CN1390149A - 避免人体脉管再狭窄的系统和器具 - Google Patents
避免人体脉管再狭窄的系统和器具 Download PDFInfo
- Publication number
- CN1390149A CN1390149A CN00813982.2A CN00813982A CN1390149A CN 1390149 A CN1390149 A CN 1390149A CN 00813982 A CN00813982 A CN 00813982A CN 1390149 A CN1390149 A CN 1390149A
- Authority
- CN
- China
- Prior art keywords
- acyl sphingosine
- utensil
- derivant
- described system
- acyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000037803 restenosis Diseases 0.000 title claims abstract description 20
- 230000012010 growth Effects 0.000 claims abstract description 20
- 230000000975 bioactive effect Effects 0.000 claims abstract description 13
- 150000002632 lipids Chemical class 0.000 claims abstract description 12
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 claims description 120
- -1 acyl sphingosine Chemical compound 0.000 claims description 92
- 210000004204 blood vessel Anatomy 0.000 claims description 30
- 239000000463 material Substances 0.000 claims description 30
- 210000004027 cell Anatomy 0.000 claims description 25
- 241001597008 Nomeidae Species 0.000 claims description 21
- 210000002464 muscle smooth vascular Anatomy 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 206010020718 hyperplasia Diseases 0.000 claims description 14
- 238000000465 moulding Methods 0.000 claims description 13
- 239000011248 coating agent Substances 0.000 claims description 8
- 238000000576 coating method Methods 0.000 claims description 8
- 230000001771 impaired effect Effects 0.000 claims description 8
- 230000030833 cell death Effects 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 210000001519 tissue Anatomy 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 231100000915 pathological change Toxicity 0.000 claims description 5
- 230000036285 pathological change Effects 0.000 claims description 5
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000022131 cell cycle Effects 0.000 claims description 3
- 238000011287 therapeutic dose Methods 0.000 claims description 3
- 210000004509 vascular smooth muscle cell Anatomy 0.000 claims description 3
- 208000024248 Vascular System injury Diseases 0.000 claims description 2
- 208000012339 Vascular injury Diseases 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims 2
- 229930195729 fatty acid Natural products 0.000 claims 2
- 239000000194 fatty acid Substances 0.000 claims 2
- 150000004665 fatty acids Chemical class 0.000 claims 2
- 230000005012 migration Effects 0.000 claims 1
- 238000013508 migration Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 2
- 208000031481 Pathologic Constriction Diseases 0.000 abstract 1
- 208000037804 stenosis Diseases 0.000 abstract 1
- 230000036262 stenosis Effects 0.000 abstract 1
- 230000006378 damage Effects 0.000 description 23
- 210000001715 carotid artery Anatomy 0.000 description 16
- 238000011282 treatment Methods 0.000 description 15
- 238000002399 angioplasty Methods 0.000 description 14
