AU2013245532B2 - Articles and methods of treating vascular conditions - Google Patents
Articles and methods of treating vascular conditions Download PDFInfo
- Publication number
- AU2013245532B2 AU2013245532B2 AU2013245532A AU2013245532A AU2013245532B2 AU 2013245532 B2 AU2013245532 B2 AU 2013245532B2 AU 2013245532 A AU2013245532 A AU 2013245532A AU 2013245532 A AU2013245532 A AU 2013245532A AU 2013245532 B2 AU2013245532 B2 AU 2013245532B2
- Authority
- AU
- Australia
- Prior art keywords
- vascular
- gel material
- treatment site
- bioactive agent
- blood
- 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.)
- Active
Links
- 230000002792 vascular Effects 0.000 title claims abstract description 359
- 238000000034 method Methods 0.000 title claims abstract description 77
- 239000000463 material Substances 0.000 claims abstract description 326
- 239000012867 bioactive agent Substances 0.000 claims abstract description 92
- 230000009974 thixotropic effect Effects 0.000 claims abstract description 74
- 239000000499 gel Substances 0.000 claims description 307
- 238000011282 treatment Methods 0.000 claims description 209
- 239000008280 blood Substances 0.000 claims description 71
- 210000004369 blood Anatomy 0.000 claims description 71
- 229960003957 dexamethasone Drugs 0.000 claims description 55
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 55
- 230000017531 blood circulation Effects 0.000 claims description 52
- 210000004204 blood vessel Anatomy 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 44
- 229920000858 Cyclodextrin Polymers 0.000 claims description 34
- 239000000017 hydrogel Substances 0.000 claims description 34
- 239000003814 drug Substances 0.000 claims description 26
- 229960005309 estradiol Drugs 0.000 claims description 24
- 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 claims description 23
- 229940079593 drug Drugs 0.000 claims description 23
- 229930182833 estradiol Natural products 0.000 claims description 23
- 229920000642 polymer Polymers 0.000 claims description 22
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 21
- 239000007924 injection Substances 0.000 claims description 16
- 238000002347 injection Methods 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 206010020718 hyperplasia Diseases 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 230000008439 repair process Effects 0.000 claims description 6
- 208000019553 vascular disease Diseases 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 230000001028 anti-proliverative effect Effects 0.000 claims description 4
- 230000000975 bioactive effect Effects 0.000 claims description 4
- 230000002269 spontaneous effect Effects 0.000 claims description 4
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 claims description 3
- 229960004195 carvedilol Drugs 0.000 claims description 3
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 claims description 3
- 229960004588 cilostazol Drugs 0.000 claims description 3
- 239000011159 matrix material Substances 0.000 claims description 3
- 230000002459 sustained effect Effects 0.000 claims description 3
- 239000012530 fluid Substances 0.000 abstract description 16
- 238000002513 implantation Methods 0.000 abstract description 12
- 210000001519 tissue Anatomy 0.000 description 118
- 239000000243 solution Substances 0.000 description 107
- 241000282465 Canis Species 0.000 description 40
- 210000003462 vein Anatomy 0.000 description 29
- -1 poly(methacrylic acid) Polymers 0.000 description 24
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 21
- 229910052722 tritium Inorganic materials 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 20
- 238000002156 mixing Methods 0.000 description 20
- 239000002953 phosphate buffered saline Substances 0.000 description 20
- 229920001223 polyethylene glycol Polymers 0.000 description 20
- 239000002202 Polyethylene glycol Substances 0.000 description 19
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)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 HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 19
- 238000002583 angiography Methods 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 229920001971 elastomer Polymers 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 11
- 208000014674 injury Diseases 0.000 description 11
- 230000005855 radiation Effects 0.000 description 10
- 239000002872 contrast media Substances 0.000 description 9
- 230000029087 digestion Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 230000000717 retained effect Effects 0.000 description 9
- 230000008733 trauma Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 description 8
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 8
- 210000001367 artery Anatomy 0.000 description 8
- 210000003191 femoral vein Anatomy 0.000 description 8
- 230000007774 longterm Effects 0.000 description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000012800 visualization Methods 0.000 description 8
- 238000002399 angioplasty Methods 0.000 description 7
- 229910021538 borax Inorganic materials 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 235000010339 sodium tetraborate Nutrition 0.000 description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 238000003780 insertion Methods 0.000 description 6
- 230000037431 insertion Effects 0.000 description 6
- 238000011002 quantification Methods 0.000 description 6
- 238000003345 scintillation counting Methods 0.000 description 6
- 230000003381 solubilizing effect Effects 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- 230000028709 inflammatory response Effects 0.000 description 5
- 210000004731 jugular vein Anatomy 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 150000005829 chemical entities Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229960002086 dextran Drugs 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 229920001282 polysaccharide Polymers 0.000 description 4
- 239000005017 polysaccharide Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- 239000004328 sodium tetraborate Substances 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 3
- 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 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000031481 Pathologic Constriction Diseases 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000003872 anastomosis Effects 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000009969 flowable effect Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 208000001297 phlebitis Diseases 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 208000037804 stenosis Diseases 0.000 description 3
- 230000036262 stenosis Effects 0.000 description 3
- 238000011477 surgical intervention Methods 0.000 description 3
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 3
- 210000005166 vasculature Anatomy 0.000 description 3
- 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
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 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
- 241001427367 Gardena Species 0.000 description 2
- 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 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 208000024248 Vascular System injury Diseases 0.000 description 2
- 206010070693 Vascular dissection Diseases 0.000 description 2
- 206010062910 Vascular infections Diseases 0.000 description 2
- 208000012339 Vascular injury Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 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 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 2
- 229960001912 dicoumarol Drugs 0.000 description 2
- HIZKPJUTKKJDGA-UHFFFAOYSA-N dicumarol Natural products O=C1OC2=CC=CC=C2C(=O)C1CC1C(=O)C2=CC=CC=C2OC1=O HIZKPJUTKKJDGA-UHFFFAOYSA-N 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 238000010562 histological examination Methods 0.000 description 2
- 230000000266 injurious effect Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 208000030613 peripheral artery disease Diseases 0.000 description 2
- 239000003186 pharmaceutical solution Substances 0.000 description 2
- 230000006461 physiological response Effects 0.000 description 2
- 229920002239 polyacrylonitrile Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000518 rheometry Methods 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 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 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- PRRZDZJYSJLDBS-UHFFFAOYSA-N 3-bromo-2-oxopropanoic acid Chemical compound OC(=O)C(=O)CBr PRRZDZJYSJLDBS-UHFFFAOYSA-N 0.000 description 1
- SATHPVQTSSUFFW-UHFFFAOYSA-N 4-[6-[(3,5-dihydroxy-4-methoxyoxan-2-yl)oxymethyl]-3,5-dihydroxy-4-methoxyoxan-2-yl]oxy-2-(hydroxymethyl)-6-methyloxane-3,5-diol Chemical compound OC1C(OC)C(O)COC1OCC1C(O)C(OC)C(O)C(OC2C(C(CO)OC(C)C2O)O)O1 SATHPVQTSSUFFW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 229920000189 Arabinogalactan Polymers 0.000 description 1
- 239000001904 Arabinogalactan Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- UEENYRGPBCHSLB-UHFFFAOYSA-N Cyclomulberrochromen Natural products O1C(C)(C)C=CC2=C1C=C1OC(C3=CC=C(O)C=C3OC3C=C(C)C)=C3C(=O)C1=C2O UEENYRGPBCHSLB-UHFFFAOYSA-N 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
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 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
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002125 Sokalan® Polymers 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
- 108090000190 Thrombin Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSNOZLZNQMLSKJ-UHFFFAOYSA-N Trapidil Chemical compound CCN(CC)C1=CC(C)=NC2=NC=NN12 GSNOZLZNQMLSKJ-UHFFFAOYSA-N 0.000 description 1
- 208000035868 Vascular inflammations Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002769 anti-restenotic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000019312 arabinogalactan Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000002302 brachial artery Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229930188773 cudraflavone Natural products 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- JVHIPYJQMFNCEK-UHFFFAOYSA-N cytochalasin Natural products N1C(=O)C2(C(C=CC(C)CC(C)CC=C3)OC(C)=O)C3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 JVHIPYJQMFNCEK-UHFFFAOYSA-N 0.000 description 1
- ZMAODHOXRBLOQO-UHFFFAOYSA-N cytochalasin-A Natural products N1C(=O)C23OC(=O)C=CC(=O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 ZMAODHOXRBLOQO-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000012282 endovascular technique Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229950010152 halofuginone Drugs 0.000 description 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 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
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 210000003090 iliac artery Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 1
- 229960001025 iohexol Drugs 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
- 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
- 229960002437 lanreotide Drugs 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- DDVBPZROPPMBLW-ZJBINBEQSA-N latrunculin a Chemical compound C([C@H]1[C@@]2(O)C[C@H]3C[C@H](O2)CC[C@@H](/C=C\C=C/CC\C(C)=C/C(=O)O3)C)SC(=O)N1 DDVBPZROPPMBLW-ZJBINBEQSA-N 0.000 description 1
- DDVBPZROPPMBLW-UHFFFAOYSA-N latrunculin-A Natural products O1C(=O)C=C(C)CCC=CC=CC(C)CCC(O2)CC1CC2(O)C1CSC(=O)N1 DDVBPZROPPMBLW-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000002324 minimally invasive surgery Methods 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- GLBLPMUBLHYFCW-UHFFFAOYSA-N n-(5,7-dimethoxy-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonamide Chemical compound N1=C2N=C(OC)C=C(OC)N2N=C1NS(=O)(=O)C1=C(OC)N=CC=C1C(F)(F)F GLBLPMUBLHYFCW-UHFFFAOYSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical class [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 229920000083 poly(allylamine) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 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 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 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 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 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
- 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 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth 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
- 229960005342 tranilast Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960000363 trapidil Drugs 0.000 description 1
- 230000003144 traumatizing effect Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 230000006439 vascular pathology Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000000196 viscometry Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Abstract
The present invention relates to articles and methods of treating vascular conditions with a thixotropic, turbid, bioactive agent-containing gel 5 material capable of being essentially removed from an implantation site upon re-establishment of fluid flow at the implantation site. 4709060) (GHMaierS) PI80S.AU.1
Description
