubated for at least 30 minutes at 65 ° C and 1400 rpm in the Thermomixer, forming multilamellar vesicles.
- the samples were first frozen in liquid nitrogen in five cycles, then thawed again at 65 ° C. in a water bath and homogenized for 1 min at 1400 rpm in a thermomixer. 200 ⁇ were taken from each sample and measured. The measurements were carried out on a Horiba Scientific FluoroMax-4 fluorescence spectrometer additionally equipped with a Horiba Scientific F-3004 digital temperature control.
- the peptides FL-GpAwt and TAMRA-GpAwt were weighed and dissolved in TFE. The measurements were carried out on an Aminco Bowman Series 2 (Thermo Spectronic) fluorescence spectrometer.
- Examples D and F showed a 10-20% stronger effect on the membrane melting point (depression) and the degree of anisotropy (increase), for which examples were N1 - N5, N15 - N20, O1, O2, P1 - P4, Q the effects comparable to the results of SNOPC and SNLPC.
- examples F, Q, R and S the effects described above were 15% to 30% less pronounced
- the addition of phospholipids with an unsaturated fatty acid lowered the degree of dimerization of the model membrane protein.
- Analogous phospholipids with a nitro group on the unsaturated fatty acid led to a significantly greater reduction in dimerization (P13, SNLPC, P14, SNOPC).
- Phospholipids with a nitrated unsaturated fatty acid have a significantly stronger effect on the membrane fluidity and thus the membrane melting point than the corresponding native phospholipids.
- a reduction in the degree of order within the membrane at temperatures in the liquid-crystalline phase, while in the gel phase and here in particular at higher Tepmeraturen the degree of order is significantly greater than in the native phospholipids.
- the increase in the degree of order is very likely the cause of the found disturbance of dimerization of model membrane proteins, which is considerably stronger in phospholipids with nitrated fatty acids than that of native phospholipids.
- nitrocarboxylic acid-containing phospholipids into a model cell membrane results in an increase in their stability at physiological temperatures, or a decrease in membrane fluidity. Since the cell perception depends to a large extent on the membrane fluidity, the effects found show a reduction in the perception of mechanical, chemical and osmotic alterations.
- nitrocarboxylic acid-containing phospholipids and phospholipid mixtures according to Examples N4-N8, N10, N1 1, D, B, 02, 04, 06, P8-P12, P15 and Q were tested.
- the collagen synthesis was assessed semiquantitatively by means of immunohistological detection.
- Mouse fibroblasts were cultured and after 5 passages with the native phospholipids SOPC, DOPC and PLPC, the nitrated phospholipids SONPC, PNOPC and PNLPC, the fatty acids oleic acid, linoleic acid and nitroolic acid and nitrolinolic acid and NaCl solution or the nitrocarboxylic acid (s) -containing phospholipids or Phospholipidgemischen according to Examples N4 - N8, N10, N1 1, D, B, 02, 04, 06, P8 - P12, P15 and Q incubated for 24 hours. The final concentrations of the phospholipids were 10 ⁇ , 100 ⁇ and 200 ⁇ , the fatty acids 10 ⁇ and 100 ⁇ .
- the secondary biotinylated link antibody (anti-mouse and anti-rabbit immunoglobulins, Dako) was incubated for 20 minutes and then washed again.
- streptavidin labeled with peroxidase (Dako) was then incubated for 10 minutes.
- the substrate chromogen AEC (3-amino-9-ethylcarbazole, Dako) was added for 10 minutes. This was followed by counterstaining with hematoxylin for 5 minutes. The preparations were evaluated semiquantitatively in a light microscope.
- Fibroblasts of the control group showed a linear increase in the amount of collagen matrix over the entire examination period; multiplication was increased disproportionately when stimulated with TGF-ß.
- the native fatty acids had no significant effect on collagen synthesis in the low concentration; at high concentrations, collagen synthesis on day 3 was reduced from control and increased on day 7.
- the nitrofatty acids caused a reduced collagen synthesis at the low concentration until day 5.
- the collagen synthesis was more reduced and the difference was still significant on day 7 compared to the control.
- Under stimulation with TGF-ß an increased collagen synthesis after incubation with native fatty acids in low concentration at all time points of investigation was shown.
- At high concentration of native fatty acids on day 3 there was a small reduction and then a significant increase in collagen synthesis.