- 238000013461 design Methods 0.000 description 10
- 230000002980 postoperative effect Effects 0.000 description 10
- 206010020880 Hypertrophy Diseases 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000026731 phosphorylation Effects 0.000 description 8
- 238000006366 phosphorylation reaction Methods 0.000 description 8
- 238000012545 processing Methods 0.000 description 7
- 208000034827 Neointima Diseases 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 238000005273 aeration Methods 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 210000002460 smooth muscle Anatomy 0.000 description 6
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 6
- 230000005540 biological transmission Effects 0.000 description 5
- 238000004043 dyeing Methods 0.000 description 5
- 238000013156 embolectomy Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 102000007469 Actins Human genes 0.000 description 4
- 108010085238 Actins Proteins 0.000 description 4
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 4
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 4
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 4
- 108091008611 Protein Kinase B Proteins 0.000 description 4
- 101710113459 RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 210000004351 coronary vessel Anatomy 0.000 description 4
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 3
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 3
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000003764 chromatophore Anatomy 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 235000021395 porridge Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 206010060965 Arterial stenosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 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 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 description 1
- 102000019040 Nuclear Antigens Human genes 0.000 description 1
- 108010051791 Nuclear Antigens Proteins 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 102000011195 Profilin Human genes 0.000 description 1
- 108050001408 Profilin Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 102000011971 Sphingomyelin Phosphodiesterase Human genes 0.000 description 1
- 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000002945 adventitial reticular cell Anatomy 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 210000003433 aortic smooth muscle cell Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 description 1
- 239000004062 cytokinin Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000000893 inhibin Substances 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940118179 lovenox Drugs 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 230000008477 smooth muscle tissue growth Effects 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Images