ARTICLES AND METHODS OF TREATING VASCULAR CONDITIONS Field of the Invention The present invention relates to articles and methods of vascular-based 5 therapies to treat a variety of vascular conditions. The present application is a divisional application from Australian Patent Application No. 2010223044, the entire disclosure of which is incorporated into the present specification by this cross-reference. 10 Background of the Invention Vascular conditions arise from a variety of causes, and in some cases, necessitate surgical or endovascular intervention. Trauma to the vascular system may also necessitate surgical intervention to treat the traumatized anatomy. The long-term implantation of vascular prostheses including vascular grafts, stent-grafts, 5 and stents, and the application of treatment modalities, including balloon angioplasty are often undertaken to treat vascular conditions including vascular disease and vascular trauma. Consequences of surgical intervention have been observed following implantation of vascular prostheses including vascular grafts, stent-grafts, stents, £ and other prostheses, particularly when an anastomosis is formed. The consequences of surgical intervention include, but are not limited to, inflammation, intimal hyperplasia, stenosis, and restenosis of the treated blood vessel near the formed anastomosis. Inflammation is a physiological response by a mammalian body to surgery, injury, irritation, or infection. An inflammatory response involves 25 complex biological activities at chemical, cellular, tissue, and organ levels. Generally, an inflammatory response is a protective attempt to remove an injurious stimulus, as well as to initiate a healing process for the diseased or traumatized tissue. Intimal hyperplasia is a pathological condition in which an overabundant inflammatory response is initiated involving stimulation, migration, and proliferation of 30 numerous cell types. Stenosis and restenosis are constrictions of the blood vessel lumen and may be caused by mechanisms including, but not limited to, compliance mismatch between the native vessel and the implanted vascular prosthesis, host tissue response to an implanted material, prior disease states, and infection. Stenosis and restenosis can progress to a point where additional surgical 35 intervention is required to enlarge the blood vessel lumen diameter of the blood
I
vessel or the implanted vascular prosthesis to establish a less restrictive conduit for blood flow. Additional vascular conditions that may require surgical or endovascular intervention include, but are not limited to, vascular injury, vascular prophylactic 5 intervention, vascular disease, phlebitis, intimal hyperplasia, vulnerable plaques, carotid plaques, coronary plaque, vascular plaque, aneurismal disease, vascular dissections, atherosclerotic plaques, atherosclerotic lesions, vascular infection, and vascular sepsis. One approach to treatment of these vascular conditions involves local delivery 10 of a suitable pharmaceutical or biologically active agent in a liquid vehicle within luminal spaces of a blood vessel at or near the site of the vascular condition. The liquid vehicle containing the pharmaceutical or biologically active agent is contacted with tissues of the luminal space at a vascular treatment site for a determined length of time (dwell time). However, this approach often requires extensive dwell times at 15 the vascular treatment site to ensure adequate delivery and retention of the bioactive agent at the vascular treatment site to treat the vascular condition. Even with extensive dwell times, the delivery and retention of the bioactive agent at the vascular treatment site using this approach may be insufficient to treat the vascular condition. 20 Another therapeutic approach is the implantation of vascular prostheses having a pharmaceutical-containing coating to deliver a pharmaceutical to a lumen of a blood vessel or other vascular conduit. Examples of vascular prostheses having a pharmaceutical-containing coating include, but are not limited to, stents, stent grafts, grafts, and angioplasty balloons. Other examples of vascular prostheses having a 25 pharmaceutical-containing coating are drug eluting stents and drug eluting stent grafts (DESs). DESs are used in the treatment of coronary artery disease and peripheral artery disease. A high degree of physician skill is often required to implant DESs without damaging or traumatizing surrounding vascular tissue, The treatment of a vascular condition by the implantation of DESs may require long term 30 implantation of the vascular prosthesis. The long term implantation of the vascular prosthesis may also result in mechanical trauma to the vascular treatment site due to a nonlubricious nature of the pharmaceutical-containing coating. The long term implantation of the vascular prosthesis may also result in an unwanted tissue reaction at the vascular treatment site due to the components of the vascular 2 prosthesis and/or the pharmaceutical-containing coating. Therefore it is desirable to have an improved method for treating vascular conditions that requires minimal physician skill to perform. It is desirable to have an improved method for treating vascular conditions that avoids long term implants. 5 Drug eluting balloons (DEBs) are additional examples of vascular prostheses having a pharmaceutical-containing coating. The literature discloses the use of DEBs for the treatment of coronary artery disease and peripheral artery disease (see e.g., U.S. Patent No. 5,102,402, issued to Dror et al.). Dror et al. disclose placing a DEBs in a blood vessel lumen to treat the vessel wall, inflating the balloon, and 10 contacting the balloon surface with the luminal vessel wall to deliver a pharmaceutical into the blood vessel wall. Another example of treatment using DEBs involves an angioplasty balloon having microneedles (see e.g., U.S. Patent Nos.: 5171217; 5,538,504; and 6,860,867). DEBs often require a high degree of physician skill to implement. The implantation of the DEBs may also result in 15 mechanical trauma to the vascular treatment site due to the components of the DEBs and/or the pharmaceutical-containing coating. It is desirable to have improved methods for treating and preventing vascular conditions that are simple and easy to implement. It is also desirable to have methods for treating and preventing vascular conditions that avoid mechanical trauma to the vascular treatment site and are !0 compatible with the delivery of a wide variety of pharmaceuticals. In addition to delivering drugs to blood vessels from stents, stent-grafts, grafts, and other prostheses, intraluminal drug delivery methods include methods that chemically "pave" luminal surfaces of a blood vessel (see e.g., U.S. Patent Nos.: 5,213,580; 5,674,287; 5,749,922; and 5,800,538). These "paving" methods involve 25 fixation, polymerization, and bonding of a drug delivery system to the lumen of a blood vessel. Degradation of such delivery systems ranges from days to weeks. The methods can be challenging as they involve chemical reactions with the blood vessel lumen. These chemical reactions may induce trauma to the vascular treatment site. It is desirable to have improved methods for treating and preventing 30 vascular conditions which avoid "paving" of the luminal surfaces of the blood vessel. Methods of delivering drugs to perivascular locations are described. U.S. Patent No. 6,726,923, issued to lyer, and U.S. Patent No. 5,527,532, issued to Edelman, disclose perivascular drug eluting wraps and matrices applied to adventitial surfaces of a blood vessel to treat vascular inflammation. 3 U.S. Patent No. 5,893,839, issued to Johnson, discloses a method of treating restenosis involving the delivery of a biologically active substance percutaneously. U.S. Patent No. 6,730,313, issued to Helmus et al., discloses a method for treating intimal hyperplasia involving contacting an exterior surface of a blood vessel 5 with a "flowable" drug delivery vehicle. These methods usually require complex procedural techniques, often implemented through invasive surgical techniques, In addition, these methods may require long term implantation of a vascular prosthesis, drug eluting wraps, matrices, and flowable drug delivery vehicles. Long term implantation of the vascular 10 prosthesis, drug eluting wraps, matrices, and flowable drug delivery vehicles may also result in an unwanted tissue reaction at the vascular treatment site due to the nature of their components. It is desirable to have improved methods for treating and preventing vascular conditions that allow delivery of a wide variety of pharmaceuticals and biologics to diseased or traumatized vascular tissue without the 15 need for long term implants, that are easily implemented, and that are applied through surgical and endovascular techniques. Li et al. (U.S. Patent Application Publication 2002/0019369) disclose an injectable cyclodextrin polymer-based composition made from cyclodextrin, polyethylene glycol, and a pharmacologically effective amount of at least one drug. 20 Li et al. further disclose their composition can be used subcutaneously, intramuscularly, intradermally, or intracranially. However, Li et al. do not teach their composition can be injected into the vasculature or into flowing blood. As is disclosed to the literature, compositions made of cyclodextrin and polyethylene glycol form inclusion complexes. The inclusion complexes have the 25 form of hydrogels, turbid solutions, and precipitates (Li, J Biomed Mater Res, 65A, 196, 2003; Harada, Macromolecules, 26, 5698, 1993; Harada, Macromolecules, 23, 2821, 1990). Indeed, as indicated by the literature, injection of particles in the form of hydrogel materials, turbid solutions, and precipitates into the vasculature or into 30 flowing blood can have adverse consequences, including decreased drug effectiveness, phlebitis, embolism, and blockage of capillaries (Nemec, Am J Heath Syst Pharm, 65, 1648, 2008; Wong, Adv Drug Del Rev, 60, 939, 2008; Minton, Nutrition, 14, 251, 1998; Tian, Polym Int, 55, 405, 2006). Instructions for use of an injectable pharmaceutical solution contraindicate injection into the vasculature or 4 flowing blood if the injectable pharmaceutical solution is turbid or contains precipitates. There remains a need for improved vascular-based therapies to treat a variety of vascular conditions. The improved therapies would be easily implemented and 5 would obviate mechanically or chemically induced trauma to the vascular treatment site. The improved therapies would allow for administration of thixotropic, turbid, bioactive agent-containing gel materials to vascular tissue at a vascular treatment site. The gel material would readily release one or more bioactive agents contained by the gel material to vascular tissue in need of treatment or repair. The gel material 0 would dissolve n the flowing blood without occluding vascular structures located distally (i.e., downstream) to the administration site. The therapies could be applied prophylactically, interventionally, surgically, or endovascularly. Summary of the Invention 15 The present invention relates to methods of treating or preventing a vascular condition with a thixotropic, turbid, bioactive agent-containing gel material. The method can also be used to treat or repair traumatized vascular structures. The gel material will readily deliver one or more bioactive agents contained by the gel material !0 to a diseased or disease-prone vascular treatment site in need of treatment or repair. In the method, the gel material is capable of being directly injected into luminal spaces of blood vessels and other fluid-conducting anatomical structures with little or no mechanical or chemical trauma to vascular tissues of the vascular treatment site. After contact with the vascular tissues, the gel material will substantially dissolve in 25 flowing blood (without occluding vascular structures located distally (i.e., downstream) to the administration site. The method could be applied prophylactically, interventionally, surgically, or endovascularly. The method does not require a high degree of skill to perform. On the contrary, the method relies on simple injection of the gel material within a vascular structure for delivery of a pharmaceutical or other 30 bioactive agent to vascular tissue in need of treatment. 5 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14 In one aspect, there is provided a method of treating a vascular condition comprising: providing a thixotropic, turbid, gel material containing at least one bioactive agent capable of treating vascular tissue in sufficient amounts to treat said vascular 5 condition in said vascular tissue upon release of said bioactive agent from said gel material; administering said gel material to a vascular treatment site within an interior space of a blood vessel; and allowing said gel material to remain at said vascular treatment site for a dwell 0 time sufficient to release said bioactive agent from said gel material wherein said gel material does not occlude vascular structures upon introduction into flowing blood. In another aspect, there is provided a method of treating a vascular condition comprising: 15 identifying a vascular structure in need of treatment or repair; surgically isolating said vascular structure; applying means for stopping any blood flow in said vascular structure; providing a thixotropic, turbid, gel material containing at least one bioactive agent capable of treating vascular tissue in sufficient amounts to inhibit vascular !0 disease in said vascular tissue upon release of said bioactive agent from said gel material; administering said gel material to a vascular treatment site within an interior space of the vascular structure; allowing said gel material to remain at said vascular treatment site for a dwell 25 time sufficient to release said bioactive agent from said gel material; removing said means for stopping blood flow; allowing said gel material to be removed within said vascular structure by flowing blood in the vascular structure; and closing said vascular structure 30 wherein said gel material does not occlude vascular structures upon introduction into flowing blood. 