- the Nitrofatty acids had comparable effects on collagen synthesis, but the reduction of collagen synthesis on day 3 was stronger (ns), on day 7 there was no difference to the native fatty acids.
- the native phospholipids had no effect on collagen synthesis when incubated at a concentration of 10 ⁇ and 100 ⁇ . At the highest concentration there was a reduction in collagen synthesis on day 3 and an increase on day 7.
- TGF- ⁇ Upon stimulation with TGF- ⁇ , there was a significant increase in collagen synthesis over control for all native phospholipids, except for the highest concentration group Day 3.
- a nitrocarboxylic acid-containing phospholipid such as SNOPC, PNOPC or PNLPC.
- Native and nitrated fatty acids can lead to a short-term reduction of collagen synthesis depending on the concentration, but have no influence on the cytokine-induced stimulation of collagen synthesis.
- Incubation with native phospholipids has no relevant effect on collagen synthesis.
- nitrocarboxylic acid-containing phospholipids cause a strong inhibition of collagen synthesis.
- this effect is retained when stimulated with cytokines.
- Balloon catheters were coated by the Langmuir-Schäfer method with the balloon area aligned coaxially with the liquid surface and immersing a region of about 1 mm in the liquid.
- the catheter was rotated 5 times around its axis.
- the phospholipids were dissolved in a concentration of 3 mmol in an ion-free aqueous solution at 50 ° C. Thereafter, the solution was cooled and placed in the coater. If the phospholipids do not dissolve completely or precipitate on cooling, then up to 20% by volume, preferably up to 10% by volume, of DMSO was added to the aqueous solution. After coating, the catheters were removed by vacuum drying for 8 hours from residual solvent.
- the coating stability was tested for its abrasion stability by placing the balloon catheters, which had an outer diameter of 0.85 mm, in a PTFE tubing with an inner diameter of 1.0 mm placed in a silicone model, which consecutively had several angulations of up to 60 ° in four levels, was advanced by means of an automated cable pulling device with a constant speed of 3cm / s.
- the tube system was filled with a 10% human albumin solution at a temperature of 35 ° C.
- the cable system which had previously been inserted through the tube system, was connected to the catheter tip and passed over deflection rollers, which allowed the rope to be moved in an exactly vertical direction from above to one motorized winch arrived.
- the winch was mounted on a precision digital car.
- the catheters thus secured were pulled through the tubing system and the weight changes due to the guided pulling work digitally recorded during the catheter passage, the readings were integrated over time. This was used to calculate the work done to estimate the total shear forces during catheter passage through the tube system.
- the abrasion or loss of the coating layers was determined by weighing the catheters before and after coating and after the mechanical stability test by shearing in the above-described tube system by means of a precision balance.
- the phospholipid-coated catheters were additionally sealed with polyethylene glycol 1000 (Roth, Germany).
- PEG 1000 was melted at 50 ° C and mixed with a 10% ethanolic solution.
- Part of the phospholipid-coated balloon catheter as described above was coated by dip coating with the 50 ° C warm PEG solution and dried again in a vacuum oven for 8 hours.
- the starting substances had only a small proportion of trans fatty acids ( ⁇ 5%) in all phospholipids studied. Twenty-four hours after application of the phospholipids to a catheter, there was a trend to higher levels of trans fatty acid in the natural phospholipids over the nitrated phospholipids. After heat treatment, the proportion of trans fatty acids in natural phospholipids increased to 80% (POPC) and 86% (SLPE), respectively. In contrast, the proportion of trans fatty acids in the nitrated phospholipids was significantly lower at 25% and 28% (PNOPL, SNLPE), respectively. After two months, the degree of transisomation was in the sole coatings with natural phospholipids at 95 and 98% and at 30% and 32% in the nitrated phospholipids. In the combination of the natural and nitrated phospholipids, the degree of tris isomerisation was significantly lower than the calculated mean of the degree of transisomension of the two pure substances.
- An improvement in the lubricity of an object / implant to be introduced into the organism may contribute to a reduction in tissue trauma. Furthermore, a material coating should have sufficient resistance to premature abrasion during introduction into the organism. Furthermore, a chemical and thermal stability should exist. These requirements were met by the Nitrocarboxylic acid (s) -containing phospholipids significantly better fulfilled than by the native phospholipids.