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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Materials For Medical Uses (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种避免在对人体脉管或具有内壁面的腔室进行干涉性手术后出现的狭窄和/或再狭窄的系统,所述系统包括沿人体血管或腔室的内壁面在必要的位置插入一涂覆有抑制生长的、脂类衍生的和生物活性的物质或所述物质的衍生物的器具。
Description
技术领域
本发明涉及一种避免人体脉管再狭窄的系统和器具。
背景技术
再狭窄是在对冠状动脉(PTCA)和其它血管进行的经皮透视血管成型术后保持血管开放的主要并发症。再狭窄是由如下诸多因素造成的:血管回缩、血管再成型失效、残余斑痕的负担和新内膜增生。新内膜增生是伴随随后在损伤部位细胞外基质成分的沉积的血管平滑肌(VSM)细胞移位和增生的反映。事实表明,就再狭窄而言,生长因素促使VSM细胞增生,导致内膜变厚。有近40%的患者在血管成型手术术后的六个月内其腔体狭窄有明显的发展。因此,虽然获得了血管成型手术的开始的治疗效果,但外科手术后几个月内流经受影响的血管的血流会再度受到损害。在血管经拉伸损伤后采用通常的包括血管紧张肽-转换酶抑制剂、抗凝剂和抑制素对避免和减少新内膜增生是无效的。对血管放射治疗经对动物和临床试验表明有一些疗效,但由于这种治疗使动脉要承受长期有害的作用,所以并不被认为是一种合适的治疗方案。
酰基鞘氨醇是鞘磷脂的生长抑制代谢产物,所述鞘磷脂是细胞膜的一种主要的类脂成分。具体地说,酰基鞘氨醇是一种存在于血浆膜中的络合类脂。可以通过鞘磷脂酶使鞘磷脂分解而产生酰基鞘氨醇。在发炎胞质分裂(IL-1、TNF和CD95配体)期间由于生长抑制和/或细胞死亡将导致此过程的加强。显然,酰基鞘氨醇起着生物活性剂的作用,所述酰基鞘氨醇可以居间调节血管平滑肌-生长抑制和/或通过直接活化激酶实现细胞编程死亡。可以预见,利用栓子切除导管的气囊端直接和立刻输送可穿透细胞的酰基鞘氨醇等或利用涂覆在支架上缓慢的输送酰基鞘氨醇的方式都将会减少VSM的增生,此点在血管成型术后对克服再狭窄是很明显的。
已知,酰基鞘氨醇通过激活c-连接N-端接激酶(JNK),实现对VSM增生的抑制,同时抑制体内的细胞外信号调节激酶(ERK)和蛋白质激酶B(PKB)。但对可穿透细胞的酰基鞘氨醇可以减少体内的VSM增生的可能性至今尚未通过试验证实。如在美国专利U.S.5,559,307中披露的内容,还已知可采用导管开启患病的动脉、体管或腔室,上述内容在此作为本发明的背景技术。但已有技术的治疗器其本身将导致在动脉中VSM大量的重新生长,此点将导致再度堵塞(即再狭窄)。
发明说明
本发明涉及一种在对人体血管或具有内壁的腔室进行干涉手术(例如血管或外科干涉)后避免狭窄和/或再狭窄的系统和器具,所述系统包括由沿人体血管或腔室的内壁在必要的位置上插入一涂覆有抑制生长的、类脂衍生的和生物活性的物质的器具。通过将物质直接传送给作用位置,可以避免随后的平滑肌细胞的再生长,因此可以克服由于伴随最初的外科手术干涉,例如血管成型术等对人体的处置而出现的发炎反应。
在一优选实施例中,本发明揭示了一种采用酰基鞘氨醇的处理,该处理将大大减少由于在颈动脉中的气囊血管成型而导致的新内膜的增生。经证明,酰基鞘氨醇将通过降低伴随损伤的细胞外信号调节激酶(ERK)和蛋白激酶B的磷酸化而实现对狭窄的缓解。如下所述,经证明,对可穿透细胞的酰基鞘氨醇的应用是一种缓解气囊血管成型术术后的狭窄的新疗法。
下面将对本发明做一详细的说明:
本发明涉及一种避免在对人体脉管或具有内壁的腔室进行干涉手术后避免狭窄和/或在狭窄的系统和器具,所述系统包括由沿人体血管或腔室的内壁在必要的位置上插入一涂覆有抑制生长的、类脂衍生的和生物活性的物质的器具。通过将物质直接和立即传送给作用位置,可以避免随后的平滑肌细胞的再生长,因此可以克服由于伴随最初的外科手术干涉,例如血管成型术等对人体的处置而出现的发炎反应。采用本发明的处理得以改善的器具包括,但并不限于此的是,简单的导管/简单的(一个)气囊设计、双气囊导管设计或支架。微孔导管设计、浸注式导管设计、旋转动脉粥斑切除器设计、聚合物(例如聚丙烯酸)覆层气囊设计、生物吸收覆层设计、支架膜和血管周基床都会得到增强和改善。
所述的“生长抑制”系指细胞(例如血管平滑肌细胞)不会对由受损的组织释放出的生长因子或细胞激动素作出反应。“类脂衍生”系指在膜上的类脂的新陈代谢时形成的物质。所以身体将对这些混合物反应产生最低限度的免疫和炎症。最后所述的“生物活性”系指因子将来自细胞的外侧膜的信息传导给细胞核,在此新的基因被激活或灭活,使细胞的表现型得以改变。例如抗有丝分裂的物质包括酰基鞘氨醇和酰基鞘氨醇衍生物,例如减少新陈代谢的类似的物质和形式。这些物质包括,但并不仅限于此的是,1-氯和1-苯甲酰(基)酰基鞘氨醇等SN-1位置的衍生物,所述衍生物并不会受到在此位置上的磷酸化的影响,以及在SN-2位置(酰胺键)的衍生物,例如氨基甲酸甲酯族或2-0-乙基替代物,所述物质不会受到酰基鞘氨酸酶衰变的影响。另外,也可以采用与酰基鞘氨醇类同的可穿透细胞形式的物质。例如这类可穿透细胞的酰基鞘氨醇和/或衍生物包含2-10个碳和具有在SN-2位置上的短链脂肪酸(C6酰基鞘氨醇)。
另外,抑制生长的、脂类衍生的、生物活性的物质例如可以是二甲基鞘氨醇、乙醚连接的二脂酰甘油酯、乙醚连接的磷脂酸和鞘氨醇。
有待涂覆的器具优选被进浸在包括二甲亚砜/乙醇的媒液中,在无菌的环境下进行实际的涂覆过程,使在器具上的可以保留有效量度的涂覆材料。接着对器具进行放射杀菌。可以针对由疏水的和亲水的覆层,以及可吸收的或聚合的基质的传送最佳地实现涂覆有酰基鞘氨醇的器具。
具体实施方式
图1示出一种包含有一个导管和单气囊设计的实施例,具有配合的气囊10的导管14被插入腔13内,所述腔被动脉壁12环围。用抑制生长的脂类衍生的生物活性的用于特殊处理的物质11对导管端15和气囊10进行涂覆,导致妨碍血流的被堵塞和/或变窄的血管的开放。
在另一优选实施例中,本发明涉及一种气囊导管和/或支架,用抑制生长的脂类衍生的生物活性的物质11对所述气囊导管和支架进行涂覆和涉及一种避免在对具有内壁面的人体血管或腔室进行干涉手术后出现再狭窄的系统,所述系统包括如下步骤:
(a)沿内壁面在在必要的位置插入用于减轻动脉狭窄的治疗器具(例如栓子切除术导管、支架和/或旋转动脉粥斑切除器),所述器具涂覆有抑制生长的脂类衍生的生物活性物质或所述物质的衍生物;
(b)对栓子切除术导管上的气囊充气或将支架设置在具有受损或病变组织的血管或腔室的部分上;
(c)(i)将材料(通过对气囊充气直接和立刻地或采用支架持续地)加在病变的部分上和(ii)由病变部分去除掉斑痕或碎屑和/或起着支架的作用;和
(d)对血管或腔室的病变或堵塞的部分进行处理。
这些步骤将防止受损血管平滑肌组织二次再生长,同时始终可以使伤口愈合。