5a 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14 In another aspect, there is provided a method of treating a vascular condition comprising: providing a cyclodextrin polymer-based composition comprising cyclodextrin, a polymer, and a pharmacologically effective amount of at least one drug; wherein the 5 polymer comprises ethylene glycol units that can form a hydrogel with the cyclodextrin, wherein the cyclodextrin and the polymer self-assemble to form a hydrogel by spontaneous association and are present in the composition in respective amounts effective to make the hydrogel thixotropic and injectable into the body of a person through a needle, and wherein the hydrogel forms a matrix for the 0 drug such that when the composition is injected into the body of the person, the drug is released from the hydrogel in a sustained manner, administering said hydrogel material to a vascular treatment site within an interior space of a blood vessel; and allowing said hydrogel material to remain at said vascular treatment site for a 5 dwell time sufficient to release said bioactive agent from said hydrogel material, wherein said hydrogel material does not occlude vascular structures upon introduction into flowing blood. The gel material used in the method is a thixotropic, turbid, gel material, having high viscosity at low shear, and therefore, coherently resides in luminal spaces of a 0 blood vessel under conditions of low or no blood flow. Upon resumption of flowing blood in the treated blood vessel, the resultant fluid shear force converts 5b 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14 the gel material to a low viscosity, blood-soluble composition that is substantially dissolved in flowing blood. Consequently, the gel material is readily and essentially removed from the vascular treatment site upon re-establishment of flowing blood without obstructing vascular structures located downstream of the treatment site. 5 The method allows for surgical, endovascular, and minimally-invasive delivery of a wide variety of pharmaceuticals and biologics for prophylactic and interventional vascular therapy. Preferred bioactive agents are pharmacologically and biologically active entities that inhibit a variety of vascular pathologies including, but not limited to, intimal hyperplasia. The gel material can be delivered through needle and 10 catheter based devices including, but not limited to, balloon catheters, infusion catheters, and micro-injection systems. In addition to placement of the gel material within a blood conduit, the composition can be applied to blood contacting surfaces of medical devices, including, but not limited to, vascular grafts, stents, stent-grafts, and balloons. 15 One embodiment of the present invention relates to a method of treating a vascular condition by providing a thixotropic, turbid, gel material containing at least one bioactive agent capable of treating vascular tissue in sufficient amounts to treat said vascular condition in said vascular tissue upon release of said bioactive agent from said gel material, administering said gel material to a vascular treatment site 20 within an interior space of a blood vessel, and allowing said gel material to remain at said vascular treatment site for a dwell time sufficient to release said bioactive agent from said gel material. In addition, the gel material does not occlude vascular structures upon introduction into flowing blood. Another embodiment of the present invention relates to a method of treating a 25 vascular condition by providing a thixotropic, turbid, gel material containing at least one bioactive agent capable of treating intimal hyperplasia in sufficient amounts to inhibit intimal hyperplasia upon release of said bioactive agent from said gel material, administering said gel material to a vascular treatment site within an interior space of a blood vessel, and allowing said gel material to remain at said vascular treatment 30 site for a dwell time sufficient to release said bioactive agent from said gel material. In addition, the gel material does not occlude vascular structures upon introduction into flowing blood. Another embodiment of the present invention relates to a method of treating a vascular condition by providing a cyclodextrin polymer-based composition 6 comprising cyclodextrin, a polymer, and a pharmacologically effective amount of at least one drug; wherein the polymer comprises ethylene glycol units that can form a hydrogel with the cyclodextrin, wherein the cyclodextrin and the polymer self assemble to form a hydrogel by spontaneous association and are present in the 5 composition in respective amounts effective to make the hydrogel thixotropic and injectable into the body of a person through a needle, and wherein the hydrogen forms a matrix for the drug such that when the composition is injected into the body of the person, the drug is released from the hydrogel in a sustained manner, administering said hydrogel material to a vascular treatment site within an interior 10 space of a blood vessel, and allowing said hydrogel material to remain at said vascular treatment site for a dwell time sufficient to release said bioactive agent from said hydrogel material. Other embodiments of the present invention relate to medical devices having thixotropic, turbid, gel materials, as described herein, applied to at least a portion of 15 the medical device. The medical devices are either implantable devices or are devices used to deliver one or more bioactive agents to a specific site in the body. A preferred medical device of the present invention comprises a cyclodextrin polymer based composition comprising cyclodextrin, a polymer, and a pharmacologically effective amount of at least one drug, wherein the polymer comprises ethylene glycol 20 units that can form a hydrogel with the cyclodextrin, wherein the cyclodextrin- and the polymer self-assemble to form a hydrogel by spontaneous association and are present in the composition in respective amounts effective to make the hydrogen thixotropic, and wherein said hydrogel is attached, or otherwise applied, to at least a portion of a medical device. Further embodiments include at least one bioactive 25 agent combined with the hydrogel. Preferably, the bioactive agent is capable of treating vascular tissue and is present in the hydrogel in sufficient amounts to treat a vascular condition upon release of the bioactive agent from the hydrogel combined therewith. Other features and advantages of the invention will be apparent from the 30 following description and from the claims. 7 Brief Description of the Drawings Figure 1 shows a table of data. Figure 2 shows two photographs (a) and (b), each containing histological data. 5 Figure 3 shows two photographs (a) and (b), each containing histological data, Figure 4 shows a table of data. Figure 5 shows four photographs (a), (b), (c), and (d). Figure 6A shows a medical device having at least one thixotropic, turbid, gel material applied to at least a portion of the medical device. 10 Figure 6B shows a medical device having at least one thixotropic, turbid, gel material applied to at least a portion of the medical device. Figure 6C shows a medical device having at least one thixotropic, turbid, gel material applied to at least a portion of the medical device, Figure 7A shows a catheter-based device having at least one thixotropic, turbid, gel 15 material applied to at least a portion of the catheter-based device. Figure 7B shows a catheter-based device having at least one thixotropic, turbid, gel material applied to at least a portion of the catheter-based device. Detailed Description of the Invention 20 The present invention relates to methods of treating or preventing a vascular condition with a thixotropic, turbid, bioactive agent-containing gel material. The invention utilizes turbid gel materials having thixotropic properties. The thixotropic properties of the gel materials permit the compositions to undergo 25 changes in viscosity in response to the presence or absence of shear forces applied to the compositions. When a shear force is applied to the gel material by injection of the gel material from a needle-containing syringe, the viscosity of the composition is altered to a point where the composition can easily pass through the needle containing syringe. When the shear force is removed from the gel material, the 30 viscosity of the composition is altered to a point where the composition will not flow under the influence of its own weight. A suitable gel material for use in the present invention is a material that can be made to flow under shear force, but exhibits no flow under the influence of its own weight under non-shear conditions. 8 When the gel material containing a bioactive agent is placed inside a blood vessel to form an indwelling composition, the bioactive agent moves from the indwelling composition to tissues of the blood vessel - independent of the viscosity of the gel material Once sufficient time has elapsed for a desired amount of bioactive 5 agent to be delivered from the indwelling composition to a vascular treatment site in need of treatment or repair, the indwelling composition is exposed to shear forces to decrease the viscosity of the gel material and begin a process of dissolution of the gel material into flowing blood. In the present invention, shear force is applied to the indwelling composition by permitting blood to flow through the vascular treatment site 10 containing the indwelling composition. As the viscosity of the gel material is reduced, the indwelling composition begins to substantially dissolve in the flowing blood. Substantial dissolution of the gel material in flowing blood continues until essentially all of the gel material has been removed from the treatment site and is present in a substantially to completely dissolved state in flowing blood. Once 15 present in flowing blood, the gel material does not diminish, limit, occlude, or otherwise interfere with the flow of blood in vascular structures located distally (i.e., downstream) to the vascular treatment site. In a preferred embodiment, a thixotropic, turbid, bioactive agent-containing gel material is administered to a vascular treatment site within an isolated interior space ?0 of an exsanguinated fluid conduit. The gel material is allowed to reside in the isolated interior space for a period of time ("dwell time"). The dwell time for the gel material is primarily determined by the rate at which a bioactive agent is delivered from the gel material to vascular tissues at a treatment site. The dwell time for the gel material can also be determined by the timing and sequencing of a similar 25 procedure at another vascular treatment site or other medical procedures being performed at the same time. Transfer of bioactive agents from a gel material used in the present invention to vascular and other tissues occurs in a range of about 5 seconds to greater than about one hour. Regardless of the delivery rate of bioactive agents to a vascular treatment site in need of treatment by the present invention, a 30 similar or different surgical procedure to another vascular treatment site can increase the dwell time of the gel material at the vascular tissue treatment site. Once sufficient bioactive agent has been delivered to a vascular treatment site in need of treatment according to methods of the present invention, blood is allowed to re-enter the isolated interior space of the fluid conduit. Shear forces 9 applied to the thixotropic gel material by the flowing blood cause the viscosity of the indwelling composition to decrease. The decrease in viscosity of the gel material causes the indwelling composition to dissolve substantially in blood flowing through the treated fluid conduit. Substantial dissolution of the gel material in flowing blood is 5 sufficient to prevent blockage, or occlusion, of vascular structures located distally (i.e., downstream) of the vascular treatment site. A "gel material" is a material that includes at least two components, a solvent component and a polymer chain component. The term "hydrogel" as used herein means a material that includes at least two components, an aqueous solvent 10 component, and a polymer chain component. The gel material of the present invention does not flow under the influence of its own weight. This property is observable by the unaided eye when about 5 ml of gel material is placed into a 13mm by 100mm standard glass test tube and inverted 180 degrees for a few seconds. 15 In addition to thixotropy, the gel material employed in the present invention is turbid. The term "turbid" means the gel material appears hazy, translucent, cloudy, opalescent, or opaque to the unaided eye. The turbidity of gel materials used in the present invention can be determined when about 5 ml of gel material is placed into a 13mm by 100mm standard glass test tube and viewed by the unaided eye at a right 20 angle to an illuminating light source and against a dark background. The terms "thixotropic" and "thixotropy" refer to physical properties of particular chemical entities. A chemical entity is thixotropic when the chemical entity exhibits behavior in which viscosity of the chemical entity decreases under an applied shear force and then increases in viscosity when the applied shear force is 25 removed. Shear forces can be applied to thixotropic gel materials by methods including, but not limited to, shaking, stirring, exposure to fluid flow, and mechanical expansion in surface area. Thixotropy can be assessed using methods such as rheometry and viscometry. The term "vascular condition" includes, but is not limited to, vascular injury, 30 vascular prophylactic intervention, vascular disease, intimal hyperplasia, phlebitis, vulnerable plaques, carotid plaques, coronary plaque, vascular plaque, aneurismal disease, vascular dissections, atherosclerotic plaques, atherosclerotic lesions, vascular infection, and vascular sepsis. 10 The term "inflammation" as used herein refers to a physiological response by a mammalian body to surgery, injury, irritation, or infection. An inflammatory response involves complex biological activities at chemical, cellular, tissue, and organ levels. Generally, an inflammatory response is a protective attempt to remove 5 an injurious stimulus, as well as to initiate a healing process for the diseased or traumatized tissue. Suitable polymer chain components for the thixotropic turbid gel materials in the present invention are natural and synthetic polymers that are capable of forming a thixotropic, turbid, gel. The polymer chain components include but are not limited 10 to polyethers such as polyethylene glycol, polypropylene glycol, poly(ethylene glycol co-propylene glycol), copolymers of polyethylene glycol, and copolymers of polypropylene glycol; polyols such as polyvinyl alcohol and polyallyl alcohol; polyanions such as polyacrylic acid and poly(methacrylic acid); polyanionic polysaccharides such as alginate, heparin, heparin sulfate, dextran sulfate, xanthan, 15 carrageenan, gum arabic, tragacanth, arabinogalactan, and pectin; neutral polysaccharides such as agar, agarose, hyaluronic acid, carboxymethylcellulose, and dextran; macrocyclic polysaccharides such as cyclodextrin and hydroxypropyl cyclodextrin; polycations such as poly(lysine), poly(allylamine), poly(ethyleneimine), poly(guanidine), poly(vinyl amine), a,w-polyethylene glycol-diamine, and 20 poly(quaternary amine); polyanionic polysaccharides such as chitin and chitosan; polyacrylonitriles such as hydrolyzed polyacrylonitrile, poly(acrylamide-co acrylonitrile), and their copolymers; and protein based polymers such as gelatin, collagen, thrombin, and fibrin. In one embodiment, the gel materials are composed of a-cyclodextrin (aCD) 25 and polyethylene glycol (PEG). Such gel materials are thixotropic and turbid. Suitable bioactive agents in the thixotropic turbid gel materials in the present invention are biologically and pharmaceutically active entities that exert a desired effect upon the native cells, microbes, intercellular environments, and tissues of the vascular treatment site. The gel material may include a solubilizing agent to improve 30 or otherwise alter the solubility of the bioactive agent in the gel material. The gel material may include a permeability agent to improve or otherwise alter the delivery of the bloactive active agent to vascular tissues. The bioactive agent may consist of simple molecules, macromolecules, inorganic molecules, and complex biological entities such as cells, tissues, or tissue aggregates. 11 Bioactive agents suitable for use in the present invention include, but are not limited to, protein based molecules such as enzymes, growth factors, proteases, glycoproteins, and cytokines; nucleic acid based molecules such as DNA, RNA, genes, gene fragments, ribozymes, and nucleic acids; carbohydrate based 5 molecules such as glucose, glycogen, cyclodextrin, and heparin; lipid based molecules such as cholesterol and prostaglandin; complex biological entities such as extracellular matrix, viruses, virenos, prions, cells, tissues, and tissue aggregates; and organic molecules such as hormones, organic catalysts, organometallics, and oleophobics. Other bioactive agents include drugs including, but not limited to, 10 cardiovascular agents, chemotherapeutics, antimicrobials, antibiotics, anesthetics, anticoagulants, hemostatics, antihistamines, antitumors, antilipids, antifungals, antimycotics, antipyretics, vasodilators, hypertensive agents, oxygen free radical scavengers, antivirals, analgesics, antiproliferatives, antiinflammatories, diagnostic agents, visualization agents, angiographic contrast agents, phase contrast agents, 15 and radiopaque agents. Other bioactive agents include but are not limited to antirestenotic drugs including, but not limited, to pimecrolimus, cytochalasin, dicumarol, cyclosporine, latrunculin A, methotrexate, tacrolimus, halofuginone, mycophenolic acid, genistein, batimistat, dexamethasone, cudraflavone, simvastatin, prednisolone, doxorubicin, bromopyruvic acid, carvedilol, mitoxantrone, tranilast, 20 etoposide, hirudin, trapidil, mitomycin C, abciximab, cilostazol, irinotecan, estradiol, diaziquone, dipyridamole, melatonin, colchicine, nifedipine, vitamin E, paclitaxol, diltiazem, vinblastine, verapamil, vincristine, rapamycin, angiopeptin, everolimus, heat shock proteins, zotarolimua, nitroglycerin, and prednisone. Bioactive agents used in the present invention inhibit or prevent pathological 25 vascular conditions. In certain embodiments, the bioactive agents have anti inflammatory properties, inhibit proliferation of smooth muscle cells, and/or influence gene expression in vascular tissue. In one embodiment, the bioactive agent is dexamethasone. Dexamethasone is considered both a smooth muscle cell anti proliferative agent and an anti-inflammatory agent. 30 In an embodiment of the present invention, a need for treating one or more vascular structures is determined. The vascular structure, or other body fluid conduit, designated for treatment is surgically exposed using conventional techniques. Once the vascular structure is surgically exposed, means for stopping blood flow in the structure are applied to isolate the structure, thus defining the 12 vascular treatment site. Such means include, but are not limited to, ligatures, ties, clamps, sutures, staples, or other devices capable of applying a compressive force to a vascular structure sufficient to stop flow of blood in the vascular structure. The vascular treatment site is accessed with a needle-containing syringe and 5 any blood or other fluid residing in the vascular treatment site is removed through the needle-containing syringe. A thixotropic, turbid, bioactive agent-containing gel material, prepared as described herein, is placed in a needle-containing syringe. To administer the gel material to a vascular treatment site at a vascular structure, the open end of the 10 needle is inserted inside the exsanguinated, vascular treatment site, and the gel material is injected inside the vascular structure and allowed to reside for a determined dwell time. As shear force is applied to the gel material during injection, the viscosity of the gel material decreases and the gel material flows through the needle into the interior space (luminal space) of the vascular treatment site. As the 15 gel material fills the vascular treatment site, the shear forces applied to the gel material during injection diminish. As shear forces on the gel material diminish, the viscosity of the gel material increases, and the gel material will not flow under the influence of its own weight. Once the gel material is inside a vascular treatment site, any bioactive agents 20 associated with the gel material can move from the gel material to tissues of the vascular treatment site. The delivery of bioactive agent from the gel material to vascular tissue can occur within a range of about 5 seconds to greater than about one hour (see e.g. Example 4, infra). The dwell time of the gel material can be chosen to be longer than is needed to deliver sufficient amounts of bioactive agent to 25 vascular tissue of a vascular treatment site to treat a vascular condition. Following a dwell time sufficient for substantial bioactive agent to be delivered to a vascular treatment site to treat the vascular tissue, the means for stopping blood flow in the isolated vascular structure are removed. Once the means are removed, flowing blood through the vascular treatment site is re-established. As flowing blood 30 is re-established in the vascular treatment site, shear force is once again applied to the gel material. As shear force is applied to the gel material, the viscosity of the gel material is decreased causing the gel material to begin substantially dissolving in the flowing blood. If the isolated, exsanguinated, vascular treatment site is transparent or translucent, then substantial dissolution of the gel material in flowing blood can be 13 observed through the vascular treatment site with the naked eye. Substantial dissolution of the gel material continues until essentially all the gel material is removed from the vascular treatment site and is substantially dissolved in the blood stream. The substantially dissolved gel material does not limit, occlude, or otherwise 5 diminish blood flow in vascular structures located distally (i.e., downstream) to the vascular treatment site. Once flowing blood is re-established in the treated vascular treatment site, the vascular treatment site is surgically closed, and any other necessary surgical procedures performed. 10 Another embodiment of the method of the present invention can be practiced using interventional techniques. Interventional techniques routinely involve minimally invasive procedures. Often this technique is initiated by a puncture or cut-down of a vascular structure and insertion of a catheter through an interventional access site into the vascular structure. Interventional access sites may include, but are not 15 limited to, access through an implanted vascular prosthesis, brachial artery, carotid artery, iliac artery, femoral artery, aorta, and other arterial or venous sites. After insertion of a catheter through an interventional access site into the vascular structure, the catheter can then be guided to a site with a vascular condition in need of vascular treatment (i.e., a vascular treatment site), from the interventional 20 access site. The vascular treatment site may include, but is not limited to, vascular conduits such as a blood vessel, a vascular graft, a vascular stent, a vascular filter, a vascular anastomosis, and a vascular stent graft. One embodiment of the method of the present invention relates to an interventional treatment of a vascular condition involving the administration of a gel 25 material to a vascular treatment site by injection through a catheter. The gel material may be injected directly to the vascular treatment site with or without prior occlusion of flowing blood at the vascular treatment site. Another embodiment of the present invention relates to catheter injection of a thixotropic, turbid, bloactive agent-containing gel material through a medical device, 30 including, but not limited to, commercially available catheters, single balloon catheters, needle-studded catheters, infusion catheters, balloon catheters, double balloon catheters, angioplasty balloon, weeping balloon catheters, infusion balloon catheters, and needle studded balloon catheters. 14 In another embodiment, the thixotropic, turbid, bloactive agent-containing gel material may be pre-applied to an implantable medical device, vascular prosthesis, or catheter-based device prior to catheter insertion into a vascular structure. For example, the thixotropic, turbid, bioactive agent-containing gel material may be 5 applied manually to an implantable medical device, vascular prosthesis, or catheter based device including, but not limited to, a stent, stent graft, vascular graft, angioplasty balloon, needle studded balloon, and other vascular prosthesis. The application may be continuous or discontinuous, covering at least a portion of the implantable 'medical device. Interventional vascular access is then used to place the 10 catheter-based device at a vascular treatment site. The catheter-based device is then placed at the vascular treatment site allowing for delivery of the thixotropic, turbid, bioactive agent-containing gel material to the vascular treatment site. Figure 6A depicts a cross section of a medical device 16 as from a stent, stent-graft, graft, balloon, or other vascular prosthesis, having a thixotropic, turbid gel 15 material 12 of the present invention applied to the medical device 16. Gel material 12 is applied to the entire surface of the medical device 16 to create an applicated medical device 10. The application may be continuous or discontinuous. Figure 6B depicts a cross section of a medical device 16 as from a stent, stent-graft, graft, balloon, or other vascular prostheses, having a thixotropic, turbid 20 gel material 12 of the present invention applied to the medical device 16. Gel material 12 is applied to one surface of the medical device 16 to create an applicated medical device 10. The application may be continuous or discontinuous Figure 6C depicts a cross section of a medical device 16, having a first application 12c and a second application 12d of the gel-material of the present 25 invention. Gel material 12c and 12d is applied to opposing sides of the medical device 16 to create an applicated medical device 10. The application may be continuous or discontinuous. In another embodiment, the thixotropic, turbid, bioactive agent-containing gel material may be pre-applied to a catheter-based device prior to catheter insertion 30 into a vascular structure. For example, the thixotropic, turbid, bioactive agent containing gel material may-be applied manually to a catheter-based device including, but not limited to, a stent, stent graft, angioplasty balloon, needle studded balloon, and other vascular prosthesis. The application may be continuous or discontinuous, covering at least a portion of the implantable medical device. 15 Catheter-based devices have a first diameter and a first surface area prior to and during insertion of the catheter-based devices into a vascular structure. After insertion into the vascular structure, the catheter-based devices are mechanically expanded to a second diameter and a second surface area within the vascular 5 structure. The thixotropic properties of the gel materials permit the compositions to undergo changes in viscosity in response to the presence or absence of shear forces applied to the compositions. When a shear force is applied to the gel material during mechanical expansion of the catheter-based device, the viscosity of the composition is decreased to a point where the composition can readily deform from the first 10 surface area to the second surface area as the catheter-based device is mechanically expanded. When the shear force is removed from the gel material after mechanical expansion of the catheter-based device, the viscosity of the composition is altered to a point where the composition will not flow under the influence of its own weight and will remain at the second surface area. The catheter 15 based device is placed at a vascular treatment site allowing for delivery of the thixotropic, turbid, bioactive agent-containing gel material to the vascular treatment site during and/or after expansion of the catheter-based device. A suitable gel material for use in the present invention is a material that can be made to flow under shear force, but exhibits no flow under the influence of its own weight under non 20 shear conditions. Figure 7A depicts a cross section of catheter-based device 16 as from a stent, stent-graft, balloon, or other vascular prosthesis, surrounding catheter 14, and having a thixotropic, turbid gel material 12 of the present invention applied to the catheter-based device 16. Gel material 12 is applied to a surface of catheter-based 25 device 16 to create an applicated catheter-based device 10 of a first diameter and a first surface area. The application may be continuous or discontinuous Figure 7B depicts a cross section of the same catheter-based device shown by Figure 7A, except that catheter-based device 16 is expanded to a second diameter and a second surface area. 30 In another embodiment, incorporation of a bioactive agent in the form of an angiographic contrast agent within the thixotropic, turbid, bioactive agent-containing gel material permits an angiographic visualization of the gel material at a vascular treatment site. The contrast agent may be incorporated within the thixotropic, turbid, bioactive agent-containing gel material through admixing, reformulation, 16 combination, direct solubilization of the agent within the gel material, or other methods of incorporating said contrast agent in said gel material. These thixotropic, turbid, bioactive agent-containing gel materials are visualized at a vascular treatment site using angiography. 5 Other embodiments of thixotropic, turbid, bioactive agent-containing gel materials capable of treating vascular tissue in sufficient amounts to treat a vascular condition may include but are not limited to gel materials made from polyethylene glycol, a-cyclodextrin, hydroxypropyl-p-cyclodextrin (HPPCD), and a bioactive agent; polyvinyl alcohol, sodium borate, polyoxyethylene sorbitol ester, and a bioactive 10 agent; sodium alginate, calcium chloride, hydroxypropyl-p-cyclodextrin, and a bioactive agent; and dextran, potassium chloride, hydroxypropyl-P-cyclodextrin (HPOCD), and a bioactive agent. A preferred thixotropic, turbid, bioactive agent-containing gel material for use in the present invention is disclosed by Li et al. (U.S. Patent Application Publication 15 2002/0019369), which is incorporated herein by reference. Examples Example 1 20 This Example describes the preparation of a thixotropic, turbid gel material that contains a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition. A first solution (referred herein as Solution 1A) was prepared by mixing phosphate buffered saline (PBS) (0.15M NaCI, pH 7.4, Invitrogen Corporation 25 Carlsbad, CA) with 0.40 g/ml hydroxypropyl-p3-cyclodextrin (HPpCD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich) through stirring and heating (60 0 C), followed by adding dexamethasone (Pharmacia & Upjohn Company, Kalamazoo, MI) at 20 mg/ml with stirring and heating (60"C). Solution 1 A did not form a gel material and was not turbid. 30 A second solution (referred herein as Solution 1 B) was prepared by dissolving polyethylene glycol (PEG, Dow Chemical, Midland, MI) of average Mn = 8kDa (0.26 g/ml) with PBS. Solution 1 B did not form a gel material and was not turbid. 17 Equal volumes of Solution 1A and Solution 1B were combined with mixing to form Gel Material A. Gel Material A was turbid, and was opaque and white in appearance. 5 Example 2 This Example describes preparation of a thixotropic, turbid gel material that contains a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition. A first solution (Solution 2A) was prepared by mixing PBS (0.15M NaCI, pH 10 7.4, Invitrogen) with 0.40 g/ml hydroxypropyl-o-cyclodextrin (HPpCD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich) through stirring and heating (60*C), followed by adding 17p-estradiol (20 mg/mI) (Sigma Aldrich) by stirring and heating (60*C). Solution 2A did not form a gel material and was not turbid. 15 A second solution (Solution 2B) was prepared by dissolving PEG (Dow Chemical, Midland, MI) of average Mn = 8kDa (0.26 g/ml) in PBS. Solution 2B did not form a gel material and was not turbid. Equal volumes of Solution 2A and Solution 2B were combined with mixing to form Gel Material B. Gel Material B was turbid, and was opaque and white in tO appearance. Example 3 This Example describes preparation of a thixotropic, turbid gel material that contains a bioactive agent capable of treating vascular tissue in sufficient amounts to 25 treat a vascular condition. A first solution (Solution 3A) was prepared by mixing PBS (0.15M NaCI, pH 7.4) with 0.40 g/ml hydroxypropyl-p-cyclodextrin (HPpCD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich) through stirring and heating (60"C), followed by adding dicumarol (0.67 mg/ml) (Sigma-Aldrich) by stirring 30 and heating (60*C). Solution 3A did not form a gel material and was not turbid. A second solution (Solution 3B) was prepared by dissolving of PEG (Dow) of average Mn = 8kDa (0.26 g/ml) in PBS. Solution 3B did not form a gel material and was not turbid. 18 Equal volumes of solutions 3A and 3B were combined with mixing to form Gel Material C. Gel Material C was turbid, and was opaque and white in appearance. Example 4 5 This Example describes in vivo delivery of dexamethasone to venous tissue ("treated vascular tissue") according to a method of the present invention. A thixotropic, turbid gel material (herein referred to as Gel Material 4A) was made by the following steps. A first solution (referred herein as Solution 4A) was prepared by mixing 10 phosphate buffered saline (PBS) (0,15M NaCl, pH 7.4, Invitrogen Corporation Carlsbad, CA) with 0.40 g/ml hydroxypropyl-p-cyclodextrin (HPPCD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich) through stirring and heating (60CC). Solution 4A did not form a gel material and was not turbid. [5 Then, a dexamethasone mixture was made by combining tritium-labeled dexamethasone (Perkin Elmer, Waltham, Massachusetts and unlabeled dexamethasone (Pharmacia & Upjohn Company) at a ratio of approximately 18 pg/g. Solution 4B was formed by solubilizing approximately 20 mg/ml of the dexamethasone mixture in Solution 4A. Solution 4B did not form a gel material and 0 was not turbid. i Solution 4C was prepared by dissolving polyethylene glycol (PEG, Dow Chemical, Midland, MI) of average Mn = 8kDa (0.26 g/ml) with PBS. Solution 4C did not form a gel material and was not turbid. Equal volumes of Solution 4B and Solution 4C were combined with mixing to 25 form Gel Material 4A. Gel Material 4A was turbid, and was opaque and white in appearance. Healthy canines were anaesthetized. A five centimeter (5 cm) segment of canine femoral vein was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with rubber ties positioned at the proximal and distal ends 30 of the segment. A vascular tissue treatment site was the length of vessel between the rubber ties. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. The lumen of the vascular treatment site was irrigated three times with saline applied with a syringe at the cannulation. One to three milliliters (1 to 3 ml) of Gel Material 4A was injected at the 19 cannulation and allowed to contact the blood vessel lumen for a treatment period of two (2), ten (10), or forty (40) minutes. No leakage of the Gel Material 4A from any treated vessel segment was observed during the treatment period. After the designated treatment period, the ties were removed from each blood 5 vessel segment, and blood flow was permitted to resume in the vascular treatment site for one hour (1 hr). Canine veins are relatively transparent, enabling observation with the unaided eye of Gel Material 4A administration and removal from the vascular treatment site. Upon re-establishment of blood flow in the vascular treatment site, Gel Material 4A was observed to substantially dissolve within 10 approximately one minute (1 min). After one hour (1 hr) of blood flow, the vascular treatment site was harvested and washed thoroughly with saline. Tissue sections (approximately 1 cm in length) were taken from each vascular treatment site and digested overnight in five milliliters (5 ml) of Solvable digestion fluid (Perkin Elmer). Fifteen milliliters (15 mi) of HiSafe 2 (Perkin Elmer), a 15 scintillation cocktail, was added to the tissue sections to permit scintillation counting and quantification of beta radiation emitted by the tritium-labeled dexamethasone within each section. A second group of healthy canines was anaesthetized. Control vein sections (approximately 1 cm in length) were obtained from these canines. The control vein 0 sections were digested overnight in 5 ml of Solvable digestion fluid (Perkin Elmer). Known amounts of tritium-labeled dexamethasone were added to the digestion fluid. Fifteen milliliters (15 ml) of HiSafe 2 (Perkin Elmer), was added to the control vein sections to permit scintillation counting and quantification of the beta-radiation emitted by the tritium-labeled dexamethasone within each control vein section. 25 A scintillation counter (Perkin Elmer) was used to measure the beta radiation (disintegrations per minute) emitted by each control vein section and to generate a linear standard curve of disintegrations per minute as a function of the tritium-labeled dexamethasone within each section. Radiation levels (disintegrations per minute) from the tissue section were then compared to the standard curve to calculate 30 tritium-labeled dexamethasone retention. The total amount of dexamethasone retained in each tissue section was determined by correlation of the total amount of dexamethasone in Gel Material 4A to the measured amount of tritium-labeled dexamethasone in each experimental tissue section. 20 Figure 1 shows the resulting amount of total dexamethasone in the experimental tissue sections. As shown, when Gel Material 4A containing dexamethasone was allowed to contact a blood vessel lumen devoid of blood for two minutes (2 min), an average of 9.3 pg dexamethasone/g tissue remained in the 5 tissue section after 1 h blood flow. The vascular treatment site included the tissue sections. Therefore, an average of 9.3 pg dexamethasone/g tissue was retained at the vascular treatment site at 1 h. Example 5 10 This Example demonstrates the use of a thixotropic, turbid gel material in canine jugular veins ("treated vascular tissue"). This example also illustrates dissolution of a gel material in the blood stream that does not occlude vascular structures upon introduction to flowing blood. Healthy canines were anaesthetized. A five centimeter (5 cm) segment of 15 canine jugular vein was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with rubber ties positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the rubber ties. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. The lumen of the vascular 20 treatment site was irrigated three times with saline applied with a syringe at the cannulation. Three to four milliliters (3 to 4 ml) of Gel Material A (described in Example 1, supra) was injected at the cannulation and allowed to contact the blood vessel lumen for a treatment period of forty (40) minutes. No leakage of the Gel Material A from any treated vessel segment was observed during the treatment 25 period. After the designated treatment period, the ties were removed from each blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for one hour (1 hr). Canine veins are relatively transparent, enabling observation with the unaided eye of Gel Material A administration and removal from the vascular 30 treatment site. Upon re-establishment of blood flow in the vascular treatment site, Gel Material A was observed to substantially dissolve within approximately one minute (1 min). All canines remained in-life for one hour (1 h) after re-establishment of blood flow in treatment site. 21 After one hour (1 hr) of blood flow, the vascular treatment site was harvested and washed thoroughly with saline. Upon visible inspection, no Gel Material A was observable on luminal surfaces of any treatment site. Tissue sections (approximately 1 cm in length) were taken from each vascular treatment site. A histological 5 examination (see Figure 2) of these sections revealed a normal appearance of these sections. The heart and lungs of canines treated with Gel Material A in the present Example were surgically excised. A pathological examination of the heart and lungs revealed no evidence of embolism or occlusion in these organs, indicating that Gel 10 Material A dissolution in the blood stream did not limit blood flow in vascular structures located distal (i.e., downstream) to the vascular tissue treatment site. These results demonstrate that the method of administering the gel material did not occlude vascular structures upon introduction into flowing blood. 15 Example 6 This Example demonstrates the use of a thixotropic, turbid gel material in canine femoral veins ("treated vascular tissue"). This example also illustrates dissolution of a gel material in the blood stream that does not occlude vascular structures upon introduction to flowing blood. 20 Healthy canines were anaesthetized. A five centimeter (5 cm) segment of canine femoral vein was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with rubber ties positioned at the proximal and distal ends' of the segment. A vascular tissue treatment site was the length of vessel between the rubber ties. The vascular treatment site was cannulated. Blood within the vessel 25 lumen was withdrawn at the cannulation using a syringe. The lumen of the vascular treatment site was irrigated three times with saline applied with a syringe at the cannulation. One to three milliliters (1 to 3 ml) of Gel Material A (described in Example 1, supra) was injected at the cannulation and allowed to contact the blood vessel lumen for a treatment period of forty (40) minutes. No leakage of the Gel 30 Material A from any treated vessel segment was observed during the treatment period. After the designated treatment period, the ties were removed from each blood vessel segment, and blood flow was permitted to resume in the vascular treatment site. Canine veins are relatively transparent, enabling observation with the unaided 22 eye of Gel Material A administration and removal from the vascular treatment site. Upon re-establishment of blood flow in the vascular treatment site, Gel Material A was observed to substantially dissolve within approximately one minute (1 min). After re-establishment of blood flow in the treatment site, subcutaneous tissue 5 and skin surrounding the treatment site were closed with sutures. All canines remained in-life for fourteen days (1 4d). After fourteen days (14d), all canines were euthanized. Then, the vascular treatment site was harvested and washed thoroughly with saline. Upon visible inspection, no Gel Material A was observable on luminal surfaces of any treatment 10 site, Tissue sections (approximately 1 cm in length) were taken from each vascular treatment site. Histological examination of these sections indicated evidence of a pharmacological effect of the delivered dexamethasone. Specifically, a delayed healing response to the surgical trauma of vein cannulation was observed, Tissue sections from uncannulated lengths of the vascular treatment site displayed normal [5 morphology as show in Figure 3. These findings demonstrated the ability of thixotropic, turbid, bioactive agent-containing gel materials to deliver an effective amount of a biological agent to a vascular treatment site. The heart and lungs of canines treated with Gel Material A in the present Example were also surgically excised at the time of euthanasia. A pathological 10 examination of the heart and lungs revealed no evidence of embolism or occlusion in these organs, indicating that Gel Material A dissolution in the blood stream did not limit blood flow in vascular structures located distal (i.e., downstream) to the vascular tissue treatment site. These results demonstrate that the method of administering the gel material did not occlude vascular structures upon introduction into flowing blood. 25 Example 7 This Example describes in vivo delivery of estradiol to venous tissue ("treated vascular tissue") according to a method of the present invention. A thixotropic, turbid gel material (herein referred to as Gel Material 7A) was 30 made by the following steps. A first solution (referred herein as Solution 7A) was prepared by mixing phosphate buffered saline (PBS) (0.15M NaCl, pH 7.4, Invitrogen Corporation Carlsbad, CA) with 0.40 g/ml hydroxypropyl-p-cyclodextrin (HPJCD) (Sigma-Aldrich, St. Louis, MO) and 0,20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich) through 23 stirring and heating (60*C). Solution 7A did not form a gel material and was not turbid. Then, an estradiol mixture was made by combining tritium-labeled estradiol (Perkin Elmer) and unlabeled estradiol (Sigma) at a ratio of approximately 27 pg/g. A 5 second solution (referred herein as Solution 7B) was formed by solubilizing approximately 20 mg/ml of the estradiol mixture in Solution 7A. Solution 7B did not form a gel material and was not turbid. A third solution (referred herein as Solution 7C) was prepared by dissolving polyethylene glycol (PEG, Dow Chemical) of average Mn = 8kDa (0.26 g/ml) with 10 PBS. Solution 7C did not form a gel material and was not turbid. Equal volumes of Solution 7B and Solution 7C were combined with mixing to form Gel Material 7A. Gel Material 7A was turbid, and was opaque and white in appearance. Healthy canines were anaesthetized. A five centimeter (5 cm) segment of 15 canine left femoral vein was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with rubber ties positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the rubber ties. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. The lumen of 20 the vascular treatment site was irrigated three times with saline applied with a syringe at the cannulation. One to three milliliters (1 to 3 ml) of Gel Material 7A was injected at the cannulation and allowed to contact the blood vessel lumen for a treatment period of forty (40) minutes. No leakage of the Gel Material 7A from any treated vessel segment was observed during the treatment period. 25 After the designated treatment period, the ties were removed from each blood vessel segment, and blood flow was permitted to resume in the vascular treatment site. Canine veins are relatively transparent, enabling observation with the unaided eye of Gel Material 7A administration and removal from the vascular treatment site. Upon re-establishment of blood flow in the vascular treatment site, Gel Material 7A 30 was observed to substantially dissolve within approximately one minute (1 min). After re-establishment of blood flow in the treatment site, subcutaneous tissue and skin surrounding the treatment site were closed with sutures. All canines remained in-life for fourteen days (14d). 24 After fourteen days (1 4d), all canines treated previously with Gel Material 7A were again anaesthetized. The vascular treatment site from the left femoral vein of each canine was then harvested and washed thoroughly with saline. With the canines still remaining in-life, a five centimeter (5 cm) segment of the 5 contralateral right femoral vein was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with rubber ties positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the rubber ties. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. The 10 lumen of the vascular treatment site was irrigated three times with saline applied with a syringe at the cannulation. One to three milliliters (1 to 3 ml) of Gel Material 7A was injected at the cannulation and allowed to contact the blood vessel lumen for a treatment period of forty (40) minutes. No leakage of the Gel Material 7A from any treated vessel segment was observed during the treatment period. 15 After the designated treatment period, the ties were removed from each blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for one hour (1 h). Canine veins are relatively transparent, enabling observation with the unaided eye of Gel Material 7A administration and removal from the vascular treatment site. Upon re-establishment of blood flow in the vascular 20 treatment site, Gel Material 7A was observed to substantially dissolve within approximately one minute (1 min). After one hour (1 hr) of blood flow, the vascular treatment site from the right femoral vein was harvested and washed thoroughly with saline. Tissue sections (approximately 1 cm in length) were taken from all vascular 25 treatment sites (from the left and right femoral veins) and digested overnight in five milliliters (5 ml) of Solvable digestion fluid (Perkin Elmer). Fifteen milliliters (15 ml) of HiSafe 2 (Perkin Elmer), a scintillation cocktail, was added to the tissue sections to permit scintillation counting and quantification of beta radiation emitted by the tritium labeled estradiol within each section. 30 A second group of untreated, healthy canines were anaesthetised. Control vein sections (approximately 1 cm in length) were obtained from these canines. The control vein sections were digested overnight in 5 ml of Solvable digestion fluid (Perkin Elmer). Known amounts of tritium-labeled estradiol were added to the digestion fluid. Fifteen milliliters (15 ml) of HiSafe 2 (Perkin Elmer), was added to the 25 control vein sections to permit scintillation counting and quantification of the beta radiation emitted by the tritium-labeled estradiol within each control vein section. A scintillation counter (Perkin Elmer) was used to measure the beta radiation (disintegrations per minute) emitted by each control vein section and to generate a 5 linear standard curve of disintegrations per minute as a function of the tritium-labeled estradiol within each section. Radiation levels (disintegrations per minute) from the tissue section were then compared to the standard curve to calculate tritium-labeled estradiol retention. The total amount of estradiol retained in each tissue section was determined by correlation of the total amount of estradiol in Gel Material 7A to the 10 measured amount of tritium-labeled estradiol in each experimental tissue section. Figure 4 shows the resulting amount of total estradiol in the experimental tissue sections. As shown, when Gel Material 7A containing estradiol was allowed to contact a blood vessel lumen devoid of blood for 40 minutes (40 min), an average of 9.8 pg estradiol/g tissue remained in the tissue section after one hour (1 h blood 15 flow). The vascular treatment site included the tissue sections. Therefore, an average of 9.8 pg estradiol/g tissue was retained in the vascular treatment site at 1 h. As shown in Figure 4, when Gel Material 7A containing estradiol was allowed to contact a blood vessel lumen devoid of blood for 40 minutes (40 min), an average of 0.3 pg estradiol/g tissue remained in the tissue section after fourteen days (14d). 20 The vascular treatment site included the tissue sections. Therefore, an average 0.3 pg estradiol/g tissue was retained in the vascular treatment site at fourteen days (1 4d). Example 8 25 This Example describes preparation of a thixotropic, turbid gel material that contains a first bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition and a second bioactive agent in the form of a phase contrast agent to assist angiographic visualization of the gel material. This example demonstrates visualization of the gel material using angiography. 30 A first solution (referred herein as Solution 8A) was prepared by mixing PBS with 0.40 g/mI hydroxypropyl-p-cyclodextrin (HPOCD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich, St. Louis, MO) through stirring and heating (600C), followed by adding dexamethasone at 20 mg/ml and 600 26 mg/ml of iohexol (Hovione, Loures, Portugal) with stirring and heating (60 0 C). Solution 8A did not form a gel material and was not turbid. A second solution (referred herein as Solution 8B) was prepared by dissolving PEG of average Mn = 8kDa (0.26 g/ml) with PBS. Solution 8B did not form a gel 5 material and was not turbid. Equal volumes of Solution 8A and Solution 8B were combined with mixing to form Gel Material D. Gel Material D was turbid, and was opaque and white in appearance. A healthy canine was anaesthetized. A segment of canine jugular vein, 10 approximately five centimeters (5 cm) in length, was surgically exposed, Blood flow in the segment was stopped by constriction of the vein with clamps positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the clamps. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. 15 One to three milliliters (3 to 4 ml) of Gel Material D was injected at the cannulation and visualized by angiography (Figure 5c). After angiography, the clamps were removed from the blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for approximately five minutes (5 min). Then, blood flow in the segment was again 20 stopped by constriction of the vein with clamps positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the clamps. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. One to three milliliters (3 to 4 ml) of Gel Material A (as described in Example 1, supra, and which 25 contained no phase contrast agent) was injected at the cannulation and visualized by angiography (Figure 5b) as a control. After angiography, the clamps were removed from the blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for approximately five minutes (5 min). Then, blood flow in the segment was again 30 stopped by constriction of the vein with clamps positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the clamps. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. One to three 27 milliliters (3 to 4 ml) of saline (Sigma) was injected at the cannulation and visualized by angiography (Figure Sa) as a control. This example demonstrates visualization of the thixotropic turbid gel material using angiography. 5 Example 9 This Example describes preparation of a thixotropic, turbid gel material that contains a first bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition and a second bioactive agent in the form of a 10 phase contrast agent to assist angiographic visualization of the gel material. This example demonstrates visualization of the gel material using angiography. A first solution (referred herein as Solution 9A) was prepared by mixing PBS with 0.40 g/ml hydroxypropyl-p-cyclodextrin (HP@CD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich, St. Louis, MO) through 15 stirring and heating (600C), followed by adding dexamethasone at 20 mg/ml and 600 mg/ml of iopamidol (Hovione, Loures, Portugal) with stirring and heating (60*C). Solution 9A did not form a gel material and was not turbid. A second solution (referred herein as Solution 9B) was prepared by dissolving PEG of average Mn = 8kDa (0.26 g/ml) with PBS. Solution 9B did not form a gel 20 material and was not turbid. Equal volumes of Solution 9A and Solution 9B were combined with mixing to form Gel Material E. Gel Material E was turbid, and was opaque and white in appearance. A healthy canine was anaesthetized. A segment of canine jugular vein, 25 approximately five centimeters (5 cm) in length, was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with clamps positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the clamps. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. 30 One to three milliliters (3 to 4 ml) of Gel Material E was injected at the cannulation and visualized by angiography (Figure 5d). After angiography, the clamps were removed from the blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for approximately five minutes (5 min). Then, blood flow in the segment was again 28 stopped by constriction of the vein with clamps positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the clamps. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. One to three 5 milliliters (3 to 4 ml) of Gel Material A (as described in Example 1, supra, and which contained no phase contrast agent) was injected at the cannulation and visualized by angiography (Figure 5b) as a control. After angiography, the clamps were removed from the blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for 10 approximately five minutes (5 min). Then, blood flow in the segment was again stopped by constriction of the vein with clamps positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the clamps. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. One to three 15 milliliters (3 to 4 ml) of saline (Sigma) was injected at the cannulation and visualized by angiography (Figure 5a) as a control. This example demonstrates visualization of the thixotropic turbid gel material using angiography. 20 Example 10 This Example describes delivery through a medical device of a thixotropic, turbid gel material containing a bioactive agent capable of treating vascular tissue in sufficient amounts to inhibit a vascular condition. Gel Material A (as described in Example 1, supra) was injected through three 25 different medical devices under hand compression of a syringe attached to each medical device: a 4 French catheter (100 cm in length) (Cordis, Warren, NJ); a 6 French catheter (90 cm in length) (Cordis); and a 20 Gauge needle (2.54 cm in length) (Monoject, Mansfield, Massachusetts). The medical device was attached to a five milliliter (5 ml) luer lock syringe (Becton Dickinson, Franklin Lakes, NJ). Gel 30 Material A passed through all three medical devices with hand compression of the attached syringe. This example demonstrates the method of administering the gel material by injection through a needle. This example also demonstrates the method of administering the gel material by endovascular delivery via a catheter. 29 Example 11 This Example describes in vivo delivery of dexamethasone to arterial tissue ("treated vascular tissue") according to a method of the present invention. A thixotropic, turbid gel material (herein referred to as Gel Material 11 A) was 5 made by the following steps. A first solution (referred herein as Solution 11 A) was prepared by mixing phosphate buffered saline (PBS) (0.15M NaCI, pH 7.4, Invitrogen Corporation Carlsbad, CA) with 0.57 g/ml hydroxypropyl-p-cyclodextrin (HPPCD) (Sigma-Aldrich, St. Louis, MO) and 0.20 g/ml alpha-cyclodextrin (aCD) (Sigma-Aldrich) through 10 stirring and heating (60*C). Solution 11A did not form a gel material and was not turbid. Then, a dexamethasone mixture was made by combining tritium-labeled dexamethasone (Perkin Elmer, Waltham, Massachusetts Perkin Elmer) and unlabeled dexamethasone (Pharmacia & Upjohn Company) at a ratio of 15 approximately 9 pg/g. Solution 11 B was formed by solubilizing approximately 20 mg/mi of the dexamethasone mixture in Solution 11 A. Solution 11 B did not form a gel material and was not turbid, Solution 11 C was prepared by dissolving polyethylene glycol (PEG, Dow Chemical, Midland, MI) of average Mn = 8kDa (0.26 g/ml) with PBS. Solution 11 C 20 did not form a gel material and was not turbid. Equal volumes of Solution 11B and Solution 11C were combined with mixing to form Gel Material 11 A. Gel Material 11 A was turbid, and was opaque and white in appearance. Healthy canines were anaesthetized. A five centimeter (5 cm) segment of 25 canine femoral artery was surgically exposed. Blood flow in the segment was stopped by constriction of the artery with rubber ties positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between the rubber ties. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. The lumen of 30 the vascular treatment site was irrigated three times with saline applied with a syringe at the cannulation. One to three milliliters (1 to 3 ml) of Gel Material 11 A was injected at the cannulation and allowed to contact the blood vessel lumen for a treatment period of two (2) minutes. No leakage of the Gel Material 11 A from any treated vessel segment was observed during the treatment period. 30 After the designated treatment period, the ties were removed from each blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for one hour (1 hr). Canine arteries are relatively transparent, enabling observation with the unaided eye of Gel Material 11 A administration and removal 5 from the vascular treatment site. Upon re-establishment of blood flow in the vascular treatment site, Gel Material 11 A was observed to substantially dissolve within approximately one minute (1 min). After approximately ore hour (1 hr) of blood flow, post-injection contrast angiography was performed to demonstrate the patency of capillaries and other 10 vascular structures located distal to the treatment site after Gel Material 11 A dissolution in the blood stream. Angiography of arteries distal to the treatment site demonstrated normal blood perfusion after gel material dissolution in the blood stream. These results demonstrate that the method of administering the gel material did not occlude vascular structures upon introduction into flowing blood. 15 "Following angiography, the vascular treatment site was harvested and washed thoroughly with saline. Tissue sections (approximately 1 cm in length) were taken from each vascular treatment site and digested overnight in five milliliters (5 ml) of Solvable digestion fluid (Perkin Elmer). Fifteen milliliters (15 ml) of HiSafe 2 (Perkin Elmer), a scintillation cocktail, was added to the tissue sections to permit 20 scintillation counting and quantification of beta radiation emitted by the tritium labeled dexamethasone within each specimen. A second group of healthy canines was anaesthetised. Control artery sections (approximately 1 cm in length) were obtained from these canines. The control artery sections were digested overnight in 5 ml of Solvable digestion fluid (Perkin Elmer). 25 Known amounts of tritium-labeled dexamethasone were added to the digestion fluid. Fifteen milliliters (15 ml) of HiSafe 2 (Perkin Elmer), was added to the control artery sections to permit scintillation counting and quantification of the beta-radiation emitted by the tritium-labeled dexamethasone within each control artery section. A scintillation counter (Perkin Elmer) was used to measure the beta radiation 30 (disintegrations per minute) emitted by each control artery section and to generate a linear standard curve of disintegrations per minute as a function of the tritium-labeled dexamethasone within each section. Radiation levels (disintegrations per minute) from the tissue section were then compared to the standard curve to calculate tritium-labeled dexamethasone retained in the tissue section. The total amount of 31 dexamethasone retained in each tissue section was determined by correlation of the total amount of dexamethasone in Gel Material 11 A to the measured amount of tritium-labeled dexamethasone in each experimental tissue section. When Gel Material 11 A containing dexamethasone was allowed to contact a 5 blood vessel lumen devoid of blood for two minutes (2 min), an average of 9.1 pg dexamethasone/g tissue was retained in each tissue section after one hour (1 h) blood flow. The vascular treatment site included the tissue sections. Therefore, an average of 9.1 pg dexamethasone/g tissue was retained in the vascular treatment site at one hour (1 h). 10 Example 12 This Example describes preparation of a thixotropic, turbid gel material that contains a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition. 15 A thixotropic, turbid gel material (herein referred to as Gel Material F) made from polyvinyl alcohol (PVA, Spectrum, Gardena, CA), sodium borate (Borax, Sigma), polyoxyethylene sorbitol ester (Tween@20, Sigma), and dexamethasone (Pharmacia & Upjohn Company) was made by the following steps. Three solutions were separately formed: 20 Solution 12A: 0.03 g PVA per milliliter water Solution 12B: 10 mg dexamethasone per milliliter polyoxyethylene sorbitol ester Solution 12C: 10 mg borax per milliliter water Then, 0.5 ml of Solution 12B was thoroughly mixed with 9.5 ml Solution 12A 25 to form Solution 12D. Next, 0.5 ml of Solution 12C was added to 5 ml of Solution D. Upon mixing, a Gel Material F was formed and was turbid. Example 13 This Example describes preparation of a thixotropic, turbid gel material that 30 contains a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition. A thixotropic, turbid gel material (herein referred to as Gel Material G) made from polyvinyl alcohol (PVA, Spectrum, Gardena, CA) and sodium borate (Borax, 32 Sigma), and HPJCD (Sigma), and dexamethasone (Pharmacia & Upjohn Company) was made by the following steps. Three solutions were separately formed: Solution 13A: 0.05 g PVA per milliliter water 5 Solution 13B: 0.20 g HPPCD per milliliter Solution 13C: 10 mg borax per milliliter water Then, Solution 13D was formed by solubilizing approximately 12 mg dexamethasone per milliliter in Solution 13B. Next, 2.5 ml Solution 13A, 2.5 ml Solution 13D, and 0.25 mi Solution 13C were thoroughly combined. Upon mixing, a 10 Gel Material G was formed and was turbid. Example 14 This Example describes in vivo delivery of dexamethasone to venous tissue ("treated vascular tissue") according to a method of the present invention using Gel 15 Material G as described in Example 13. Healthy canines were anaesthetized. A five centimeter (5 cm) segment of canine jugular vein was surgically exposed. Blood flow in the segment was stopped by constriction of the vein with rubber ties positioned at the proximal and distal ends of the segment. A vascular tissue treatment site was the length of vessel between MO the rubber ties. The vascular treatment site was cannulated. Blood within the vessel lumen was withdrawn at the cannulation using a syringe. The lumen of the vascular treatment site was irrigated three times with saline applied with a syringe at the cannulation. One to three milliliters (3 to 4 ml) of Gel Material G was injected at the cannulation and allowed to contact the blood vessel lumen for a treatment period of 25 forty (40) minutes. No leakage of the Gel Material G from any treated vessel segment was observed during the treatment period. After the designated treatment period, the ties were removed.from each blood vessel segment, and blood flow was permitted to resume in the vascular treatment site for one hour (1 hr). Canine veins are relatively transparent, enabling observation 30 with the unaided eye of Gel Material G administration and removal from the vascular treatment site. Upon re-establishment of blood flow in the vascular treatment site, Gel Material G was observed to substantially dissolve within approximately one minute (1 min). After one hour (1 hr) of blood flow, the vascular treatment site was harvested and washed thoroughly with saline. 33 Tissue sections (approximately 1 cm in length) were taken from each vascular treatment site. A histological examination of these sections revealed a normal appearance of these sections, Three additional sections of the vascular treatment site were analyzed for dexamethasone content by tissue extraction and quantified 5 with high performance liquid chromatography combined with dual mass spectroscopy. Dexamethasone levels in these tissue sections were approximately 15.9 ± 9.8 pg per gram tissue, demonstrating that the method of the present invention delivers a bloactive agent to a vascular tissue treatment site. 10 Example 15 This Example describes the preparation of a thixotropic, turbid gel material that contains a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition. A thixotropic, turbid gel material (herein referred to as Gel Material H) made 15 from sodium alginate (Sigma), calcium chloride (Sigma), hydroxypropyl-p cyclodextrin (HPpCD) (Sigma), and dexamethasone (Pharmacia & Upjohn Company) was made by the following steps. Three solutions were separately formed: Solution 15A: 1.7 mg calcium chloride per milliliter water 20 Solution 15B: 0.40 g HPpCD per milliliter water Solution 15C: 20 mg sodium alginate per milliliter water Then, Solution 15D was formed by solubilizing approximately 20 mg dexamethasone per milliliter of Solution 15B. Next, 2.5 ml Solution 15A, 2.5 ml Solution 15D, and 2.5 ml Solution 15C were combined. Upon mixing, a Gel Material 25 H was formed and was turbid. Example 16 This Example describes the preparation of a thixotropic, turbid gel material that contains a bioactive agent capable of treating vascular tissue in sufficient 30 amounts to treat a vascular condition. A thixotropic, turbid gel material (herein referred to as Gel Material X) made from dextran (Mn=4kDa, Sigma) and potassium chloride (Sigma) and hydroxypropyl p-cyclodextrin (HPpCD) (Sigma), and dexamethasone (Pharmacia & Upjohn Company) is made by the following steps. 34 Two solutions are separately formed: Solution 16A: 0.40 g HPpCD per ml water Solution 16B: 0.22 g potassium chloride per g water Then, Solution 16C is formed by solubilizing 10 mg/ml dexamethasone in 5 Solution 16A. Next, 0.5 g dextran is solubilized by 0.5 ml of Solution 16C. Finally, 0.5 ml Solution 16B is added. Upon mixing, Gel Material X is formed and was turbid. Example 17 This Example describes characterization of a thixotropic, turbid gel material 10 that contains a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition. Thixotropy of Gel Material A was demonstrated by rheometry. The viscosity of Gel Material A was characterized over a range of shear rates using a rheometer (Model AR-G2, TA Instruments, New Castle, DE). This analysis 15 technique involved measurement of shear stress during shear rate "ramp up" and subsequent "ramp down." Samples were analyzed at 25"C with a forty millimeter (40mm) cone and plate geometry. About one milliliter (1 ml) of Gel Material A was injected from a needle-less syringe onto the plate and allowed to equilibrate for 3 minutes. Then, a shear "ramp up" step was performed, whereby the shear rate was 20 increased from 0.1 to 1.0 s- over two minutes (2 min). Subsequently, a "ramp down" step was performed, whereby the shear rate was decreased from 1.0 to 0.1 s&1 over two minutes (2 min). Apparent viscosity at each point was calculated as the ratio of shear stress to shear rate. Initial viscosity at 0.1 s-1 was approximately 90 Pa.s. The viscosity of Gel 25 Material A was observed to decrease with increasing shear (during the shear "ramp up"). At 1.0 s", the viscosity of Gel Material A was approximately 17 Pa-s. As the shear rate was then decreased (the "ramp down" step), the viscosity of Gel Material A was seen to increase. At the conclusion of the ramp down step, the viscosity of Gel Material A at 0.1 s- was approximately 55 Pa.s. 30 Example 18 This Example describes an implantable medical device having a thixotropic, turbid, gel material containing a bioactive agent capable of treating vascular tissue in 35 sufficient amounts to treat a vascular condition applied to at least a portion of the implantable medical device. The implantable medical device used in this example was in the form of a nitinol wire reinforced tube made of a porous, expanded, polytetrafluoroethylene 5 (ePTFE) material obtained from W.L. Gore & Associates, Inc., Flagstaff, AZ under the tradename VIABAHN® Endoprosthesis. The tubular device was fifteen centimeters (15 cm) in length and six millimeters (6 mm) in diameter, Gel Material A (described in Example 1, supra) was applied to an exterior surface of the implantable medical device using a needle-containing syringe. Once 10 applied, the gel material was seen to adhere to the exterior surface of the implantable medical device. The implantable medical device was mechanically expanded. Upon expansion, the implantable medical device expanded from a first diameter and a first surface area to a second diameter and a second surface area. A substantial portion 15 of Gel Material A applied to the exterior surface of the implantable medical device was seen to remain adherent to the exterior surface of the implantable medical device during expansion of the implantable medical device. Example 19 20 This Example describes an implantable medical device having a thixotropic, turbid, gel material containing a bioactive agent capable of treating vascular tissue in sufficient amounts to treat a vascular condition applied to at least a portion of the implantable medical device. The implantable medical device used in this example was in the form of a 25 catheter-based device. The catheter-based device was in the form of an endovascular angioplasty balloon (POWERFLEX® P3, Cat. No. 420-4040L, Cordis Corporation). The restraining sheath of the balloon was removed from the implantable medical device. Then, Gel Material A (described in Example 1, supra) was applied to an exterior surface of the balloon of the implantable medical device 30 using a needle-containing syringe. Once applied, the gel material was seen to adhere to the exterior surface of the balloon. The balloon was mechanically expanded according to instructions for use provided with the packaging. Upon mechanical expansion, the balloon expanded from a first diameter and a first surface area to a second diameter and a second 36 surface area. A substantial portion of Gel Material A applied to the exterior surface of the implantable medical device was seen to remain adherent to the exterior surface of the implantable medical device during and after mechanical expansion of the implantable medical device. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. -37 4791864_1 {GHMatters) PSOSS.AU.1
Claims (19)
1. A method of treating a vascular condition comprising: providing a thixotropic, turbid, gel material containing at least one bioactive 5 agent capable of treating vascular tissue in sufficient amounts to treat said vascular condition in said vascular tissue upon release of said bioactive agent from said gel material; administering said gel material to a vascular treatment site within an interior space of a blood vessel; and 0 allowing said gel material to remain at said vascular treatment site for a dwell time sufficient to release said bioactive agent from said gel material wherein said gel material does not occlude vascular structures upon introduction into flowing blood. 15
2. The method of claim 1 further comprising removing said gel material from within said blood vessel.
3. The method of claim 1 or claim 2 wherein said bioactive agent has anti inflammatory properties. !0
4. The method of claim 1 or claim 2 wherein said bioactive agent has anti proliferative properties.
5. The method of claim 1 or claim 2 wherein said bioactive agent is 25 dexamethasone.
6. The method of claim 1 or claim 2 wherein said bioactive agent is selected from the group consisting of dexamethasone, estradiol, carvedilol, and cilostazol. 30
7. The method of any one of claims 1 to 6 wherein said vascular disease is intimal hyperplasia. 38 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14
8. The method of any one of claims 1 to 7 wherein administrating said gel material includes injection through a needle-containing syringe. 5
9. The method of any one of claims 1 to 7 wherein administrating said gel material includes injection through a catheter.
10. The method of any one of claims 1 to 7 wherein administrating said gel material includes injection through a balloon. 0
11. A method of treating a vascular condition comprising: identifying a vascular structure in need of treatment or repair; surgically isolating said vascular structure; applying means for stopping any blood flow in said vascular structure; 15 providing a thixotropic, turbid, gel material containing at least one bioactive agent capable of treating vascular tissue in sufficient amounts to inhibit vascular disease in said vascular tissue upon release of said bioactive agent from said gel material; administering said gel material to a vascular treatment site within an interior !0 space of the vascular structure; allowing said gel material to remain at said vascular treatment site for a dwell time sufficient to release said bioactive agent from said gel material; removing said means for stopping blood flow; allowing said gel material to be removed within said vascular structure by 25 flowing blood in the vascular structure; and closing said vascular structure wherein said gel material does not occlude vascular structures upon introduction into flowing blood. 30
12. The method of claim 11 wherein said bioactive agent has anti-inflammatory properties. 39 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14
13. The method of claim 11 wherein said bioactive agent has anti-proliferative properties. 5
14. The method of claim 11 wherein said bioactive agent is dexamethasone.
15. The method of claim 11 wherein said bioactive agent is selected from the group consisting of dexamethasone, estradiol, carvedilol, and cilostazol. 0
16. The method of any one of claims 11 to 15 wherein administrating said gel material includes injection through a needle-containing syringe.
17. The method of any one of claims 11 to 15 wherein administrating said gel material includes injection through a catheter. 15
18. The method of any one of claims 11 to 15 wherein administrating said gel material includes injection through a balloon.
19. A method of treating a vascular condition comprising: !0 providing a cyclodextrin polymer-based composition comprising cyclodextrin, a polymer, and a pharmacologically effective amount of at least one drug; wherein the polymer comprises ethylene glycol units that can form a hydrogel with the cyclodextrin, wherein the cyclodextrin and the polymer self-assemble to form a hydrogel by spontaneous association and are present in the composition in 25 respective amounts effective to make the hydrogel thixotropic and injectable into the body of a person through a needle, and wherein the hydrogel forms a matrix for the drug such that when the composition is injected into the body of the person, the drug is released from the hydrogel in a sustained manner, administering said hydrogel material to a vascular treatment site within an 30 interior space of a blood vessel; and 40 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14 allowing said hydrogel material to remain at said vascular treatment site for a dwell time sufficient to release said bioactive agent from said hydrogel material, wherein said hydrogel material does not occlude vascular structures upon introduction into flowing blood. 41 5728506_1 (GHMatters) P88055.AU.1 JBECKER 2-Sep-14
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2013245532A AU2013245532B2 (en) | 2009-03-13 | 2013-10-18 | Articles and methods of treating vascular conditions |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/404,083 | 2009-03-13 | ||
AU2010223044A AU2010223044B2 (en) | 2009-03-13 | 2010-03-11 | Articles and methods of treating vascular conditions |
AU2013245532A AU2013245532B2 (en) | 2009-03-13 | 2013-10-18 | Articles and methods of treating vascular conditions |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2010223044A Division AU2010223044B2 (en) | 2009-03-13 | 2010-03-11 | Articles and methods of treating vascular conditions |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2013245532A1 AU2013245532A1 (en) | 2013-11-07 |
AU2013245532B2 true AU2013245532B2 (en) | 2014-09-25 |
Family
ID=49515685
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2013245532A Active AU2013245532B2 (en) | 2009-03-13 | 2013-10-18 | Articles and methods of treating vascular conditions |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2013245532B2 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020019369A1 (en) * | 2000-05-19 | 2002-02-14 | Jun Li | Injectable drug delivery systems with cyclodextrin-polymer based hydrogels |
US20040072799A1 (en) * | 2002-07-19 | 2004-04-15 | Omeros Corporation | Biodegradable triblock copolymers, synthesis methods therefore, and hydrogels and biomaterials made there from |
-
2013
- 2013-10-18 AU AU2013245532A patent/AU2013245532B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020019369A1 (en) * | 2000-05-19 | 2002-02-14 | Jun Li | Injectable drug delivery systems with cyclodextrin-polymer based hydrogels |
US20040072799A1 (en) * | 2002-07-19 | 2004-04-15 | Omeros Corporation | Biodegradable triblock copolymers, synthesis methods therefore, and hydrogels and biomaterials made there from |
Non-Patent Citations (1)
Title |
---|
LI, j., et al., J Biomedical Materials Research Part A (2003) vol 65A, no. 2, pages 196-202 * |
Also Published As
Publication number | Publication date |
---|---|
AU2013245532A1 (en) | 2013-11-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20190247306A1 (en) | Articles and methods of treating vascular conditions | |
Kempe et al. | In situ forming implants—an attractive formulation principle for parenteral depot formulations | |
JP5438878B2 (en) | Methods to prevent the formation of endoleaks associated with endovascular repair of celiac aortic aneurysms | |
US10675038B2 (en) | Compositions and devices for the occlusion of cavities and passageways | |
ES2454559T3 (en) | Implant comprising a bioabsorbable coating with regulated hydrophobicity | |
Lee et al. | Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury | |
US9844597B2 (en) | Biocompatible in situ hydrogel | |
US20150017265A9 (en) | Methods of modifying myocardial infarction expansion | |
JP2019081805A (en) | Compounds and methods for prevention or treatment of restenosis | |
JP2008534058A5 (en) | ||
JP2009530031A5 (en) | ||
JP2009530039A5 (en) | ||
Li et al. | Application of responsive polymers in implantable medical devices and biosensors | |
Barnett et al. | Assessment of EmboGel—A selectively dissolvable radiopaque hydrogel for embolic applications | |
CN113873956A (en) | Embolization using temporary materials | |
AU2013245532B2 (en) | Articles and methods of treating vascular conditions | |
Yang et al. | In vivo quantitative assessment of catheter patency in rats | |
JP2023518271A (en) | liquid embolic agent | |
Rajiv et al. | Nanoburrs: a novel approach in the treatment of cardiovascular disease | |
JP2002536406A (en) | Alkylating agents for the treatment of cell proliferation | |
Ning et al. | Evaluating thermosensitive chitosan/beta-glycerophosphate sodium and fibroblast embolization for the treatment of cerebral arteriovenous malformation in a porcine model | |
RU2474423C1 (en) | Method of treatment of liver metastases | |
JP2003135587A (en) | Drug delivery via conformal film | |
UA55726U (en) | method for treatment of patients with sarcoma osteogenous |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FGA | Letters patent sealed or granted (standard patent) | ||
PC | Assignment registered |
Owner name: W. L. GORE & ASSOCIATES, INC. Free format text: FORMER OWNER WAS: GORE ENTERPRISE HOLDINGS, INC. |