- the physico-chemical membrane properties of a cell represent a significant resistance factor to physical, chemical and immunological external influences.
- human erythrocytes and mouse mast cells were treated with physiological NaCl solution, the natural one Phospholipids SOPC and PLPC as well as the analogous phospholipids with nitration of the unsaturated fatty acids (1-stearoyl-2- (9-nitrooleoyl) -sn-PC (example P14) and 1-palmitoyl-2- (9-nitrolinoleoyl) - sn-PC) (Example P7) was incubated at a concentration of 30 mmol / l for one hour.
- the cells were treated with mixtures of nitrocarboxylic acid-containing phospholipids according to Examples F, Q, S, N2-N14, 03-06, P1-P3 and P6.
- the erythrocytes separated from the serum by centrifugation were first cleaned three times with physiological NaCl solution.
- the erythrocytes were resuspended in physiological NaCl solution and the suspended phospholipids were added. This stock was agitated on a slow speed rotisserie plate at 30 ° C for 1 hour. From this aliquots of 3 ml were filled into glass tubes and centrifuged. After removal of the supernatant, distilled water and NaCl solutions of increasing concentration of 0.1 to 1.0 g / dl were added. After incubation for 30 minutes under the above conditions, the tubes were centrifuged and an aliquot taken for photometric measurement of the hemoglobin by absorbance at a wavelength of 546 nm and 30 ° C temperature.
- C2 cells dog mast cells
- the cells were cultured in 5% FCS medium under standard conditions.
- the cells were washed several times in a calcium- and magnesium-free buffer solution and finally concentrated.
- the cells were distributed on 96-well plates and incubated with NaCl solution and the above-mentioned phospholipids for one hour at 37 ° C.
- mastoparan Sigma, Germany
- the determination of Ca 2+ influx was determined with a calcium ionophore (A23187, Sigma Germany).
- the calcium influx was normalized to the respective baseline measurement and expressed as a percentage increase.
- Histamine release from the C2 cells was determined using a histamine ELISA (ILB, Germany).
- Toxic effects of substances on cells can be mediated in a number of ways: (1) damage to surface features of the cell translating alteration by membrane proteins into the cell, (2) direct damage to the cell membrane or (3) transmembrane uptake of the substance into the cell. Irrespective of the basic principle of these types of damage, the degree of damage depends essentially on the physico-chemical properties of the cell membrane. Therefore, it should be investigated whether the membrane-stabilizing effects of nitrated phospholipids alter the cytotoxicity of known cytotoxic agents mediated through one or more of these mechanisms. Since vascular and tubular endothelial cells are particularly sensitive to cytotoxic substances, they were exposed to various substances under in vitro culture conditions.
- the cell line LLC-PK1 was cultured in complete medium (D-MEM medium) with 10% fetal calf serum (FCS) and sodium bicarbonate (26 mmol / L) in 5% CO2 atmosphere.
- cisplatin 25 and 50 ⁇ / ⁇
- cyclosporin 50 and 100 ⁇ / ⁇
- murine aortic endothelial cells were cultured in standard medium with 10% FCS.
- Cell suspensions of the lysates were preincubated as previously described.
- lipopolysaccharide of Escherichia coli (4 and 8 pg / ml, Simga) was added to the cell suspensions and the procedure described above.
- the cell suspensions were labeled with two fluorescent dyes (LIVE / DEAD®, Molecular Probes). This was followed by flow cytometry (FACSCalibur, Becton & Dickinson). The proportion of avital cells was calculated from the ratio between the red fluorescent cells and the total number of cells determined.
- Freshly harvested porcine iliacae were initially prepared except for the adventitia and then cultured for three days in PBS with 1% FCS. Segments 5mm in length were atraumatically separated and placed in culture vessels containing the natural phospholipids POPC and SLPC and the analogous phospholipids with nitration of the unsaturated fatty acids (1-palmitoyl-2- (9-nitrooleoyl) -sn-PC and 1-stearoyl-2 - (9-nitrolinoleoyl) -sn-PC) in each case in a concentration of 50mmol, as well as with the nitrated free fatty acids nitroolic acid (NOA) and nitrolinols (NLA) in each case in a concentration of 30 ⁇ inserted for a further two days.
- NOA nitroolic acid
- NLA nitrolinols
- the phospholipids according to the invention according to the examples N1 - N5, N1 1, N15 - N17, N20, O2 - O5, P4 - P6, E, G and Q were tested.