旨在对气囊血管成型术术后就血管狭窄的涂覆有酰基鞘氨醇的栓子切除导管的治疗作用的评估,进行了试验。最初的研究对在作为时间的函数的气囊成型术术后兔子颈动脉中狭窄的程度进行了评定。动物分别在气囊损伤后1、2、4和6周死亡。最初在术后一周将观察到出现明显的新内膜增生并在四周时达到峰值(图2A)。假治疗的颈动脉在任何时候未有征兆表明新内膜增生。中间的血管平滑肌层也表明在气囊处理后严重的肥大损伤。根据该试验结果,对在气囊损伤后两周的酰基鞘氨醇对动态再狭窄VSM生长的作用进行了调研。图2B-E示出用苏木精和曙红染色的兔子颈动脉的冷冻切片。除了作为参照物的假处理的动脉(图2B)外,三个处理组分别包括一个载色剂处理的气囊(图2C)、一个C6-酰基鞘氨醇涂覆的气囊(图2D)和一个二氢-C6-酰基鞘氨醇(非活性、惰性的物质)涂覆的气囊(图2E)。意想不到地发现,采用C6-酰基鞘氨醇治疗可以明显地减少由于气囊血管成型术而导致的新内膜增生。定量分析表明作为减少新内膜/中间层比例(图2F)的结果酰基鞘氨醇将抑制掉因气囊引起的新内膜形成的92%。与此相比,作为C6-酰基鞘氨醇的非活性的同型物的二氢-C6-酰基鞘氨醇并不会减少气囊损伤后的再狭窄。所以需要采用生物活性的酰基鞘氨醇实现抑制作用并且采用结构类似但非活性的类脂是不能重复实现的。另外,可以推理出酰基鞘氨醇的疗效是由于生物化学作用,而不是由于亲油的特性造成的。
具体地说,在图2中示出C6-酰基鞘氨醇,而不是二氢-C6-酰基鞘氨醇起着在兔子的颈动脉的气囊成型术术后抑制新内膜增生的作用。最初的试验最佳地提出了一种在对新西兰白兔的颈动脉成型术术后导致在狭窄的方法。二十一只兔子被分成三个试验组,这三个组分别接受采用载色体处理导管、C6-酰基鞘氨醇处理导管或二氢-C6-酰基鞘氨醇处理导管的气囊成型手术试验。每只兔子接受相同的手术,剥离内皮公共颈动脉并建立细胞条件,促使出现再狭窄。右侧的公共颈动脉为假处理作为参照物,同时左侧颈动脉作为试验侧。在虚假参照物、载色体参照物或酰基鞘氨醇处理的动脉之间就组织湿重或细胞蛋白含量是没有明显的区别的。图2A示出血管成型手术术后再狭窄的时间过程,同时图2B-2E示出典型的苏木精/曙红染色的切片。左上部分的切片(图2B)示出作为参照物的虚假处理,同时右上部分的切片(图2C)示出采用DMOS/乙醇(1∶1,v/v)涂覆的气囊处理的动脉。下左部分的切片(图2D)示出采用C6-酰基鞘氨醇涂覆的气囊处理的动脉并且右下部分的切片(图2E)示出采用作为酰基鞘氨醇生物逻辑非活性的形式的二氢-C6-酰基鞘氨醇处理的动脉。这些显微照相的尺寸是200微米。图2F对再狭窄损伤的程度进行了量化。
在临床试验中不能实现有效治疗往往是由于在相应时间加在损伤部位的治疗剂量不是最佳的缘故。另外,疗效是由充气的气囊将酰基鞘氨醇传送给血管损伤部位的生物机械力的结果。所以,进行试验对气囊与颈动脉之间的酰基鞘氨醇的传送进行量化。采用作为示踪剂的[3H]C6-酰基鞘氨醇,计算得出作为5微摩尔的C6-酰基鞘氨醇溶液的凝胶体涂覆在气囊上的C6-酰基鞘氨醇为70±10毫微摩尔。图3A示出在插入和充气后在气囊上保留有12±2毫微摩尔。此点在血管成型手术过程中将实现由气囊导管大致58毫微摩尔的传送。为检测在颈动脉中对气囊的充气对实现酰基鞘氨醇的最佳的传送是否特别重要的,采用未充气的气囊进行了外科手术。覆盖在插入的但为充气的气囊上的酰基鞘氨醇为14±3毫微摩尔。将放射性类脂均匀地涂覆在处理的兔子的颈动脉上,并且用薄层色谱仪(TLC)对类脂产品进行分析(图3A)。采用充气的气囊处理时,血管成型手术术后15分钟被分离出的未被触及的酰基鞘氨醇的质量是2.7±0.4毫微摩尔并且采用未充气的气囊处理时为0.7±0.2毫微摩尔。被被切割的组织重新覆盖的酰基鞘氨醇的量度与作为气囊充气的结果传送给组织的酰基鞘氨醇的量度没有明显的区别。作为被传送的酰基鞘氨醇最初时分配给0.0365cm3腔体容积,在气囊损伤部位的酰基鞘氨醇的有效浓度的估计值为1.5毫摩尔/升。所以作为气囊充气的结果可以实现将酰基鞘氨醇的有效的可再现的对受损动脉的剂量分配。
采用位置自动方式造影的方法,以便确证在血管成型术后由气囊导管传送的[3H]C6-酰基鞘氨醇对动脉的渗透(图3B至3D)。与未被失踪的动脉(照片B)相比,在血管成型手术后15分钟[3H]C6-酰基鞘氨醇渗透过动脉的中间层(照片C)。此点将提高表明未触及的酰基鞘氨醇增多的象素密度,例如在此时间点采用经认证的C6-酰基鞘氨醇标准为放射示踪荧光光栅的89±4%。充气时的动脉的(照片C)象素密度大于非充气时的动脉的(照片D)的象素密度。当对10个随机选取的组的每平方毫米的的象素密度用提取的底数表示时,则与未充气的气囊相比,酰基鞘氨醇涂覆的充气气囊的平均染色增长4.7±0.2倍。此点再次支持了气囊充气将导致最大的传送和穿透的结论。因此涂覆类脂的气囊将把酰基鞘氨醇的治疗剂量传送给血管拉伸损伤部位的组织并表明,少量的使用可穿透细胞的酰基鞘氨醇足以完全渗透到受损动脉内并在发炎的环境下也可减少内膜增生。
同时还对采用TLC快速介入放射示踪的酰基鞘氨醇的衰变进行了评估。在15分钟血管成型术术后时间点,采用经认证的C6-酰基鞘氨醇标准,TLC分离的类脂的荧光光栅为89±4%。这相当于补偿的酰基鞘氨醇的质量为2.7±0.4毫微摩尔。在血管成型手术术后60分钟,补偿1.3±0.6毫微摩尔。因此,在1小时后作为未触及的酰基鞘氨醇仍可以补偿50%放射示踪。此点将与提高TLC分离的神经节苷脂和脑苷,但不包括鞘氨醇,相符减少酰基鞘氨醇质量。
这里要指出的是,浸注型导管的优点是,可以以个别的剂量将在BSA-载体上的酰基鞘氨醇输送给动脉伤损部位。因此可以确定采用浸注型导管通过溶液输送的酰基鞘氨醇是否与具有涂覆在气囊端的凝胶的导管输送的酰基鞘氨醇减少狭窄的效果相同。对在图4F所示的动脉双腔冲洗栓子切除术导管端的气囊充气,使其直径等于前面试验时的直径。每1分钟三次浸注10毫微摩尔C6-酰基鞘氨醇将减少血管成型术后狭窄的39%。但相同剂量的二氢-C6-酰基鞘氨醇对狭窄损伤无效。这些研究进一步支持酰基鞘氨醇涂覆的气囊导管以及动脉内侧部位-专用分配器具的新颖性和有效性。
为避免血栓的形成,患者在接受经皮的穿透腔体的冠状动脉成型术治疗之前患者必须例行接受抗凝固剂治疗。所以对抗凝固剂治疗对酰基鞘氨醇治疗效果的作用做了研究。不管是酰基鞘氨醇-还是载体处理气囊血管成型都不会导致形成血栓。在外科手术后7天皮下注射(2.5mg/kg)Lovenox(一种低分子量肝素)本身并不会减少狭窄并加强由酰基鞘氨醇导致的对狭窄的抑制作用,因而可以得出如下提示,酰基鞘氨醇处理与两种抗凝固治疗和未处理的记录的效果相同。
同时还对酰基鞘氨醇治疗对体内VSM细胞生长的作用做了研究。采用免疫组织化学技术确定平滑肌细胞-特异性的肌动蛋白抗体(图4A-4B)的VSM和采用增生细胞核抗原(PCNA)抗体(图4C-F)时的细胞生长。采用肌动蛋白的抗体时的阳性染色表明VSM是气囊损伤导致的新内膜的形成的主要成分(图4B)。该显微照片示出气囊成型术导致明显褶皱和VSM在中间层的分散。在细胞循环周期的早期的G1和S阶段中被合成PCNA,并被作为细胞增生的标志。在图4C-F中,分别针对参照气囊损伤的、经酰基鞘氨醇治疗和经二氢-酰基鞘氨醇治疗的颈动脉示出PCNA阳性染色的典型的显微照片。与参照血管(0.2%±0.1%)相比,在气囊损伤的动脉中的PCNA阳性细胞的百分比(2.8%±0.1%)得到大幅度的提高。正是C6-酰基鞘氨醇(0.6%±0.1%),而不是二氢-C6-酰基鞘氨醇可以减少在新内膜层内的,而不是颈动脉中间层内的PCNA阳性细胞的数量。该数据表明,酰基鞘氨醇通过减少在血管壁损伤后进入细胞循环周期内的VSM的百分比可以减少新内膜增生。
具体地说,在图4中示出,在血管成型术后酰基鞘氨醇处理的导管将减少表现在血管平滑肌细胞的PCNA。通过采用单细胞抗-α平滑肌抗体的免疫组织化学对平滑肌肌动蛋白的表示进行分析,并且采用用于PCNA的鼠原代单细胞IgG2a抗体对PCNA阳性细胞数量进行评估。用染色检验载片代替具有非特异性的鼠IgG的原代抗体并未显示出特异性或选择性的染色。照片A-B分别表示作为参照物和作为气囊损伤的动脉的平滑肌肌动蛋白染色,同时照片C-F分别表示作为参照物的、气囊损伤的、酰基鞘氨醇涂覆的气囊损伤的和二氢-酰基鞘氨醇涂覆的气囊损伤的颈动脉。这些显微照片的尺寸为200微米。
体内研究的数据表明酰基鞘氨醇通过抑制导致生长因素的细胞外信号调整激酶(ERP)级联并且有时通过抑制蛋白激酶B(PKB)级联可阻止细胞的生长。所以为了阐明酰基鞘氨醇避免再狭窄的机理,采用血管成型术后新鲜的颈动脉切片对ERK2和PKBα的磷酸化状态进行了研究(图5)。在气囊损伤后15分钟和24小时将增大ERK2和PKBα的磷酸化。这些激酶的不断的磷酸化很易于反映了受损动脉的连续的再成型。在酰基鞘氨醇处理后紧接着这些激酶的磷酸化状态被降低到基础活性的程度。因此,应急酰基鞘氨醇治疗将直接对激酶进行调整或调整假想的酰基鞘氨醇激活的蛋白磷酸酶,这些将实现信号路径的下调。
具体地说,如图5中所示,在兔子的颈动脉上进行酰基鞘氨醇涂覆的气囊血管成型术后将减少ERK2和PKBα的磷酸化。图片A示出采用磷酸化-特异性抗体试验时的典型的ERK-2和PKBα的韦斯特(Western)斑。采用或不采用PDGF处理的NIH3T3细胞的溶解产物分别作为阳性的和阴性的参照物。该免疫斑是采用8只动物进行相同的试验得出的典型数据。图片B-C对免疫斑数据进行了量化。
预先表明,C6-酰基鞘氨醇模拟了A7r5主动脉平滑肌细胞和鼠的肾小球膜细胞的IL-1抑制酪氨酸激酶受体-和G-蛋白受体-连接的促有丝分裂作用。酰基鞘氨醇处理与在G0G1处的阻止生长相关联并且不会在这些平滑肌细胞类似的外膜细胞中编程细胞死亡。本发明表明,与根据采用预先所述的成对物鉴别记录在对丙锭碘化物染色后采用荧光激活细胞分类的评估相同,C6-酰基鞘氨醇在原代VSM中不会有明显的编程细胞死亡,所述原代VSM是由兔子的颈动脉中分离出的。具体地说,采用5微摩尔C6-酰基鞘氨醇或双氢-C6-酰基鞘氨醇分别经24小时或40小时处理的原代兔子的VSM表明编程细胞死亡少于1%。作为参照物,采用冈田酸进行的处理(100毫微摩尔)将在24小时(52%)和40小时(69%±2%)后明显地导致编程细胞死亡。穿透细胞的酰基鞘氨醇对狭窄的疗效包括其可以防止VSM的生长,而不会导致明显地编程细胞死亡。
其它的可穿透细胞的酰基鞘氨醇衍生物也可以起着限制新内膜增生的作用。酰基鞘氨醇衍生物,其中可以用二甲基碳水化合物的部分替代酰胺结合的脂酰辅酶链,例如二甲基鞘氨醇对限制由于损伤导致的增生也是有效的。
虽然选择的酰基鞘氨醇代谢交织在粥样硬化、糖尿病和癌病中,但尚未将酰基鞘氨醇等考虑作为对增生血管病症治疗的药物。在动脉粥样硬化和糖尿病的情况下,将在消耗内源酰基鞘氨醇的同时增大乳糖-和葡萄糖-酰基鞘氨醇共轭物的浓度,并且此点将伴随VSM增生和血管收缩而减少体内酰基鞘氨醇。在耗尽内源酰基鞘氨醇的情况下,可以考虑采用外原酰基鞘氨醇等作为抗动脉血管粥样硬化的药剂。本发明表明,酰基鞘氨醇是一种非常有效的避免血管成型术后再狭窄的候选药物。本发明对治疗诸如冠状动脉、肾动脉和股动脉的狭窄也是有效的,并且具有多种应用,例如作为门腔静脉分流术或阻塞的隐静脉曲张以及用于冠状动脉搭桥术等。另外本发明还可用于糖尿病视网膜病,其中平滑肌类细胞被激活并且视网膜前端增生,导致失明。还可以将局部输送的酰基鞘氨醇用于潜在的治疗在透析后血管接口管狭窄造成的平滑肌生长障碍的治疗。另外除了将药剂涂覆在气囊导管端,通过浸注口或涂覆在支架上,可以将该抗促有丝分裂鞘脂衍生物作为传统的或阳离子脂质矢量的成分进行输送,因而可以潜在地改善基因转移的效率和定向。
所以,本发明表明,当将酰基鞘氨醇或其它的防止生长、类脂的衍生物涂覆在气囊或支架上实现局部用药时,可实现对损伤部位的平滑肌细胞生长的抑制。另外,酰基鞘氨醇或其它的防止生长、类脂衍生的、生物活性的物质可以利用浸注或微孔导管设计以实现固定的剂量的输送。浸注导管是通过与充气气囊相背的口实现物质的输送。微孔导管是通过在气囊表面上微细的孔眼实现物质的输送的。而且本发明的物质还可以通过双气囊、浸注口、导管设计,被隔离在两个充气气囊之间,实现对受损动脉壁的输送。根据本发明的一优选实施例,C6-酰基鞘氨醇,一种可穿透细胞的酰基鞘氨醇,可以抑制在血管成型部位上的平滑肌细胞的增生。另外,其它的可穿透细胞的酰基鞘氨醇衍生物也可以限制新内膜的增生。酰基鞘氨醇的衍生物,其中可以用二甲基碳水化合物的部分替代酰胺结合的脂酰辅酶链,对限制血管成型导致的损伤也是有效的。
Claims (18)
1.一种避免在对人体血管或具有一个内壁面的腔室进行干涉性手术后出现再狭窄的系统,所述系统包括沿人体血管或腔室的内壁面在必要的位置插入一涂覆有抑制生长的、脂类衍生的和生物活性的物质或所述物质的衍生物的器具。
2.按照权利要求1所述的系统,其中所述器具是导管或支架。
3.按照权利要求1所述的系统,其中所述的抑制生长的、脂类衍生的、生物活性的物质是由酰基鞘氨醇、二甲基鞘氨醇、乙醚连接的二脂酰甘油酯、乙醚连接的磷脂酸、鞘氨醇或前者的衍生物构成的组中选出的一种。
4.按照权利要求3所述的系统,另外还包括如下步骤:
(a)沿内壁面在必要的位置插入包括有抑制生长的、脂类衍生的、生物活性的物质的治疗器具;
(b)将器具设置在具有受损或病变的组织的血管或腔室的一部分内;
(c)(i)将材料加在病变的部分上和(ii)由病变部分去除掉斑痕或碎屑或起着支架的作用;和
(d)对血管或腔室的病变的部分进行处理。
5.按照权利要求4所述的系统,其中酰基鞘氨醇衍生物包含有2-10个碳的可穿透细胞的脂肪酸。
6.按照权利要求4所述的系统,其中酰基鞘氨醇的输送是通过与涂覆有酰基鞘氨醇充气的气囊相背一浸注口实现的。
7.按照权利要求4所述的系统,其中酰基鞘氨醇衍生物是C6-酰基鞘氨醇。
8.按照权利要求4所述的系统,其中所述器具减少因气囊血管成型或支撑造成的内膜增生。
9.按照权利要求4所述的系统,其中器具将酰基鞘氨醇的治疗剂量输送到血管损伤部位。