- the vessels were placed in a pressure chamber and a Exposed to pressure of 15 bar for one hour. Thereafter, rapidly releasing the pressure within 5 seconds.
- the culture bottles were slowly agitated for 7 days on a vibratory plate under standardized culture conditions.
- the culture medium was changed after the 3rd day and further analyzed to determine microparticles.
- the vessel segments were then fixed and embedded.
- TUNEL staining In Situ Cell Death Detection Kit, AP, Boehringer, Germany
- the evaluation was carried out by light microscopy, a differentiation between apoptosis and necrosis was not made and the number of cells stained in relation to the total number of cells analyzed.
- annexin V-allophycocyanin APC
- BD Pharmingen annexin V-allophycocyanin
- the number of microparticles was then determined by flow cytometry (FACSCanto, Becton & Dickinson). The measurement window was set to particle diameters of 0.3 to 1, 0 ⁇ .
- the effect of the nitrocarboxylic acid-containing phospholipids according to the invention is independent of the phospholipid used, ie also independent of the head group of the phospholipid and independent of the phospholipid mixture, and thus the decisive factor is the presence of at least one nitrated carboxylic acid or nitrated fatty acid in the phospholipid appears to be.
- Barotrauma occurs in particular in angioplasty, in which, for example, a balloon catheter is advanced to the narrowed point in the blood vessel to be filled there under considerable pressure (up to 20 bar).
- the resulting vessel wall damage causes a wound reaction that contributes to re-constriction of the vessel under the clinical picture of restenosis.
- the nitrocarboxylic acid-containing phospholipids can counteract this effect and are therefore particularly suitable for all indications in which cells / tissue are exposed to a pneumatic / compressive stress.
- Neurons were prepared from young mice according to a published method (Goldberg MP, Choi DW, Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury, J Neurosci 1993; 13: 3510-3524).
- the freshly prepared cortex tissue was separated with papain and the tissue suspension was cultured in culture vessels (Primara, BD Biosciences, USA) with Neurobasal A / B27 medium (Invitrogen) for 10-12 days.
- the cell suspension was then divided, with the addition of NaCl (0.9%), the natural phospholipids SOPC and PLPC and the analogous phospholipids with nitration of the unsaturated fatty acids (1-stearoyl-2- (9-nitrooleoyl) -sn-PC and 1 Palmitoyl-2- (9-nitrolinoleoyl) -sn-PC) at a concentration of 10 and 50 ⁇ / ⁇ .
- the phospholipids according to the invention according to Examples C, D, F, N3-N7, N13-N19, O1, O2, O5, 06, P3, P8 and Q were used.
- the cells were rinsed three times with buffered NaCl solution and added to the buffered NaCl solution with the addition of MgCl 2 and CaCl 2 of an anaerobic atmosphere (85% N 2 , 5% H 2 , 10% CO 2 , 35 ° C ) for 10 and 30 minutes. Subsequently, the cells were washed once and cultured in the culture medium under aerobic conditions for 24 hours.
- the cells were then separated according to a published technique (Meiler R, Skradski SL, Simon RP, Henshall DC, Expression proteolysis and activation of caspases 6 and 7 during rat C6 glioma cell apoptosis, Neurosci Lett 2002; 324: 33-36).
- the cells were washed with Annexin V-FITC and propidium iodide (Molecular Probes, USA) stained.
- the vital and avital cells were determined by flow cytometry (FACSCalibur, Becton & Dickinson).
- the volume of the culture medium was determined and an aliquot taken to determine the LDH concentration.
- Cardiac myocytes were obtained from neonatal rat hearts (Nitobe J, et al, Reactive oxygene species regulate FLICE inhibitory protein and susceptibility to FAS mediated apoptosis in cardiac myocytes, Cardiovasc Res 2003, 1 19-28).
- the heart muscle cells were cultured in Dulbecco / Eagle medium (DMEM) with 10% FCS for two days under standard conditions. The incubation with the natural and nitrated phospholipids as well as the Hypoxie collectede carried out as described above.
- the cells were cultured in culture medium for 24 hours under standard conditions. This was followed by vitality staining as described above. A portion of the cell suspensions were frozen immediately after hypoxia end and after 10 and 30 minutes in liquid nitrogen.
- the frozen cells were later thawed to -4 ° C for NAD + analysis and homogenized.
- NAD + analysis and homogenized.
- a pellet was separated with mitochondria (Di Lisa, et al., 1993; Am. J. Physiol. 264, H2188-H2197).
- the NAD + content was determined fluorometrically and normalized against protein content (Veloso, D., and Veech, R.L., 1974, Anal. Biochem., 449-1550).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Environmental Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Dentistry (AREA)
- Molecular Biology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Organic Chemistry (AREA)
- Plant Pathology (AREA)
- Vascular Medicine (AREA)
- Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Materials Engineering (AREA)
- Transplantation (AREA)
- Biomedical Technology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR112013030644A BR112013030644A2 (pt) | 2011-06-06 | 2012-06-06 | fosfolipídios contendo ácido(s) nitrocarboxílico(s) da estrutura geral (i), e uso dos mesmos, dispositivo médico e composições biopassivadoras |
US14/123,816 US20140099354A1 (en) | 2011-06-06 | 2012-06-06 | Biopassivating membrane stabilization by means of nitrocarboxylic acid-containing phospholipids in preparations and coatings |
CN201280034834.3A CN103717211B (zh) | 2011-06-06 | 2012-06-06 | 在配制剂和涂层中通过含有硝基羧酸的磷脂来实现的生物钝化性膜稳定化 |
RU2013158673/15A RU2013158673A (ru) | 2011-06-06 | 2012-06-06 | Биопассивирующая стабилизация мембран посредством содержащих нитрокарбоновую кислоту фосфолипидов в препаратах и покрытиях |
EP12727358.9A EP2717864A1 (de) | 2011-06-06 | 2012-06-06 | Biopassivierende membranstabilisation mittels nitrocarbonsäuren-enthaltenden phospholipiden in zubereitungen und beschichtungen |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102011103948A DE102011103948A1 (de) | 2011-06-06 | 2011-06-06 | Biopassivierende Beschichtung von Gefäßprothesen mit Nitrocarbonsäuren enthaltenden Phospholipiden |
DE102011103948.5 | 2011-06-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012168342A1 true WO2012168342A1 (de) | 2012-12-13 |
WO2012168342A9 WO2012168342A9 (de) | 2013-02-28 |
Family
ID=46275822
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/060773 WO2012168342A1 (de) | 2011-06-06 | 2012-06-06 | Biopassivierende membranstabilisation mittels nitrocarbonsäuren-enthaltenden phospholipiden in zubereitungen und beschichtungen |
Country Status (7)
Country | Link |
---|---|
US (1) | US20140099354A1 (de) |
EP (1) | EP2717864A1 (de) |
CN (1) | CN103717211B (de) |
BR (1) | BR112013030644A2 (de) |
DE (1) | DE102011103948A1 (de) |
RU (1) | RU2013158673A (de) |
WO (1) | WO2012168342A1 (de) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103435493A (zh) * | 2013-09-10 | 2013-12-11 | 大连医诺生物有限公司 | 一种硝基油酸及其衍生物的制备方法 |
KR20220139825A (ko) | 2022-09-27 | 2022-10-17 | 하나제약 주식회사 | 콜린알포세레이트 에스테르 유도체의 제조방법과 그 용도 |
DE102022134188B3 (de) | 2022-12-20 | 2024-03-28 | Universität Augsburg - Körperschaft des öffentlichen Rechts | Verfahren zur in-situ Erfassung von Änderungen eines Lipidsystems bei dessen Lagerung bei einer Lagertemperatur unterhalb von -60 °C |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2575487B (en) * | 2018-07-12 | 2023-02-08 | Cook Medical Technologies Llc | Coated medical device and method of coating such a device |
CN109486790B (zh) * | 2018-12-10 | 2021-08-03 | 南通励成生物工程有限公司 | 一种以磷脂酶d转化制备磷酯酰丝氨酸的方法 |
CN110452262A (zh) * | 2019-08-22 | 2019-11-15 | 深圳上泰生物工程有限公司 | 血小板激活因子(paf)类似物的合成方法 |
CA3159716A1 (en) * | 2019-12-05 | 2021-06-10 | Fresenius Kabi Usa, Llc | Method for analyzing degarelix and associated products |
WO2021262298A1 (en) * | 2020-06-23 | 2021-12-30 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Electrophilic compounds and electrophilic prodrugs for treating aneurysm |
CN114953465B (zh) * | 2022-05-17 | 2023-04-21 | 成都信息工程大学 | 一种基于Marlin固件的3D打印方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080064645A1 (en) * | 2006-08-15 | 2008-03-13 | Pagano Richard E | Non-Natural Sphingolipid Analogs and Uses Thereof |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3100783B2 (ja) * | 1992-10-15 | 2000-10-23 | キユーピー株式会社 | ホスファチジルコリンおよびその製造方法 |
US6583251B1 (en) * | 1997-09-08 | 2003-06-24 | Emory University | Modular cytomimetic biomaterials, transport studies, preparation and utilization thereof |
US6838452B2 (en) * | 2000-11-24 | 2005-01-04 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
US7731947B2 (en) * | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
CN1897918A (zh) * | 2003-11-17 | 2007-01-17 | 阿尔萨公司 | 包含两亲性分子作为混悬载体的组合物和剂型 |
US20090048423A1 (en) * | 2007-08-15 | 2009-02-19 | Tyco Healthcare Group Lp | Phospholipid Copolymers |
ES2692291T3 (es) * | 2008-05-01 | 2018-12-03 | Complexa Inc. | Ácidos grasos vinil sustituidos |
WO2009155439A2 (en) * | 2008-06-19 | 2009-12-23 | University Of Utah Research Foundation | Use of nitrated lipids for treatment of side effects of toxic medical therapies |
EP2542232A4 (de) * | 2009-11-02 | 2013-08-28 | Life Technologies Corp | Fettsäurehemmer |
-
2011
- 2011-06-06 DE DE102011103948A patent/DE102011103948A1/de not_active Ceased
-
2012
- 2012-06-06 EP EP12727358.9A patent/EP2717864A1/de not_active Withdrawn
- 2012-06-06 BR BR112013030644A patent/BR112013030644A2/pt not_active Application Discontinuation
- 2012-06-06 CN CN201280034834.3A patent/CN103717211B/zh not_active Expired - Fee Related
- 2012-06-06 US US14/123,816 patent/US20140099354A1/en not_active Abandoned
- 2012-06-06 RU RU2013158673/15A patent/RU2013158673A/ru not_active Application Discontinuation
- 2012-06-06 WO PCT/EP2012/060773 patent/WO2012168342A1/de active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080064645A1 (en) * | 2006-08-15 | 2008-03-13 | Pagano Richard E | Non-Natural Sphingolipid Analogs and Uses Thereof |
Non-Patent Citations (42)
Title |
---|
"Problematik der Wanderungen von Estergruppen in Diolen siehe Adlercreutz", BIOCATAL. BIOTRANSFOR., vol. 18, 2000, pages 1 |
A. MAKRIYANNIS, J. LAB. COMP. RADIOPHARM., vol. 46, 2003, pages 645 |
AHERN GP; BROOKS IM; MIYARES RL; WANG XB: "Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signalling", J NEUROSCI, vol. 25, 2005, pages 5109 - 5116 |
B. BRANCHAUD, ORG. LETT., vol. 8, 2006, pages 3931 |
B. KING, ORG. LETT., vol. 8, 2006, pages 2305 |
B. SMITH, J. ORG: CHEM., vol. 73, 2008, pages 6058 |
BIOTECHNOL. BIOENG., vol. 78, 2002, pages 403 |
C. C. LAI, B. J. FINLAYSON-PITTS: "Reactions of dinitrogen pentoxide and nitrogen dioxide with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine", LIPIDS, vol. 26, no. 4, 1991, pages 306 - 314, XP009162640 * |
CHIRONI ET AL., CELL TISSUE RES, vol. 335, 2009, pages 143 - 151 |
D'ARRIGO, SERVI, MOLECULES, vol. 15, 2010, pages 1354 |
DASCAL, N.: "The use of Xenopus oocytes for the study of Ion Channels", CRC CRITICAL REVIEWS IN BIOCHEMISTRY, vol. 22, 1987, pages 317 - 387 |
DI LISA ET AL., AM. J. PHYSIOL., vol. 264, 1993, pages H2188 - H2197 |
FREE RAD. BIOL. & MED., vol. 50, 2011, pages 411 |
GOLDBERG MP; CHOI DW: "Combined oxygen and glucose deprivation in cortical cell culture: calciumdependent and calcium-independent mechanisms of neuronal injury", J NEUROSCI, vol. 13, 1993, pages 3510 - 3524 |
GORCZYNSKI, MICHAEL J.; HUANG, JINMING; KING, S. BRUCE, ORGANIC LETTERS, vol. 8, no. 11, 2006, pages 2305 - 2308 |
H. BROCKERHOFF; M. YURKOWSKI, CAN. J. BIOCHEM., vol. 43, 1965, pages 1777 |
ISHIBASHI, ORG. LETT., vol. 12, 2010, pages 124 |
J. BRIMACOMBE, J. CHEM. SOC. PERKIN TRANS., vol. I, 1995, pages 1673 |
J. SAKAKIBARA, TETRAHEDRON LETT., vol. 34, 1993, pages 2487 |
KING, ORG. LETT., vol. 8, 2006, pages 2305 |
M. BALAZY, FREE RAD. BIOL. & MED., vol. 45, 2008, pages 269 |
M. D'LSCHIA, J. ORG. CHEM., vol. 65, 2000, pages 4853 |
M. D'LSCHIA, J. ORG. CHEM., vol. 73, 2008, pages 7517 |
MELLER R; SKRADSKI SL; SIMON RP; HENSHALL DC: "Expression proteolysis and activation of caspases 6 and 7 during rat C6 glioma cell apoptosis", NEUROSCI LETT, vol. 324, 2002, pages 33 - 36 |
MEZIANI ET AL., PHARMACOL REP, vol. 60, 2008, pages 75 - 84 |
NACH B. BRANCHAUD, ORG. LETT., vol. 8, 2006, pages 3931 |
NITOBE J ET AL.: "Reactive oxygene species regulate FLICE inhibitory protein and susceptibility to FAS-mediated apoptosis in cardiac myocytes", CARDIOVASC RES, 2003, pages 119 - 28 |
P. KONRADSSON, J. ORG. CHEM., vol. 67, 2002, pages 194 |
PAYNTER SJ; COOPER A; FULLER BJ; SHAW RW: "Cryopreservation of bovine ovarian tissue: structural normality of follicles after thawing and culture in vitro", CRYOBIOLOGY, vol. 38, 1999, pages 301 - 309 |
R. ANEJA, TETRAHEDRON LETT., vol. 41, 2000, pages 847 |
R. SALOMON, BIORG. & MED. CHEM., vol. 19, 2011, pages 580 |
R. SALOMON, BIORG.& MED. CHEM., vol. 19, 2011, pages 580 |
SALOMON, BIORG. & MED. CHEM., vol. 19, 2011, pages 580 |
See also references of EP2717864A1 |
SERVI, CHEM. PHYS. LIPIDS, vol. 147, 2007, pages 113 |
SERVI, ORG. BIOMOL. CHEM., vol. 4, 2006, pages 2974 |
SHANNON TR; GINSBURG KS; BERS DM: "Quantitative assessment of the SRCa2+ leak-load relationship", CIRC RES., vol. 91, 2002, pages 594 - 600 |
VAN DER GIESSEN ET AL.: "Marked inflammatory sequelae to implantation of biodegradable polymers in porcine coronary arteries", CIRCULATION, vol. 94, 1996, pages 1690 - 7 |
VELOSO, D.; VEECH, R. L., ANAL. BIOCHEM., 1974, pages 449 - 450 |
VON G. ZANONI; G. VIDARI, J. ORG. CHEM., vol. 75, 2010, pages 8311 |
W. BOLAND, TETRAHEDRON, vol. 59, 2003, pages 135 |
WOODCOCK, ORG. LETT., vol. 8, 2006, pages 3931 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103435493A (zh) * | 2013-09-10 | 2013-12-11 | 大连医诺生物有限公司 | 一种硝基油酸及其衍生物的制备方法 |
KR20220139825A (ko) | 2022-09-27 | 2022-10-17 | 하나제약 주식회사 | 콜린알포세레이트 에스테르 유도체의 제조방법과 그 용도 |
DE102022134188B3 (de) | 2022-12-20 | 2024-03-28 | Universität Augsburg - Körperschaft des öffentlichen Rechts | Verfahren zur in-situ Erfassung von Änderungen eines Lipidsystems bei dessen Lagerung bei einer Lagertemperatur unterhalb von -60 °C |
Also Published As
Publication number | Publication date |
---|---|
RU2013158673A (ru) | 2015-07-20 |
BR112013030644A2 (pt) | 2017-12-19 |
CN103717211B (zh) | 2017-11-17 |
US20140099354A1 (en) | 2014-04-10 |
DE102011103948A1 (de) | 2012-12-06 |
EP2717864A1 (de) | 2014-04-16 |
WO2012168342A9 (de) | 2013-02-28 |
CN103717211A (zh) | 2014-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2717864A1 (de) | Biopassivierende membranstabilisation mittels nitrocarbonsäuren-enthaltenden phospholipiden in zubereitungen und beschichtungen | |
JP7046237B2 (ja) | 手術部位感染の処置および予防のための組成物および方法 | |
DE69633012T2 (de) | Stickstoffoxyd-freisetzende verbindungen sowie methoden und intravaskuläre vorrichtungen zu ihrem gebrauch zum vorbeugen von restenosen | |
Tao et al. | Osteoimmunomodulation mediating improved osteointegration by OGP-loaded cobalt-metal organic framework on titanium implants with antibacterial property | |
EP2303948B1 (de) | Verfahren zur herstellung eines kieselsol-materials mit mindestens einem therapeutisch aktiven wirkstoff zur herstellung von biologisch degradierbaren und/oder resorbierbaren kieselgel-materialen für die humanmedizin und/oder medizintechnik | |
EP1967217B1 (de) | Antimikrobielles medizintechnisches Produkt, Verfahren zu seiner Herstellung und Verwendung | |
DE102005044360A1 (de) | Antimikrobielles medizintechnisches Produkt, Verfahren zu seiner Herstellung und Verwendung | |
CN104195368A (zh) | 一种Zn-Sr系锌合金及其制备方法与应用 | |
US20130039956A1 (en) | Use of nitrocarboxylic acids for the treatment, diagnosis and prophylaxis of aggressive healing patterns | |
EP1841471A2 (de) | Antimikrobielles medizintechnisches produkt, verfahren zu seiner herstellung und verwendung | |
Wang et al. | Construction of perfluorohexane/IR780@ liposome coating on Ti for rapid bacteria killing under permeable near infrared light | |
US20210023259A1 (en) | Poly (ionic liquid) compositions and their use as tissue adhesives | |
WO2019008192A1 (de) | Bioresorbierbare oberflächenbeschichtung zur degradationsverzögerung | |
DE60020681T2 (de) | Zusammensetzungen und verfahren zur verbesserung der integrität von angegriffenen körperpassagewegen und höhlen | |
DE102005044361A1 (de) | Antimikrobielles medizintechnisches Produkt, Verfahren zu seiner Herstellung und Verwendung | |
Zhang et al. | Immunomodulatory gallium/glycyrrhizic acid hydrogels for treating multidrug-resistant Pseudomonas aeruginosa-infected pressure ulcers | |
EP3032949B1 (de) | Mittel enthaltend mikropartikel zur reinigung und zum schutz von technischen oberflächen | |
EP1523346B1 (de) | Beschichtungszusammensetzung für eine implantierbare medizinische vorrichtung und verfahren zur beschichtung einer solchen vorrichtung | |
DE102009042036B4 (de) | Verwendung einer lichthärtenden, biokompatiblen und biologisch abbaubaren Polymermischung | |
DE602004012894T2 (de) | Oberflächenschutz von frei liegenden biologischen geweben | |
EP2433660B1 (de) | Beschichtetes Implantat aus einer biokorrodierbaren Magnesiumlegierung | |
DE102006011217A1 (de) | Antimikrobielles medizintechnisches Produkt, Verfahren zu seiner Herstellung und Verwendung | |
Lazurko | Nanomaterial and Biomaterial Approaches for Treating Chronic Wounds | |
DE19604484C2 (de) | Farbstoffzubereitung zum Markieren von Operationsfeldern in Lebewesen | |
Palai et al. | Feasibility Insights of the Green-Assisted Calcium-Phosphate Coating on Biodegradable Zinc Alloys for Biomedical Application: In Vitro and In Vivo Studies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12727358 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012727358 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14123816 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2013158673 Country of ref document: RU Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013030644 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112013030644 Country of ref document: BR Kind code of ref document: A2 Effective date: 20131128 |