10.按照权利要求8所述的系统,所述器具通过降低血管壁受损后开始的细胞周期的血管平滑肌的百分比减少内膜增生。
11.按照权利要求10所述的系统,所述器具减少血管平滑肌细胞增生和迁移的百分比例,而不会导致的明显的编程细胞死亡。
12.一种用于避免在对具有内壁面的人体血管或腔室进行干涉性手术后出现的狭窄的系统,所述系统包括沿人体血管或腔室的内壁面的必要位置上插入一个器具,所述器具涂覆有抑制生长、脂类衍生的、生物活性的物质或其衍生物。
13.按照权利要求12所述的系统,所述的抑制生长的、脂类衍生的、生物活性的物质是由酰基鞘氨醇、二甲基鞘氨醇、乙醚连接的二脂酰甘油酯、乙醚连接的磷脂酸、鞘氨醇或前者的衍生物构成的组中选出的一种。
14.一种用于避免在对具有内壁面的人体血管或腔室进行干涉性手术后出现的狭窄和再狭窄的器具,所述器具包括一抑制生长的、脂类衍生的、生物活性的物质或前者的衍生物的覆层。
15.按照权利要求14所述的器具,其中所述的抑制生长的、脂类衍生的、生物活性的物质是由酰基鞘氨醇、二甲基鞘氨醇、乙醚连接的二脂酰甘油酯、乙醚连接的磷脂酸、鞘氨醇或前者的衍生物构成的组中选出的一种。
16.按照权利要求15所述的器具,其中酰基鞘氨醇衍生物是包含有2-10个碳的可穿透细胞的脂肪酸。
17.按照权利要求15所述的器具,其中酰基鞘氨醇衍生物是C6-酰基鞘氨醇。
18.按照权利要求15所述的器具,其中所述人体脉管是血管。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15796099P | 1999-10-06 | 1999-10-06 | |
US60/157,960 | 1999-10-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1390149A true CN1390149A (zh) | 2003-01-08 |
Family
ID=22566085
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN00813982.2A Pending CN1390149A (zh) | 1999-10-06 | 2000-10-05 | 避免人体脉管再狭窄的系统和器具 |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP1221997B1 (zh) |
JP (1) | JP2003511110A (zh) |
CN (1) | CN1390149A (zh) |
AU (1) | AU773899B2 (zh) |
CA (1) | CA2386007A1 (zh) |
DE (1) | DE60037264D1 (zh) |
RU (1) | RU2002108119A (zh) |
WO (1) | WO2001024866A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102470196A (zh) * | 2009-08-27 | 2012-05-23 | 泰尔茂株式会社 | 药物输送用医疗器具 |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6955661B1 (en) | 1999-01-25 | 2005-10-18 | Atrium Medical Corporation | Expandable fluoropolymer device for delivery of therapeutic agents and method of making |
US7947015B2 (en) | 1999-01-25 | 2011-05-24 | Atrium Medical Corporation | Application of a therapeutic substance to a tissue location using an expandable medical device |
DE10115740A1 (de) | 2001-03-26 | 2002-10-02 | Ulrich Speck | Zubereitung für die Restenoseprophylaxe |
EP1485042A1 (en) * | 2002-03-18 | 2004-12-15 | Medtronic AVE Inc. | Medical devices for delivering anti-proliferative compositions to anatomical sites at risk of restenosis |
EP2324866B1 (en) | 2002-07-12 | 2014-06-18 | Cook Medical Technologies LLC | Angioplasty balloons drug-coated in an expanded condition |
DE10244847A1 (de) | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medizinische Vorrichtung zur Arzneimittelabgabe |
US20040224003A1 (en) | 2003-02-07 | 2004-11-11 | Schultz Robert K. | Drug formulations for coating medical devices |
US8021331B2 (en) | 2003-09-15 | 2011-09-20 | Atrium Medical Corporation | Method of coating a folded medical device |
WO2005027996A2 (en) | 2003-09-15 | 2005-03-31 | Atrium Medical Corporation | Application of a therapeutic substance to a tissue location using an expandable medical device |
WO2005039556A1 (ja) * | 2003-10-29 | 2005-05-06 | Institute Of Medicinal Molecular Design. Inc. | 血行再建術後の再狭窄又は再閉塞の治療及び/又は予防のための医薬 |
US9000040B2 (en) | 2004-09-28 | 2015-04-07 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US9801982B2 (en) | 2004-09-28 | 2017-10-31 | Atrium Medical Corporation | Implantable barrier device |
US9801913B2 (en) | 2004-09-28 | 2017-10-31 | Atrium Medical Corporation | Barrier layer |
US9012506B2 (en) | 2004-09-28 | 2015-04-21 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US8263102B2 (en) | 2004-09-28 | 2012-09-11 | Atrium Medical Corporation | Drug delivery coating for use with a stent |
US9278161B2 (en) | 2005-09-28 | 2016-03-08 | Atrium Medical Corporation | Tissue-separating fatty acid adhesion barrier |
US9427423B2 (en) | 2009-03-10 | 2016-08-30 | Atrium Medical Corporation | Fatty-acid based particles |
CA2626030A1 (en) | 2005-10-15 | 2007-04-26 | Atrium Medical Corporation | Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings |
US10045953B2 (en) | 2006-07-06 | 2018-08-14 | Case Western Reserve University | Ceramide composition and method of use |
US9492596B2 (en) | 2006-11-06 | 2016-11-15 | Atrium Medical Corporation | Barrier layer with underlying medical device and one or more reinforcing support structures |
WO2008057328A2 (en) | 2006-11-06 | 2008-05-15 | Atrium Medical Corporation | Tissue separating device with reinforced support for anchoring mechanisms |
US9126025B2 (en) | 2008-05-01 | 2015-09-08 | Bayer Intellectual Property Gmbh | Method of coating a folded catheter balloon |
US20110038910A1 (en) | 2009-08-11 | 2011-02-17 | Atrium Medical Corporation | Anti-infective antimicrobial-containing biomaterials |
EP2593141B1 (en) | 2010-07-16 | 2018-07-04 | Atrium Medical Corporation | Composition and methods for altering the rate of hydrolysis of cured oil-based materials |
WO2013162366A1 (en) | 2012-04-27 | 2013-10-31 | Stichting Vu-Vumc | Protection of materials by sphingosine based compounds |
US9867880B2 (en) | 2012-06-13 | 2018-01-16 | Atrium Medical Corporation | Cured oil-hydrogel biomaterial compositions for controlled drug delivery |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6515009B1 (en) * | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5634901A (en) * | 1992-11-02 | 1997-06-03 | Localmed, Inc. | Method of using a catheter sleeve |
WO1994021308A1 (en) * | 1993-03-18 | 1994-09-29 | Cedars-Sinai Medical Center | Drug incorporating and releasing polymeric coating for bioprosthesis |
US5509899A (en) * | 1994-09-22 | 1996-04-23 | Boston Scientific Corp. | Medical device with lubricious coating |
US5830430A (en) * | 1995-02-21 | 1998-11-03 | Imarx Pharmaceutical Corp. | Cationic lipids and the use thereof |
-
2000
- 2000-10-05 CA CA002386007A patent/CA2386007A1/en not_active Abandoned
- 2000-10-05 EP EP00968771A patent/EP1221997B1/en not_active Expired - Lifetime
- 2000-10-05 CN CN00813982.2A patent/CN1390149A/zh active Pending
- 2000-10-05 DE DE60037264T patent/DE60037264D1/de not_active Expired - Lifetime
- 2000-10-05 RU RU2002108119/14A patent/RU2002108119A/ru not_active Application Discontinuation
- 2000-10-05 AU AU78637/00A patent/AU773899B2/en not_active Ceased
- 2000-10-05 WO PCT/US2000/027565 patent/WO2001024866A1/en active IP Right Grant
- 2000-10-05 JP JP2001527865A patent/JP2003511110A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102470196A (zh) * | 2009-08-27 | 2012-05-23 | 泰尔茂株式会社 | 药物输送用医疗器具 |
Also Published As
Publication number | Publication date |
---|---|
EP1221997B1 (en) | 2007-11-28 |
JP2003511110A (ja) | 2003-03-25 |
DE60037264D1 (de) | 2008-01-10 |
EP1221997A4 (en) | 2006-05-31 |
WO2001024866A1 (en) | 2001-04-12 |
AU773899B2 (en) | 2004-06-10 |
AU7863700A (en) | 2001-05-10 |
RU2002108119A (ru) | 2003-11-27 |
CA2386007A1 (en) | 2001-04-12 |
EP1221997A1 (en) | 2002-07-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1390149A (zh) | 避免人体脉管再狭窄的系统和器具 | |
US6682545B1 (en) | System and device for preventing restenosis in body vessels | |
US6645464B1 (en) | Loading metal particles into cell membrane vesicles and metal particular use for imaging and therapy | |
JP2828433B2 (ja) | 強化された感染抵抗を有する筋肉内刺激リード | |
McDannold et al. | Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption | |
Nelson et al. | Ultrasonically activated chemotherapeutic drug delivery in a rat model | |
WO1996022111A1 (en) | Local delivery and monitoring of drugs | |
US20150224221A1 (en) | Method for preparing microspheres for emboli, and method for preparing microspheres to which drug-containing carrier is bound | |
CN107073178A (zh) | 提供药物微贮库的接触转移的管腔内可扩张导管的涂层 | |
Deaciuc et al. | Modulation of hepatic sinusoidal endothelial cell function by Kupffer cells: an example of intercellular communication in the liver | |
JP7053463B2 (ja) | 超音波システムを使用して脳腫瘍を治療するための方法及びキット | |
Lis et al. | Leksell gamma knife lesioning of the rat hippocampus: the relationship between radiation dose and functional and structural damage | |
CN106693040A (zh) | 一种可载药聚乙烯醇洗脱微球的制备方法 | |
CN102256596A (zh) | 用于增强对流递送到中枢神经中心的脂质体组合物 | |
Geraci et al. | Radiation hepatology of the rat: microvascular fibrosis and enhancement of liver dysfunction by diet and drugs | |
Hamilton et al. | Statin treatment of hypercholesterolemic-induced aortic valve sclerosis | |
Leré et al. | A model of ‘epileptic tolerance’for investigating neuroprotection, epileptic susceptibility and gene expression-related plastic changes | |
Durand et al. | Tumour blood flow influences combined radiation and doxorubicin treatments | |
EP3558408B1 (en) | Intratumoral drug delivery materials and methods for treating breast cancer | |
US20080260790A1 (en) | Plasmid Enhancement Agent for High Intensity Focused Ultrasound Treatment and Use Thereof | |
CN115141319A (zh) | 工程化放射性聚合物微球及其制备方法和用途 | |
Gregoriadis | The physiology of the liposome | |
Nguyen et al. | Perivascular innate immune events modulate early murine vein graft adaptations | |
Braunhut | Protection against radiation damage to vascular tissues | |
Sridhar-Keralapura et al. | Structural changes and imaging signatures of acoustically sensitive microcapsules under ultrasound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |