CN101420922B - 多孔磷酸钙骨材料 - Google Patents
多孔磷酸钙骨材料 Download PDFInfo
- Publication number
- CN101420922B CN101420922B CN2006800520527A CN200680052052A CN101420922B CN 101420922 B CN101420922 B CN 101420922B CN 2006800520527 A CN2006800520527 A CN 2006800520527A CN 200680052052 A CN200680052052 A CN 200680052052A CN 101420922 B CN101420922 B CN 101420922B
- Authority
- CN
- China
- Prior art keywords
- poly
- calcium phosphate
- compositions according
- bmp
- compositions
- 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
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 246
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 245
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 239
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 238
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 78
- 239000000463 material Substances 0.000 title claims description 55
- 239000000203 mixture Substances 0.000 claims abstract description 210
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 73
- 239000007943 implant Substances 0.000 claims abstract description 52
- 239000004088 foaming agent Substances 0.000 claims description 57
- -1 Tri-Compress Chemical compound 0.000 claims description 53
- 239000011575 calcium Substances 0.000 claims description 47
- 239000003814 drug Substances 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 35
- 208000034189 Sclerosis Diseases 0.000 claims description 30
- 239000012530 fluid Substances 0.000 claims description 26
- 108090000623 proteins and genes Proteins 0.000 claims description 26
- 235000018102 proteins Nutrition 0.000 claims description 23
- 102000004169 proteins and genes Human genes 0.000 claims description 23
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 229910052586 apatite Inorganic materials 0.000 claims description 17
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims description 17
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 16
- 229920001661 Chitosan Polymers 0.000 claims description 16
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 16
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 15
- 229910019142 PO4 Inorganic materials 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 239000010452 phosphate Substances 0.000 claims description 15
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 13
- 229910052791 calcium Inorganic materials 0.000 claims description 13
- 239000003112 inhibitor Substances 0.000 claims description 13
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 10
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 8
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 102000013275 Somatomedins Human genes 0.000 claims description 8
- 239000001569 carbon dioxide Substances 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 239000004310 lactic acid Substances 0.000 claims description 8
- 235000014655 lactic acid Nutrition 0.000 claims description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 claims description 7
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 claims description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 7
- 239000005557 antagonist Substances 0.000 claims description 7
- 230000003115 biocidal effect Effects 0.000 claims description 7
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 claims description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 7
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 7
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 7
- 238000005115 demineralization Methods 0.000 claims description 7
- 230000002328 demineralizing effect Effects 0.000 claims description 7
- 235000019821 dicalcium diphosphate Nutrition 0.000 claims description 7
- 239000002532 enzyme inhibitor Substances 0.000 claims description 7
- 229940125532 enzyme inhibitor Drugs 0.000 claims description 7
- 229940088597 hormone Drugs 0.000 claims description 7
- 239000005556 hormone Substances 0.000 claims description 7
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 7
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 claims description 6
- 102100022544 Bone morphogenetic protein 7 Human genes 0.000 claims description 6
- 102000008186 Collagen Human genes 0.000 claims description 6
- 108010035532 Collagen Proteins 0.000 claims description 6
- 210000002805 bone matrix Anatomy 0.000 claims description 6
- ROPDWRCJTIRLTR-UHFFFAOYSA-L calcium metaphosphate Chemical compound [Ca+2].[O-]P(=O)=O.[O-]P(=O)=O ROPDWRCJTIRLTR-UHFFFAOYSA-L 0.000 claims description 6
- 229940043256 calcium pyrophosphate Drugs 0.000 claims description 6
- 229920001436 collagen Polymers 0.000 claims description 6
- 108020004707 nucleic acids Proteins 0.000 claims description 6
- 150000007523 nucleic acids Chemical class 0.000 claims description 6
- 102000039446 nucleic acids Human genes 0.000 claims description 6
- 238000011275 oncology therapy Methods 0.000 claims description 6
- 239000008363 phosphate buffer Substances 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 6
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 6
- 229960005486 vaccine Drugs 0.000 claims description 6
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 claims description 5
- 108010049974 Bone Morphogenetic Protein 6 Proteins 0.000 claims description 5
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 claims description 5
- 102100022525 Bone morphogenetic protein 6 Human genes 0.000 claims description 5
- 229920001503 Glucan Polymers 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 5
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 5
- 239000004571 lime Substances 0.000 claims description 5
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 150000004804 polysaccharides Chemical class 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 claims description 5
- 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 claims description 4
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims description 4
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 4
- 229940122815 Aromatase inhibitor Drugs 0.000 claims description 4
- 108010049976 Bone Morphogenetic Protein 5 Proteins 0.000 claims description 4
- 101710118482 Bone morphogenetic protein 10 Proteins 0.000 claims description 4
- 102100028726 Bone morphogenetic protein 10 Human genes 0.000 claims description 4
- 102100022526 Bone morphogenetic protein 5 Human genes 0.000 claims description 4
- 229920000049 Carbon (fiber) Polymers 0.000 claims description 4
- 229920002101 Chitin Polymers 0.000 claims description 4
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 4
- 229920000858 Cyclodextrin Polymers 0.000 claims description 4
- 229940121889 Endothelin A receptor antagonist Drugs 0.000 claims description 4
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 claims description 4
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 229920002527 Glycogen Polymers 0.000 claims description 4
- 102100035379 Growth/differentiation factor 5 Human genes 0.000 claims description 4
- 101710204282 Growth/differentiation factor 5 Proteins 0.000 claims description 4
- 102100035368 Growth/differentiation factor 6 Human genes 0.000 claims description 4
- 101710204281 Growth/differentiation factor 6 Proteins 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 4
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 4
- 108010076876 Keratins Proteins 0.000 claims description 4
- 102000011782 Keratins Human genes 0.000 claims description 4
- 102000005741 Metalloproteases Human genes 0.000 claims description 4
- 108010006035 Metalloproteases Proteins 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 239000004952 Polyamide Substances 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 229920001710 Polyorthoester Polymers 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 229940123934 Reductase inhibitor Drugs 0.000 claims description 4
- 108010022394 Threonine synthase Proteins 0.000 claims description 4
- 102000005497 Thymidylate Synthase Human genes 0.000 claims description 4
- 101710183280 Topoisomerase Proteins 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 239000000556 agonist Substances 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 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 claims description 4
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 4
- 230000000340 anti-metabolite Effects 0.000 claims description 4
- 230000002927 anti-mitotic effect Effects 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 229940100197 antimetabolite Drugs 0.000 claims description 4
- 239000002256 antimetabolite Substances 0.000 claims description 4
- 239000003886 aromatase inhibitor Substances 0.000 claims description 4
- 229920001400 block copolymer Polymers 0.000 claims description 4
- 150000001720 carbohydrates Chemical class 0.000 claims description 4
- 235000014633 carbohydrates Nutrition 0.000 claims description 4
- 239000004917 carbon fiber Substances 0.000 claims description 4
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 4
- 229960005188 collagen Drugs 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- YIOJGTBNHQAVBO-UHFFFAOYSA-N dimethyl-bis(prop-2-enyl)azanium Chemical compound C=CC[N+](C)(C)CC=C YIOJGTBNHQAVBO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003062 endothelin A receptor antagonist Substances 0.000 claims description 4
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)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 GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 4
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 229940014259 gelatin Drugs 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 229960005150 glycerol Drugs 0.000 claims description 4
- 229940096919 glycogen Drugs 0.000 claims description 4
- 150000002337 glycosamines Chemical class 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 229940027278 hetastarch Drugs 0.000 claims description 4
- 229920002674 hyaluronan Polymers 0.000 claims description 4
- 229960003160 hyaluronic acid Drugs 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 4
- 150000003949 imides Chemical class 0.000 claims description 4
- 239000002955 immunomodulating agent Substances 0.000 claims description 4
- 229940121354 immunomodulator Drugs 0.000 claims description 4
- 230000002584 immunomodulator Effects 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000002777 nucleoside Substances 0.000 claims description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 4
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 4
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 4
- 229920001042 poly(δ-valerolactone) Polymers 0.000 claims description 4
- 229920002647 polyamide Polymers 0.000 claims description 4
- 229920001610 polycaprolactone Polymers 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 claims description 4
- 239000000018 receptor agonist Substances 0.000 claims description 4
- 229940044601 receptor agonist Drugs 0.000 claims description 4
- 102000027483 retinoid hormone receptors Human genes 0.000 claims description 4
- 108091008679 retinoid hormone receptors Proteins 0.000 claims description 4
- 229960002901 sodium glycerophosphate Drugs 0.000 claims description 4
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 4
- REULQIKBNNDNDX-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl hydrogen phosphate Chemical compound [Na+].OCC(O)COP(O)([O-])=O REULQIKBNNDNDX-UHFFFAOYSA-M 0.000 claims description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 4
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- 108010049951 Bone Morphogenetic Protein 3 Proteins 0.000 claims description 3
- 102000003928 Bone morphogenetic protein 15 Human genes 0.000 claims description 3
- 108090000349 Bone morphogenetic protein 15 Proteins 0.000 claims description 3
- 102100024504 Bone morphogenetic protein 3 Human genes 0.000 claims description 3
- 102100022545 Bone morphogenetic protein 8B Human genes 0.000 claims description 3
- 108010041881 Growth Differentiation Factor 10 Proteins 0.000 claims description 3
- 108010090290 Growth Differentiation Factor 2 Proteins 0.000 claims description 3
- 102100040895 Growth/differentiation factor 10 Human genes 0.000 claims description 3
- 101710194452 Growth/differentiation factor 11 Proteins 0.000 claims description 3
- 102100040898 Growth/differentiation factor 11 Human genes 0.000 claims description 3
- 102100040892 Growth/differentiation factor 2 Human genes 0.000 claims description 3
- 229940122597 Histone acetyltransferase inhibitor Drugs 0.000 claims description 3
- 101000899368 Homo sapiens Bone morphogenetic protein 8B Proteins 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 229940088710 antibiotic agent Drugs 0.000 claims description 3
- 239000003667 hormone antagonist Substances 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 102000040430 polynucleotide Human genes 0.000 claims description 2
- 108091033319 polynucleotide Proteins 0.000 claims description 2
- 239000002157 polynucleotide Substances 0.000 claims description 2
- QXKAIJAYHKCRRA-JJYYJPOSSA-N D-arabinonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(O)=O QXKAIJAYHKCRRA-JJYYJPOSSA-N 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 27
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 239000000126 substance Substances 0.000 abstract description 11
- 239000011148 porous material Substances 0.000 abstract description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract description 4
- 239000011707 mineral Substances 0.000 abstract description 3
- 230000008439 repair process Effects 0.000 abstract description 2
- 239000000843 powder Substances 0.000 description 76
- 239000000243 solution Substances 0.000 description 25
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 19
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 19
- 229940112869 bone morphogenetic protein Drugs 0.000 description 19
- 239000007789 gas Substances 0.000 description 18
- 239000008187 granular material Substances 0.000 description 18
- 210000004369 blood Anatomy 0.000 description 17
- 239000008280 blood Substances 0.000 description 17
- 230000008569 process Effects 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 229920003023 plastic Polymers 0.000 description 15
- 239000004033 plastic Substances 0.000 description 15
- 239000000835 fiber Substances 0.000 description 12
- 235000021317 phosphate Nutrition 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- UUVBYOGFRMMMQL-UHFFFAOYSA-N calcium;phosphoric acid Chemical compound [Ca].OP(O)(O)=O UUVBYOGFRMMMQL-UHFFFAOYSA-N 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
- 238000010316 high energy milling Methods 0.000 description 10
- 230000011164 ossification Effects 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000001768 cations Chemical class 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000002513 implantation Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 7
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 7
- 229960002014 ixabepilone Drugs 0.000 description 7
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 7
- 239000011343 solid material Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000007547 defect Effects 0.000 description 6
- 239000003292 glue Substances 0.000 description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 230000036760 body temperature Effects 0.000 description 5
- 238000005520 cutting process Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 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 4
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HECLRDQVFMWTQS-UHFFFAOYSA-N Dicyclopentadiene Chemical compound C1C2C3CC=CC3C1C=C2 HECLRDQVFMWTQS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 102000009618 Transforming Growth Factors Human genes 0.000 description 4
- 108010009583 Transforming Growth Factors Proteins 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 4
- 229960003437 aminoglutethimide Drugs 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 229910052792 caesium Inorganic materials 0.000 description 4
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 238000006471 dimerization reaction Methods 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 230000035876 healing Effects 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 239000011572 manganese Substances 0.000 description 4
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 4
- 210000004623 platelet-rich plasma Anatomy 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 229910052701 rubidium Inorganic materials 0.000 description 4
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 239000004332 silver Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229910052716 thallium Inorganic materials 0.000 description 4
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 4
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 3
- 108010059616 Activins Proteins 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 229930003347 Atropine Natural products 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 3
- 102100026818 Inhibin beta E chain Human genes 0.000 description 3
- 102000002746 Inhibins Human genes 0.000 description 3
- 108010004250 Inhibins Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- 239000000488 activin Substances 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 239000003570 air Substances 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 3
- 229960000396 atropine Drugs 0.000 description 3
- 239000004068 calcium phosphate ceramic Substances 0.000 description 3
- 239000004568 cement Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 229960000633 dextran sulfate Drugs 0.000 description 3
- KQYGMURBTJPBPQ-UHFFFAOYSA-L disodium;2-(2-sulfonatoethyldisulfanyl)ethanesulfonate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)CCSSCCS([O-])(=O)=O KQYGMURBTJPBPQ-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 239000004744 fabric Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 239000000893 inhibin Substances 0.000 description 3
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 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 3
- 229960003299 ketamine Drugs 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 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 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000000963 osteoblast Anatomy 0.000 description 3
- 230000002188 osteogenic effect Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000004584 polyacrylic acid Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000003634 thrombocyte concentrate Substances 0.000 description 3
- 230000001228 trophic effect Effects 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 2
- BCXHDORHMMZBBZ-DORFAMGDSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;sulfuric acid Chemical compound OS(O)(=O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC BCXHDORHMMZBBZ-DORFAMGDSA-N 0.000 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 2
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 description 2
- WUIABRMSWOKTOF-OYALTWQYSA-O 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS(O)(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-O 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 2
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 description 2
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 101150015280 Cel gene Proteins 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 2
- 206010015548 Euthanasia Diseases 0.000 description 2
- 244000060234 Gmelina philippensis Species 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108010049264 Teriparatide Proteins 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 2
- 101100472152 Trypanosoma brucei brucei (strain 927/4 GUTat10.1) REL1 gene Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 210000004381 amniotic fluid Anatomy 0.000 description 2
- 229960004701 amonafide Drugs 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000001166 anti-perspirative effect Effects 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229940111136 antiinflammatory and antirheumatic drug fenamates Drugs 0.000 description 2
- 239000003213 antiperspirant Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 229960003644 aztreonam Drugs 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 239000010836 blood and blood product Substances 0.000 description 2
- 229940125691 blood product Drugs 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052793 cadmium Inorganic materials 0.000 description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 238000009566 cancer vaccine Methods 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000008619 cell matrix interaction Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 2
- 229960002559 chlorotrianisene Drugs 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 210000001136 chorion Anatomy 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 229960003871 codeine sulfate Drugs 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- GJQPMPFPNINLKP-UHFFFAOYSA-N diclofenamide Chemical compound NS(=O)(=O)C1=CC(Cl)=C(Cl)C(S(N)(=O)=O)=C1 GJQPMPFPNINLKP-UHFFFAOYSA-N 0.000 description 2
- 229960005081 diclofenamide Drugs 0.000 description 2
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 2
- 229960000452 diethylstilbestrol Drugs 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960002568 ethinylestradiol Drugs 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229940060037 fluorine Drugs 0.000 description 2
- 229960001751 fluoxymesterone Drugs 0.000 description 2
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 238000000713 high-energy ball milling Methods 0.000 description 2
- 230000020245 homoiothermy Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000001861 immunosuppressant effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 210000004880 lymph fluid Anatomy 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052748 manganese Inorganic materials 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 229960004616 medroxyprogesterone Drugs 0.000 description 2
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229960004715 morphine sulfate Drugs 0.000 description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 102000045246 noggin Human genes 0.000 description 2
- 108700007229 noggin Proteins 0.000 description 2
- 210000003458 notochord Anatomy 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- BWKDAMBGCPRVPI-ZQRPHVBESA-N ortataxel Chemical compound O([C@@H]1[C@]23OC(=O)O[C@H]2[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]2(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]21)OC(C)=O)C3(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC(C)C)C(=O)C1=CC=CC=C1 BWKDAMBGCPRVPI-ZQRPHVBESA-N 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 229960001789 papaverine Drugs 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Chemical compound CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 description 2
- 229960003893 phenacetin Drugs 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 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 2
- 230000001737 promoting effect Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 229960004432 raltitrexed Drugs 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 239000004945 silicone rubber Substances 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229910052712 strontium Inorganic materials 0.000 description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- 229960000894 sulindac Drugs 0.000 description 2
- 210000001179 synovial fluid Anatomy 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 2
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 2
- 229960001017 tolmetin Drugs 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 229960003741 tranylcypromine Drugs 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 210000001325 yolk sac Anatomy 0.000 description 2
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- 229930007631 (-)-perillyl alcohol Natural products 0.000 description 1
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- JMPZTWDLOGTBPM-OUQSKUGOSA-N (2e,4e,6e)-7-(3,5-ditert-butylphenyl)-3-methylocta-2,4,6-trienoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)C1=CC(C(C)(C)C)=CC(C(C)(C)C)=C1 JMPZTWDLOGTBPM-OUQSKUGOSA-N 0.000 description 1
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 1
- GTXSRFUZSLTDFX-HRCADAONSA-N (2s)-n-[(2s)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-4-methyl-2-[[(2s)-2-sulfanyl-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butanoyl]amino]pentanamide Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](S)CCN1C(=O)N(C)C(C)(C)C1=O GTXSRFUZSLTDFX-HRCADAONSA-N 0.000 description 1
- PSVUJBVBCOISSP-SPFKKGSWSA-N (2s,3r,4s,5s,6r)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@@H](OP(=O)(NCCCl)NCCCl)[C@H](O)[C@@H](O)[C@@H]1O PSVUJBVBCOISSP-SPFKKGSWSA-N 0.000 description 1
- NBRQRXRBIHVLGI-OWXODZSWSA-N (4as,5ar,12ar)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C(C2=O)[C@@H]1C[C@@H]1[C@@]2(O)C(O)=C(C(=O)N)C(=O)C1 NBRQRXRBIHVLGI-OWXODZSWSA-N 0.000 description 1
- OJHZNMVJJKMFGX-BWCYBWMMSA-N (4r,4ar,7ar,12bs)-9-methoxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC OJHZNMVJJKMFGX-BWCYBWMMSA-N 0.000 description 1
- HGPQAWTZLJXCTC-SSTWWWIQSA-N (4r,4ar,7s,7ar,12bs)-7,9-dimethoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline Chemical compound C([C@@H](N(CC1)C)[C@@H]2C=C[C@@H]3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 HGPQAWTZLJXCTC-SSTWWWIQSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- KMSKQZKKOZQFFG-YXRRJAAWSA-N (7S,9S)-7-[[(2R,4S,5S,6S)-4-amino-6-methyl-5-[[(2R)-2-oxanyl]oxy]-2-oxanyl]oxy]-6,9,11-trihydroxy-9-(2-hydroxy-1-oxoethyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-YXRRJAAWSA-N 0.000 description 1
- RGVRUQHYQSORBY-JIGXQNLBSA-N (7s,9r)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyethyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@](O)(CCO)CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 RGVRUQHYQSORBY-JIGXQNLBSA-N 0.000 description 1
- BSRQHWFOFMAZRL-BODGVHBXSA-N (7s,9s)-7-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@@H](O)C[C@H](O[C@@H]2C3=C(O)C=4C(=O)C5=CC=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)O[C@H]1C BSRQHWFOFMAZRL-BODGVHBXSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- JWDYCNIAQWPBHD-UHFFFAOYSA-N 1-(2-methylphenyl)glycerol Chemical compound CC1=CC=CC=C1OCC(O)CO JWDYCNIAQWPBHD-UHFFFAOYSA-N 0.000 description 1
- YGEIMSMISRCBFF-UHFFFAOYSA-M 1-[bis(4-chlorophenyl)methyl]-3-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazol-3-ium;chloride Chemical compound [Cl-].C1=CC(Cl)=CC=C1C([N+]1=CN(CC(OCC=2C(=CC(Cl)=CC=2)Cl)C=2C(=CC(Cl)=CC=2)Cl)C=C1)C1=CC=C(Cl)C=C1 YGEIMSMISRCBFF-UHFFFAOYSA-M 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- UKNVCOILWOLTLJ-UHFFFAOYSA-N 10-(3-aminopropylimino)-6,8-dihydroxy-14-[2-(2-hydroxyethylamino)ethyl]-14,15-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-1,4,6,8,11,13(16)-hexaen-3-one Chemical compound C1=CC(=NCCCN)C2=C(C3=C(C=CC(=O)C3=C4C2=C1N(N4)CCNCCO)O)O UKNVCOILWOLTLJ-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- QMVPQBFHUJZJCS-NTKFZFFISA-N 1v8x590xdp Chemical compound O=C1N(NC(CO)CO)C(=O)C(C2=C3[CH]C=C(O)C=C3NC2=C23)=C1C2=C1C=CC(O)=C[C]1N3[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QMVPQBFHUJZJCS-NTKFZFFISA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- QCEWCMMSOWEHFC-UHFFFAOYSA-N 2-(diethylamino)-1-phenothiazin-10-ylpropan-1-one Chemical compound C1=CC=C2N(C(=O)C(C)N(CC)CC)C3=CC=CC=C3SC2=C1 QCEWCMMSOWEHFC-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PBUUPFTVAPUWDE-UGZDLDLSSA-N 2-[[(2S,4S)-2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2lambda5-oxazaphosphinan-4-yl]sulfanyl]ethanesulfonic acid Chemical compound OS(=O)(=O)CCS[C@H]1CCO[P@](=O)(N(CCCl)CCCl)N1 PBUUPFTVAPUWDE-UGZDLDLSSA-N 0.000 description 1
- GNXFOGHNGIVQEH-UHFFFAOYSA-N 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate Chemical compound COC1=CC=CC=C1OCC(O)COC(N)=O GNXFOGHNGIVQEH-UHFFFAOYSA-N 0.000 description 1
- FFRFGVHNKJYNOV-DOVUUNBWSA-N 3',4'-Anhydrovinblastine 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)CC)N2CCC2=C1NC1=CC=CC=C21 FFRFGVHNKJYNOV-DOVUUNBWSA-N 0.000 description 1
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 1
- OFKWWALNMPEOSZ-UHFFFAOYSA-N 3-(hydrazinylmethyl)phenol Chemical compound NNCC1=CC=CC(O)=C1 OFKWWALNMPEOSZ-UHFFFAOYSA-N 0.000 description 1
- ZCNBZFRECRPCKU-UHFFFAOYSA-N 3-[2-[4-[bis(4-fluorophenyl)methylidene]-1-piperidinyl]ethyl]-2-sulfanylidene-1H-quinazolin-4-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)=C1CCN(CCN2C(C3=CC=CC=C3NC2=S)=O)CC1 ZCNBZFRECRPCKU-UHFFFAOYSA-N 0.000 description 1
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 0.000 description 1
- WELIVEBWRWAGOM-UHFFFAOYSA-N 3-amino-n-[2-[2-(3-aminopropanoylamino)ethyldisulfanyl]ethyl]propanamide Chemical compound NCCC(=O)NCCSSCCNC(=O)CCN WELIVEBWRWAGOM-UHFFFAOYSA-N 0.000 description 1
- ASYYOZSDALANRF-UHFFFAOYSA-K 3-bis[(2-methyl-4-oxopyran-3-yl)oxy]gallanyloxy-2-methylpyran-4-one Chemical compound [Ga+3].CC=1OC=CC(=O)C=1[O-].CC=1OC=CC(=O)C=1[O-].CC=1OC=CC(=O)C=1[O-] ASYYOZSDALANRF-UHFFFAOYSA-K 0.000 description 1
- UQTZMGFTRHFAAM-ZETCQYMHSA-N 3-iodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(I)=C1 UQTZMGFTRHFAAM-ZETCQYMHSA-N 0.000 description 1
- DEHHYUARFKIUDI-UHFFFAOYSA-N 3-phenylprop-2-yn-1-amine Chemical compound NCC#CC1=CC=CC=C1 DEHHYUARFKIUDI-UHFFFAOYSA-N 0.000 description 1
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- ZFTBZKVVGZNMJR-UHFFFAOYSA-N 5-chlorouracil Chemical compound ClC1=CNC(=O)NC1=O ZFTBZKVVGZNMJR-UHFFFAOYSA-N 0.000 description 1
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 1
- MFVJXLPANKSLLD-UHFFFAOYSA-N 6-[2-[4-[(4-fluorophenyl)-phenylmethylidene]-1-piperidinyl]ethyl]-7-methyl-5-thiazolo[3,2-a]pyrimidinone Chemical compound CC=1N=C2SC=CN2C(=O)C=1CCN(CC1)CCC1=C(C=1C=CC(F)=CC=1)C1=CC=CC=C1 MFVJXLPANKSLLD-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 241001132374 Asta Species 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 239000004604 Blowing Agent Substances 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- PPLORYOLFQMIAS-UHFFFAOYSA-N C=1C=NNC=1.C1=CC=CC2=CC3=CC=CC=C3C=C21 Chemical class C=1C=NNC=1.C1=CC=CC2=CC3=CC=CC=C3C=C21 PPLORYOLFQMIAS-UHFFFAOYSA-N 0.000 description 1
- VSEIDZLLWQQJGK-CHOZPQDDSA-N CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O Chemical compound CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O VSEIDZLLWQQJGK-CHOZPQDDSA-N 0.000 description 1
- 108010004480 CTP37 peptide Proteins 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000202252 Cerberus Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000005696 Diammonium phosphate Substances 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 102000027587 GPCRs class F Human genes 0.000 description 1
- 108091008884 GPCRs class F Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 108010043766 IRX 2 Proteins 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102100030694 Interleukin-11 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- 241001484259 Lacuna Species 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 235000019738 Limestone Nutrition 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- UZUUQCBCWDBYCG-UHFFFAOYSA-N Mitomycin B Natural products O=C1C(OC)=C(C)C(=O)C2=C1C(COC(N)=O)C1(O)N2CC2C1N2C UZUUQCBCWDBYCG-UHFFFAOYSA-N 0.000 description 1
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 1
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 1
- 101100175313 Mus musculus Gdf3 gene Proteins 0.000 description 1
- XKCWNEVAXQCMGP-YFKPBYRVSA-N N(5)-methyl-L-arginine Chemical compound NC(=N)N(C)CCC[C@H](N)C(O)=O XKCWNEVAXQCMGP-YFKPBYRVSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 206010029379 Neutrophilia Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- APSUXPSYBJVPPS-YAUKWVCOSA-N Norbinaltorphimine Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C=3C[C@]4(O)[C@]67CCN(CC8CC8)[C@@H]4CC=4C7=C(C(=CC=4)O)O[C@H]6C=3NC=25)O)CC1)O)CC1CC1 APSUXPSYBJVPPS-YAUKWVCOSA-N 0.000 description 1
- ONBWJWYUHXVEJS-ZTYRTETDSA-N Normorphine Chemical compound C([C@@H](NCC1)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ONBWJWYUHXVEJS-ZTYRTETDSA-N 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 229960005524 O6-benzylguanine Drugs 0.000 description 1
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 241000906034 Orthops Species 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 1
- 108091007643 Phosphate carriers Proteins 0.000 description 1
- 102100036154 Platelet basic protein Human genes 0.000 description 1
- 101710195957 Platelet basic protein Proteins 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Porfiromycine Chemical compound O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- DYAHQFWOVKZOOW-UHFFFAOYSA-N Sarin Chemical compound CC(C)OP(C)(F)=O DYAHQFWOVKZOOW-UHFFFAOYSA-N 0.000 description 1
- 190014017285 Satraplatin Chemical compound 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 102100031372 Thymidine phosphorylase Human genes 0.000 description 1
- 108700023160 Thymidine phosphorylases Proteins 0.000 description 1
- HWHLPVGTWGOCJO-UHFFFAOYSA-N Trihexyphenidyl Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 HWHLPVGTWGOCJO-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 108010059993 Vancomycin Proteins 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
- IUHMWLMDASQDJQ-ZBFHGGJFSA-N [(3ar,8bs)-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indol-7-yl] n,n-dimethylcarbamate Chemical compound C12=CC(OC(=O)N(C)C)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C IUHMWLMDASQDJQ-ZBFHGGJFSA-N 0.000 description 1
- XMYKNCNAZKMVQN-NYYWCZLTSA-N [(e)-(3-aminopyridin-2-yl)methylideneamino]thiourea Chemical compound NC(=S)N\N=C\C1=NC=CC=C1N XMYKNCNAZKMVQN-NYYWCZLTSA-N 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 1
- 229960002519 amoxapine Drugs 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- UVJYAKBJSGRTHA-ZCRGAIPPSA-N arglabin Chemical compound C1C[C@H]2C(=C)C(=O)O[C@@H]2[C@@H]2C(C)=CC[C@]32O[C@]31C UVJYAKBJSGRTHA-ZCRGAIPPSA-N 0.000 description 1
- UVJYAKBJSGRTHA-UHFFFAOYSA-N arglabin Natural products C1CC2C(=C)C(=O)OC2C2C(C)=CCC32OC31C UVJYAKBJSGRTHA-UHFFFAOYSA-N 0.000 description 1
- MCGDSOGUHLTADD-UHFFFAOYSA-N arzoxifene Chemical compound C1=CC(OC)=CC=C1C1=C(OC=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 MCGDSOGUHLTADD-UHFFFAOYSA-N 0.000 description 1
- 229950005529 arzoxifene Drugs 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 229950004810 atamestane Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- CWNBRNSIRVKSDC-UHFFFAOYSA-N azonafide Chemical compound C1=CC=C2C(C(N(CCN(C)C)C3=O)=O)=C4C3=CC=CC4=CC2=C1 CWNBRNSIRVKSDC-UHFFFAOYSA-N 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
- 229950011276 belotecan Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UJMDYLWCYJJYMO-UHFFFAOYSA-N benzene-1,2,3-tricarboxylic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1C(O)=O UJMDYLWCYJJYMO-UHFFFAOYSA-N 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical compound C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 1
- 229960003003 biperiden Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- CGVWPQOFHSAKRR-NDEPHWFRSA-N biricodar Chemical compound COC1=C(OC)C(OC)=CC(C(=O)C(=O)N2[C@@H](CCCC2)C(=O)OC(CCCC=2C=NC=CC=2)CCCC=2C=NC=CC=2)=C1 CGVWPQOFHSAKRR-NDEPHWFRSA-N 0.000 description 1
- 229950005124 biricodar Drugs 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- UBJAHGAUPNGZFF-XOVTVWCYSA-N bms-184476 Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC(C)=O)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)C=3C=CC=CC=3)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OCSC)C(=O)C1=CC=CC=C1 UBJAHGAUPNGZFF-XOVTVWCYSA-N 0.000 description 1
- GMJWGJSDPOAZTP-MIDYMNAOSA-N bms-188797 Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](OC(C)=O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)C=4C=CC=CC=4)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)OC)C(=O)C1=CC=CC=C1 GMJWGJSDPOAZTP-MIDYMNAOSA-N 0.000 description 1
- 229940036811 bone meal Drugs 0.000 description 1
- 239000002374 bone meal Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229950007296 cantuzumab mertansine Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- NMMGUHANGUWNBN-OGLOGDKOSA-N cep-751 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1C[C@](OC)(CO)[C@]4(C)O1 NMMGUHANGUWNBN-OGLOGDKOSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- IQCIQDNWBGEGRL-UHFFFAOYSA-N chembl1614651 Chemical compound O=C1C2=C(O)C=CC(O)=C2N2N=C(CNCCO)C3=CC=C(NCCCN)C1=C32 IQCIQDNWBGEGRL-UHFFFAOYSA-N 0.000 description 1
- ROWSTIYZUWEOMM-UHFFFAOYSA-N chembl488755 Chemical compound C12=CC=CC=C2C(=O)C2=C1C1=CC=C(O)C=C1N=C2NCCN(C)C ROWSTIYZUWEOMM-UHFFFAOYSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OSLQQDMGHVQLCH-HRMPSQMFSA-N chlornaltrexamine Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC[C@H]5N(CCCl)CCCl)O)CC1)O)CC1CC1 OSLQQDMGHVQLCH-HRMPSQMFSA-N 0.000 description 1
- 229940127069 chlornaltrexamine Drugs 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 229950002858 clorgiline Drugs 0.000 description 1
- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-UHFFFAOYSA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- POADTFBBIXOWFJ-VWLOTQADSA-N cositecan Chemical compound C1=CC=C2C(CC[Si](C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 POADTFBBIXOWFJ-VWLOTQADSA-N 0.000 description 1
- 238000011262 co‐therapy Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- JURKNVYFZMSNLP-UHFFFAOYSA-N cyclobenzaprine Chemical compound C1=CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 JURKNVYFZMSNLP-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940094111 depo-testosterone Drugs 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 1
- 235000019838 diammonium phosphate Nutrition 0.000 description 1
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- LFQCJSBXBZRMTN-OAQYLSRUSA-N diflomotecan Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC(F)=C(F)C=C3N=C21 LFQCJSBXBZRMTN-OAQYLSRUSA-N 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229940090949 docosahexaenoic acid Drugs 0.000 description 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 1
- 108010045524 dolastatin 10 Proteins 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 229960002406 edrophonium chloride Drugs 0.000 description 1
- BXKDSDJJOVIHMX-UHFFFAOYSA-N edrophonium chloride Chemical compound [Cl-].CC[N+](C)(C)C1=CC=CC(O)=C1 BXKDSDJJOVIHMX-UHFFFAOYSA-N 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 1
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960003399 estrone 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
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229940099283 flexeril Drugs 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229940020947 fluorescein sodium Drugs 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229940053641 forteo Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000002272 genistein Chemical class 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229950011595 glufosfamide Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 239000004047 hole gas Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 229960002899 hydroxyprogesterone Drugs 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- MPGWGYQTRSNGDD-UHFFFAOYSA-N hypericin Chemical compound OC1=CC(O)=C(C2=O)C3=C1C1C(O)=CC(=O)C(C4=O)=C1C1=C3C3=C2C(O)=CC(C)=C3C2=C1C4=C(O)C=C2C MPGWGYQTRSNGDD-UHFFFAOYSA-N 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 description 1
- 239000000960 hypophysis hormone Substances 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- VDJHFHXMUKFKET-WDUFCVPESA-N ingenol mebutate Chemical compound C[C@@H]1C[C@H]2C(C)(C)[C@H]2[C@@H]2C=C(CO)[C@@H](O)[C@]3(O)[C@@H](OC(=O)C(\C)=C/C)C(C)=C[C@]31C2=O VDJHFHXMUKFKET-WDUFCVPESA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 229940074383 interleukin-11 Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940070023 iproniazide Drugs 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229950005254 irofulven Drugs 0.000 description 1
- NICJCIQSJJKZAH-AWEZNQCLSA-N irofulven Chemical compound O=C([C@@]1(O)C)C2=CC(C)=C(CO)C2=C(C)C21CC2 NICJCIQSJJKZAH-AWEZNQCLSA-N 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- KXJTWOGIBOWZDJ-LELJLAJGSA-N l-blp25 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)[C@@H](C)O)C1=CNC=N1 KXJTWOGIBOWZDJ-LELJLAJGSA-N 0.000 description 1
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000006028 limestone Substances 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229950000547 mafosfamide Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 229960004090 maprotiline Drugs 0.000 description 1
- QSLMDECMDJKHMQ-GSXCWMCISA-N maprotiline Chemical compound C12=CC=CC=C2[C@@]2(CCCNC)C3=CC=CC=C3[C@@H]1CC2 QSLMDECMDJKHMQ-GSXCWMCISA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000901 mepacrine Drugs 0.000 description 1
- 229960003861 mephenesin Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- IMSSROKUHAOUJS-MJCUULBUSA-N mestranol Chemical compound C1C[C@]2(C)[C@@](C#C)(O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 IMSSROKUHAOUJS-MJCUULBUSA-N 0.000 description 1
- 229960001390 mestranol Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229960002931 methacholine chloride Drugs 0.000 description 1
- JHPHVAVFUYTVCL-UHFFFAOYSA-M methacholine chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(C)=O JHPHVAVFUYTVCL-UHFFFAOYSA-M 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 description 1
- 229960002330 methocarbamol Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- UZUUQCBCWDBYCG-DQRAMIIBSA-N mitomycin B Chemical compound O=C1C(OC)=C(C)C(=O)C2=C1[C@H](COC(N)=O)[C@]1(O)N2C[C@H]2[C@@H]1N2C UZUUQCBCWDBYCG-DQRAMIIBSA-N 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- AARXZCZYLAFQQU-UHFFFAOYSA-N motexafin gadolinium Chemical compound [Gd].CC(O)=O.CC(O)=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 AARXZCZYLAFQQU-UHFFFAOYSA-N 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Polymers CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- YKQOSKADJPQZHB-YNWHQGOSSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1s)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Polymers CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O YKQOSKADJPQZHB-YNWHQGOSSA-N 0.000 description 1
- LPTMSYYPRXIMMJ-UHFFFAOYSA-N n-chloro-1-phenylethanamine Chemical compound ClNC(C)C1=CC=CC=C1 LPTMSYYPRXIMMJ-UHFFFAOYSA-N 0.000 description 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 1
- 229960000805 nalbuphine Drugs 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- AJPSBXJNFJCCBI-YOHUGVJRSA-N naloxonazine Chemical compound C([C@@H](N(CC1)CC=C)[C@]2(O)CC\C3=N/N=C4/[C@H]5[C@]67CCN(CC=C)[C@@H]([C@@]7(CC4)O)CC4=CC=C(C(O5)=C46)O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 AJPSBXJNFJCCBI-YOHUGVJRSA-N 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- DKJCUVXSBOMWAV-PCWWUVHHSA-N naltrindole Chemical compound N1([C@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC2=C3[CH]C=CC=C3N=C25)O)CC1)O)CC1CC1 DKJCUVXSBOMWAV-PCWWUVHHSA-N 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229960001499 neostigmine bromide Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 229960003057 nialamide Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- XHWRWCSCBDLOLM-UHFFFAOYSA-N nolatrexed Chemical compound CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 XHWRWCSCBDLOLM-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- HKOIXWVRNLGFOR-KOFBORESSA-N norcodeine Chemical compound O[C@H]([C@@H]1O2)C=C[C@H]3[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 HKOIXWVRNLGFOR-KOFBORESSA-N 0.000 description 1
- 229950004392 norcodeine Drugs 0.000 description 1
- HKOIXWVRNLGFOR-UHFFFAOYSA-N norcodeine Natural products O1C2C(O)C=CC3C4CC5=CC=C(OC)C1=C5C23CCN4 HKOIXWVRNLGFOR-UHFFFAOYSA-N 0.000 description 1
- 229940053934 norethindrone Drugs 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- 230000002642 osteogeneic effect Effects 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 108700027936 paclitaxel poliglumex Proteins 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 108010013121 palladium-bacteriopheophorbide Proteins 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960001779 pargyline Drugs 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 210000000062 pectoralis major Anatomy 0.000 description 1
- 210000002976 pectoralis muscle Anatomy 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 235000005693 perillyl alcohol Nutrition 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- 229940085991 phosphate ion Drugs 0.000 description 1
- YPDVTKJXVHYWFY-UHFFFAOYSA-N phosphoric acid;n'-propan-2-ylpyridine-4-carbohydrazide Chemical compound OP(O)(O)=O.CC(C)NNC(=O)C1=CC=NC=C1 YPDVTKJXVHYWFY-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229960001621 povidone-iodine Drugs 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
- 238000003825 pressing Methods 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000044 progesterone antagonist Substances 0.000 description 1
- 229960002662 propylthiouracil Drugs 0.000 description 1
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940030966 pyrrole Drugs 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- 229960001424 quinestrol Drugs 0.000 description 1
- PWZUUYSISTUNDW-VAFBSOEGSA-N quinestrol Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@]4(O)C#C)C)CC2=CC=3OC1CCCC1 PWZUUYSISTUNDW-VAFBSOEGSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 150000003349 semicarbazides Chemical class 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 108010047846 soblidotin Proteins 0.000 description 1
- DZMVCVHATYROOS-ZBFGKEHZSA-N soblidotin Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1=CC=CC=C1 DZMVCVHATYROOS-ZBFGKEHZSA-N 0.000 description 1
- VZWGHDYJGOMEKT-UHFFFAOYSA-J sodium pyrophosphate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O VZWGHDYJGOMEKT-UHFFFAOYSA-J 0.000 description 1
- SDKPSXWGRWWLKR-UHFFFAOYSA-M sodium;9,10-dioxoanthracene-1-sulfonate Chemical compound [Na+].O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)[O-] SDKPSXWGRWWLKR-UHFFFAOYSA-M 0.000 description 1
- 229950004330 spiroplatin Drugs 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229950010924 talaporfin Drugs 0.000 description 1
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960005460 teriparatide Drugs 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- GFFXZLZWLOBBLO-ASKVSEFXSA-N tezacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(=C/F)/[C@H](O)[C@@H](CO)O1 GFFXZLZWLOBBLO-ASKVSEFXSA-N 0.000 description 1
- 229950006410 tezacitabine Drugs 0.000 description 1
- 229960002178 thiamazole Drugs 0.000 description 1
- CFBLUORPOFELCE-BACVZHSASA-N thymectacin Chemical compound N1([C@@H]2O[C@@H]([C@H](C2)O)COP(=O)(N[C@@H](C)C(=O)OC)OC=2C=CC=CC=2)C=C(\C=C\Br)C(=O)NC1=O CFBLUORPOFELCE-BACVZHSASA-N 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- ZHAKYGFJVGCOAE-UHFFFAOYSA-N topixantrone Chemical compound OCCNCCN1N=C2C3=CN=CC=C3C(=O)C3=C2C1=CC=C3NCCN(C)C ZHAKYGFJVGCOAE-UHFFFAOYSA-N 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960005526 triapine Drugs 0.000 description 1
- 229960001032 trihexyphenidyl Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000035899 viability Effects 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
- 229960004528 vincristine Drugs 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
- 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
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- ZPUHVPYXSITYDI-HEUWMMRCSA-N xyotax Chemical compound OC(=O)[C@@H](N)CCC(O)=O.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 ZPUHVPYXSITYDI-HEUWMMRCSA-N 0.000 description 1
- 229950003684 zibotentan Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
- A61L2300/256—Antibodies, e.g. immunoglobulins, vaccines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
- A61L2300/434—Inhibitors, antagonists of enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
提供了化学组成与天然骨材料相似的多孔磷酸钙植入组合物。除磷酸钙以外,该组合物还含有促进互相连通孔形成的发泡剂和保持硬化的组合物的形状和硬度的黏聚剂。当加入到植入部位时,该磷酸钙组合物重建成骨骼。还提供了使用该磷酸钙组合物(例如)修复或替换骨骼的方法。
Description
发明背景
本发明的领域是骨修复和替换。更具体地说,本发明涉及一种自硬化的多孔磷酸钙复合物,它具有理想的加工性能和力学性质。
天然存在的骨骼包括有机和无机组分。有机组分包括生长因子、软骨、胶原和其它蛋白质。无机骨组分包括非化学计量的低晶磷灰石(PCA)磷酸钙,其Ca/P比在1.45和1.75之间(Besic等(1969),J.Dental Res.48(1):131)。这种无机骨矿物质在体内被破骨细胞和成骨细胞连续地吸收和再生,此过程称为骨重建。
骨植入物常用来在骨缺损和受伤的事件中增进天然的再生过程。这些植入物必须是生物相容的,在植入前能被外科医生操纵,并且具有能使植入物在体内保持其形状的强度和成分。
考虑到它的再生能力,天然骨是一种可能的植入材料。然而,自生的、同种异体的和异种的骨的使用,由于相关的疾病传播、免疫原性植入物排斥、患者发病率和复杂的手术步骤而变得复杂。因此,合成的骨植入材料成为日益关注的焦点。
可塑的自固化磷酸钙粘固剂显示出良好的强度性质,并且能容易地原位成形以填充多种临床缺损,但是由于细胞不能透过该致密材料而重建缓慢。多孔磷酸钙陶瓷是优选的植入材料,因为它们允许血管、细胞和组织、以及药物透过,而这些对于促进骨形成和防止感染是重要的。当作为植入材料使用时,多孔磷酸钙陶瓷优选具有高孔隙率。这一高孔隙率会造成多孔基体的机械强度较低,因此抵消了它们作为需要高机械强度的骨植入物的好处。另外,预先形成的多孔的小块和颗粒会难以操纵和植入,而且能导致缺损填充不完全。因此,需要兼有优异的生物相容性和机械强度的多孔磷酸钙陶瓷。
发明概要
提供了与天然骨的化学成分相近的自硬化多孔磷酸钙组合物。该磷酸钙组合物的孔隙率(孔的数目和大小)由硬化过程中从混合物中逸出的发泡剂气相组分的释放速率决定。
在第一方面,本发明的特色在于一种组合物,其中包含磷酸钙、发泡剂和生物相容的黏聚剂(例如,黏合剂)。该组合物用一种磷酸钙源制备,选自无定形磷酸钙、低晶磷酸钙、羟基磷灰石、碳酸化磷灰石(贫钙羟基磷灰石)、磷酸一钙、偏磷酸钙、磷酸七钙、二水合磷酸二钙、磷酸四钙、磷酸八钙、焦磷酸钙和磷酸三钙,或它们的混合物。或者是,该组合物用一种无定形磷酸钙和一种第二磷酸钙源制备,后者的实例包括,低晶磷酸钙、羟基磷灰石、磷酸化磷灰石(贫钙羟基磷灰石)、磷酸一钙、偏磷酸钙、磷酸七钙、二水合磷酸二钙、磷酸四钙、磷酸八钙、焦磷酸钙或磷酸三钙,或它们的混合物。
在一项实施方案中,发泡剂包括碳酸盐/碳酸氢盐混合物,其中碳酸盐和碳酸氢盐组分按预定的摩尔比组合,例如,比例为约1∶1至约1∶9的碳酸盐/碳酸氢盐,优选为约1∶1、1∶2、1∶3、1∶4、1∶5、1∶6、1∶7、1∶8或1∶9。在一项实施方案中,发泡剂是化学式为MxCO3/M’yHCO3的碳酸盐/碳酸氢盐化合物的混合物,其中M和M’是一价阳离子,例如,钠(Na)、钾(K)、锂(Li)、铷(Rb)、铯(Cs)、银(Ag)、铊(Tl)和铵(NH4 +),x=2,y=1。在另一实施方案中,发泡剂是化学式为MxCO3/M’yHCO3的碳酸盐/碳酸氢盐化合物的混合物,其中M是一个二价阳离子,例如,钡(Ba)、镉(Cd)、钙(Ca)、钴(Co)、铜(Cu)、铁(Fe)、镁(Mg)、锰(Mn)、镍(Ni)、锶(Sr)和锌(Zn),M’是一价阳离子,例如,钠(Na)、钾(K)、锂(Li)、铷(Rb)、铯(Cs)、银(Ag)、铊(Tl)和铵(NH4 +),x=1和y=1。在一项优选的实施方案中,选择发泡剂中碳酸盐与碳酸氢盐的摩尔比以促进在磷酸钙组合物硬化时从中受控释放出二氧化碳。在另一实施方案中,选择起泡剂中碳酸盐/碳酸氢盐组分的摩尔比以促进相互连通的孔的形成,这些孔的中值孔径为约1至约1000μm,更优选约1-100μm。在另一实施方案中,通过自发泡剂中释放二氧化碳至少1分钟,更优选至少2、3或4分钟,最优选约5分钟或更长,促进孔的形成;发泡剂中碳酸氢盐相对于碳酸盐的摩尔比的增加会增加二氧化碳的释放时间,同时孔隙率提高。
在另一实施方案中,发泡剂是在植入前溶在磷酸酸组合物中的一种气体,它在硬化期间以选定能产生所要求数量的互连孔的速率从磷酸钙组合物中释放出来。例如,选择发泡剂,使其在硬化期间能释放1分钟,优选2、3或4分钟,更优选约5分钟或更长时间的气体,从而制得孔隙率至少为约5-60%的硬化的磷酸钙。优选磷酸钙组合物的孔隙率为约5%,更优选为约10%、20%或30%,最优选孔隙率为约40%、50%或60%。在一项优选的实施方案中,磷酸钙有至少约50%的孔隙率。最好是,选择发泡剂以促进形成中值孔径约1-1000μm、更优选约10-100μm的互连孔。在优选的实施方案中,气体是选自二氧化碳、空气、氮气、氦、氧和氩。在另一实施方案中,发泡剂是在溶解时释放气体的固体物质(例如碳酸盐,如碳酸氢钠)。在一项优选的实施方案中,发泡剂在磷酸钙组合物硬化期间产生具有互连孔隙的连续基质。在另一优选的实施方案中,发泡剂的用量为约1-40重量%。在另一实施方案中,根据其在生物温度下缓慢发泡的能力选择发泡剂,该温度优选为约4-42℃,更优选为约15-37℃,最优选在约37℃。
在其它实施方案中,无定形磷酸钙和第二磷酸钙的平均晶畴大小小于100nm(例如,在约1-99nm的范围,优选50nm或更小,更优选10nm或更小)。
在另一实施方案中,磷酸钙是一种非晶化的磷酸钙,其平均晶畴大小小于例如约100nm,振实密度大于0.7g/cm3。在另一实施方案中,该非晶化的磷酸钙选自一种或多种无定形磷酸钙、低晶磷酸钙、羟基磷灰石、碳酸化碳灰石(贫钙羟基磷灰石)、磷酸一钙、偏磷酸钙、磷酸七钙、二水合磷酸二钙、磷酸四钙、磷酸八钙、焦磷酸钙和磷酸三钙,或它们的混合物。
在另一实施方案中,组合物中包含一种生物相容性黏聚剂。在优选的实施方案中,该黏聚剂包括聚合物,选自:多糖类,核酸,碳水化合物,蛋白质,多肽,聚(α-羟基酸),聚(内酯),聚(氨基酸),聚(酸酐),聚(原酸酯),聚(酸酐-CO-酰亚胺),聚(原碳酸酯),聚(α-羟基烷酸酯),聚(二噁烷酮),聚(磷酸酯),聚(L-丙交酯)(PLLA),聚(D,L-丙交酯)(PDLLA),聚乙交酯(PGA),聚(丙交酯-CO-乙交酯)(PLGA),聚(L-丙交酯-CO-D,L-丙交酯),聚(D,L-丙交酯-CO-亚丙基碳酸酯),聚羟基丁酸酯(PHB),聚(ε-己内酯),聚(δ-戊内酯),聚(γ-丁内酯),聚(己内酯),聚丙烯酸,聚羧酸,聚(盐酸烯丙胺)。聚(氯化二烯丙基二甲铵),聚(亚乙基亚胺),聚富马酸丙二醇酯,聚乙烯醇,聚乙烯基吡咯烷酮,聚乙烯,聚甲基丙烯酸甲酯,碳纤维,聚乙二醇,聚氧乙醇,聚(乙烯基醇),聚(乙烯基吡咯烷酮),聚(乙基噁唑啉),环氧乙烷-CO-环氧丙烷嵌段共聚物,聚(对苯二甲酸乙二醇酯),聚酰胺,及它们的共聚物。优选的黏聚剂还包括藻酸,阿拉伯胶,瓜尔胶,黄原胶,明胶,壳多糖,脱乙酰壳多糖,乙酸脱乙酰壳多糖,乳酸脱乙酰壳多糖,硫酸软骨素,N,O-羧甲基脱乙酰壳多糖,葡聚糖(例如,α-环糊精,β-环糊精,γ-环糊精,或硫酸葡聚糖钠),纤维蛋白胶,甘油,透明质酸,透明质酸钠,纤维素(例如,甲基纤维素,羧甲基纤维素,羟丙基甲基纤维素或羟乙基纤维素),葡糖胺,蛋白聚糖,淀粉(例如,羟乙基淀粉或可溶性淀粉),乳酸,环氧乙烷与环氧丙烷共聚物,甘油磷酸钠,胶原,糖原,角蛋白,丝及它们的混合物。在另一项优选的实施方案中,组合物中的生物相容性黏聚剂的数量为约0.5-20%重量(例如少于约20%,优选少于约10%,更优选少于约5%,最优选少于约1%重量)。
在其它实施方案中,当把生理上可接受的流体加到组合物的干组分中时,产生自硬化的糊或油灰状物。在本发明的几个实施方案中,合适的生理上可接受的流体包括,但不限于,水、盐水和磷酸盐缓冲液。在其它实施方案中,该流体可以是一种生物流体,例如与活的生命体有关的处理过或未处理过的流体(包括悬浮液),特别是血液,包括全血、温血或冷血,以及储存血或新鲜血;处理过的血,例如用至少一种生理溶液(包括但不限于盐水、营养液和/或抗凝血溶液)稀释过的血液;血液组分,例如血小板浓缩物(PC)、采集分离的血小板、富血小板血浆(PRP)、贫血小板血浆(PPP)、无血小板血浆、血浆、血清、新鲜冷冻血浆(FFP)、从血浆得到的组分、浓缩红细胞(PRC)、血沉棕黄层(BC);从血液或血液组分衍生的或从骨髓中衍生的血液产物;从血浆中分离后再悬浮于生理流体中的红血球;以及从血浆中分离后再悬浮于生理流体中的血小板。在其它实施方案中,该生物流体包括,例如,奶、尿、唾液、精液或阴道流体,滑膜流体,淋巴液,羊水,卵的卵黄囊,卵壳或尿壳内的流体,汗和眼泪。
本发明的磷酸钙组合物一旦水化形成糊状物之后,与大多数先前已知的骨植入材料相比,其流动特性改善。可以向粉末中加入不同数量的流体以产生具有所希望的特性的糊状物。例如,在至少某些实施方案中,每克粉末使用0.5-2.0cc的流体,以制备可成型的,即能够被模制并保持其形状的糊状物。在至少某些实施方案中,该糊状物是可注射的,即,能通过一只16至18号针头。糊状物也能制备成用于经由导管输送(例如,一只有7-15号针头,更优选一只有7、8、9、10、11、12、13、14或15号针头的导管)。
在另一方面,组合物在水化时产生一种可成型的自硬化的糊状物,它是可模制的,当施加到体内的移植部位时有黏聚性,并且硬化形成多孔的磷酸钙组合物。在至少某些实施方案中,该糊状物硬化形成具有显著的抗压强度的磷酸钙组合物(例如低晶磷灰石(PCA)磷酸钙)。该组合物可从以糊状形式或以硬化的磷酸钙的形式植入。组合物可以用来修复骨骼,例如损伤的骨骼,或者用来作为输运生物活性剂的载体。
根据一些实施方案,组合物中另外还包含一种生物活性剂。可以在本文中所述的组合物和方法中使用的生物活性剂包括,但不限于,抗体、抗生素、多核苷酸、多肽、蛋白质(例如成骨蛋白)、抗癌药物、生长因子和疫苗。成骨蛋白包括,但不限于,BMP-2、BMP-3、BMP-3b、BMP-4、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9、BMP-10、BMP-11、BMP-12、BMP-13、BMP-14、BMP-15、BMP-16、BMP-17和BMP-18。抗癌药物包括,但不限于,烷基化剂、铂试剂、抗代谢药、拓扑异构酶抑制剂、抗肿瘤抗体、抗有丝分裂药、芳化酶抑制剂、胸苷酸合成酶抑制剂、DNA拮抗剂、法呢基转移酶抑制剂、泵抑制剂、组蛋白脱乙酰酶抑制剂、金属蛋白酶抑制剂、核苷还原酶抑制剂、TNFα激动剂、TNFα拮抗剂、内皮素A受体拮抗剂、维甲酸受体激动剂、免疫调节剂、激素药物、抗激素药物、光动力学药物和酪氨酸激酶抑制剂。
在另一优选的实施方案中,组合物中包含去矿化的骨基质(DBM)。在一项优选的实施方案中,该DBM的粒子大小为53-850μm。在其它实施方案中,DBM的粒子大小为53-125μm(即,细粒)或125-850μm(即,全范围DBM颗粒)。
在其它实施方案中,磷酸钙组合物的Ca/P比小于1.67。在特别优选的实施方案中,可成型的自硬化多孔磷酸钙糊硬化形成磷酸钙。其总Ca/P比为1.0-1.67,优选为1.3-1.65,更优选为1.4-1.6,最优选接近于数值为1.45-1.67的天然存在的骨骼的Ca/P比。在一项优选的实施方案中,磷酸钙组合物的Ca/P比等于或小于约1.5。
在其它实施方案中,这种多孔的硬化磷酸钙组合物显示出等于或大于1或2MPa的抗压强度。在其它实施方案中,该抗压强度在约1MPa至约150MPa的范围内(例如,20、30、40、50、60、70、80、90或100MPa)。在其它优选的实施方案中,抗压强度为120MPa或更高(例如120至150MPa)。
在第二方面,本发明的特色在于一种骨修复的方法,包括向需要修复的对象施用一种自固化的多孔磷酸钙组合物,其中含有和生理上可接受的流体混合的磷酸钙、发泡剂和生物相容性黏聚剂(即,本发明第一方面中所述的组合物)。本发明第一方面的所有实施方案都适用于本发明第二方面中使用的组合物。
本文中使用的术语“约”,意味着所述数值的±10%。
本文中对磷酸钙使用的“无定形”一词,是指没有或只有短程晶序的磷酸钙,即,晶序小于100nm。
“非晶化”或“非晶化的”是指在热力学稳定形式中,晶格内,例如晶态或半晶态物质的原子、分子、离子和配位体之间存在的有序、重复的三维空间关系的机械或能量破坏的过程。该过程将平均的物质结晶度指数由其原始的有序态变为有序度变差的状态。
这里所说的“生物相容性”物质,是在接受者内不产生不可接受的或不良的生理响应,例如免疫响应的物质。
这里对组合物使用的“黏聚性”一词,是指组合物在与生物相容性流体混合时保持其形状和无质量损失的能力。如果组合物在水基环境中温育至少10分钟后,其初始质量和体积的90%以上保留在其初始形状轮廓内,则被认为是黏聚的。
本文中所说的“黏聚剂”是指一种添加剂,当它被包含在本发明的磷酸钙组合物中时,会改善磷酸钙组合物保持其黏聚性的能力。优选的黏聚剂包括聚合物,选自:多糖类,核酸,碳水化合物,蛋白质,多肽,聚(α-羟基酸),聚(内酯),聚(氨基酸),聚(酸酐),聚(原酸酯),聚(酸酐-CO-酰亚胺),聚(原碳酸酯),聚(α-羟基烷酸酯),聚(二噁烷酮),聚(磷酸酯),聚(L-丙交酯)(PLLA),聚(D,L-丙交酯)(PDLLA),聚乙交酯(PGA),聚(丙交酯-CO-乙交酯)(PLGA),聚(L-丙交酯-CO-D,L-丙交酯),聚(D,L-丙交酯-CO-亚丙基碳酸酯),聚羟基丁酸酯(PHB),聚(ε-己内酯),聚(δ-戊内酯),聚(γ-丁内酯),聚(己内酯),聚丙烯酸,聚羧酸,聚(盐酸烯丙胺)。聚(氯化二烯丙基二甲铵),聚(亚乙基亚胺),聚富马酸丙二醇酯,聚乙烯醇,聚乙烯基吡咯烷酮,聚乙烯,聚甲基丙烯酸甲酯,碳纤维,聚乙二醇,聚氧乙醇,聚(乙烯基醇),聚(乙烯基吡咯烷酮),聚(乙基噁唑啉),环氧乙烷-CO-环氧丙烷嵌段共聚物,聚(对苯二甲酸乙二醇酯),聚酰胺,及它们的共聚物。优选的黏聚剂还包括藻酸,阿拉伯胶,瓜尔胶,黄原胶,明胶,壳多糖,脱乙酰壳多糖,乙酸脱乙酰壳多糖,乳酸脱乙酰壳多糖,硫酸软骨素,N,O-羧甲基脱乙酰壳多糖,葡聚糖(例如,α-环糊精,β-环糊精,γ-环糊精,或硫酸葡聚糖钠),纤维蛋白胶,甘油,透明质酸,透明质酸钠,纤维素(例如,甲基纤维素,羧甲基纤维素,羟丙基甲基纤维素或羟乙基纤维素),葡糖胺,蛋白聚糖,淀粉(例如,羟乙基淀粉或可溶性淀粉),乳酸,环氧乙烷与环氧丙烷共聚物,甘油磷酸钠,胶原,糖原,角蛋白,丝及它们的混合物。
“发泡剂”是指能在组合物内产生气泡的试剂或从组合物中以气泡形式放出的试剂;组合物中气泡的产生或释放是组合物内产生孔隙的原因。
这里所说的“低晶磷灰石(PCA)磷酸钙”是指一种合成的磷酸钙材料,它具有与天然存在的骨赂中发现的相近的小晶畴,其特征是有一个宽的不太清晰的X射线衍射峰和Ca/P比小于1.67。PCA磷酸钙不必限于单一的磷酸钙相,只要它显示磷灰石矿物的特征X射线衍射峰,即,在20-35℃有两个宽峰,一个峰中心在26°,第二个峰中心在32°。
附图简述
参照以下附图来说本发明,列出该图只是为了说明,而无意用来限制本发明。
图1表示了含有无定形磷酸钙和二水合磷酸二钙(DCPD)的磷酸钙粉末在高能球磨机中高能磨研磨之前和研磨3、10、15和24小时后的X-射线衍射图。
发明详述
提供了可成型的自硬化多孔磷酸钙组合物,其化学成分与天然骨骼相近,并且当被引入到体内的植入部位里保持黏聚性。这些骨植入材料,不管其化学成分如何,都是高度诱导成骨的。磷酸钙组合物的孔隙率(孔的数目和大小)由硬化过程中从混合物中逸出的发泡剂的释放速率决定。另外,在硬化时,这些孔性植入材料显示出显著的抗压强度。
这种可成型的、自硬化多孔磷酸钙组合物包含磷酸钙粉、发泡剂和生物相容性黏聚剂(例如黏合剂)。当与生理上可接受的流体结合时,磷酸钙粉产生一种可成型的糊体,它硬化和反应,形成低晶磷灰石磷酸钙。优选该低晶磷灰石磷酸钙的Ca/P比小于1.67。例如,该低晶磷灰石磷酸钙的总Ca/P比在1.0-1.67的范围内,优选1.3-1.65,更优选1.4-1.6,最优选为1.45-1.67(即,接近天然存在的骨骼)。最好是,低晶磷灰石磷酸钙的Ca/P比为约1.5。这种PCA磷酸钙在体内重建形成骨骼。磷酸钙粉末的本性和/或生物相容性黏聚剂的存在,使得在骨植入材料中能包含大量的补充物质,例如,生物活性剂,如DBM颗粒,而不会损害它们的成型能力或机械强度。于是,植入材料在植入到体内的植入部位后,保持其黏聚性并在硬化时显示出显著的抗压强度。此外,包含发泡剂促进了在硬化的磷酸钙植入材料中孔的形成,这使血管、细胞、组织及药物的渗透成为可能,而不会损害植入材料的机械强度。特别是,至少在某些实施方案中,植入材料是高度诱导成骨的,尽管存在无机磷酸钙源。
磷酸钙组合物的一个特点是其受发泡剂的存在促进的孔隙率。磷酸钙组合物的孔隙率是一种理想的特性,因为它有利于细胞迁移和渗透到磷酸钙组合物之内,从而细胞能分泌胞外骨基质。它还为血管形成提供了通路。孔性还提供了高表面积,用于提高活性物质的吸收和释放,以及增强细胞-基质相互作用。
磷酸钙
本发明的磷酸钙组合物可以只用一种无定形磷酸钙制备,或是将其与第二种磷酸钙源组合制备。无定形的磷酸钙具有宽的弥散的X-射线衍射图,它在纳米尺度上量度是均匀的,是从含钙和磷酸根离子源的溶液中快速沉淀形成的凝胶状物质。这种快速沉淀在磷酸钙晶核中产生了许多缺陷。在生理条件下,无定形磷酸钙具有高溶解度,高形成速率,和向PCA磷酸钙的高转化率。
无定形磷酸钙的Ca/P摩尔比在约1.1至约1.9的范围内。在至少某些本发明实施方案中,无定形磷酸钙的Ca/P摩尔比小于1.5。在特定的实施方案中,Ca/P摩尔比为约1.3-1.49。无定形磷酸钙的Ca/P摩尔比可以通过向含钙和磷酸根离子的溶液中加入另外的离子来改变。这些另外的离子的非限制性实例包括CO3 2-、Mg2+、P2O7 4-、硝酸根、亚硝酸根或乙酸根离子。在美国专利5,650,176和6,214,368中进一步描述了无定形磷酸钙的制备和表征,该专利被并入本文中作为参考文献。
在至少某些实施方案中,无定形磷酸钙的含量大于或等于粉末组分的约20%重量。在特定的实施方案中,无定形磷酸钙的含量大于或等于粉末的约30%重量。
在一些实施方案中,磷酸钙粉末中含有第二种磷酸钙源。该第二磷酸钙源可以是晶态或是无定形。适合用在本发明中的第二磷酸钙源包括酸性和中性磷酸钙,其化学计量比使得它们在与无定形磷酸钙反应时生成磷灰石磷酸钙。合适的酸性磷酸钙的非限制性实例包括偏磷酸钙,二水合磷酸二钙,磷酸七钙,磷酸三钙,二水合焦磷酸钙,低晶羟基磷灰石,焦磷酸钙和磷酸八钙。在特定的实施方案中,该第二磷酸钙是二水合磷酸二钙(DCPD)。
应当选择无定形磷酸钙和第二磷酸钙源,使得它们形成具有所要的总Ca/P摩尔比的磷酸钙粉末。于是,无定形磷酸钙和第二磷酸钙源的用量比为1∶10至10∶1或1∶5至5∶1,或约1∶1。在至少某些实施方案中,所要的磷酸钙产物是低晶磷灰石(PCA)磷酸钙。因为从无定形磷酸钙和第二磷酸钙源形成PCA磷酸钙的反应基本上进行到反应完全,所以无定形磷酸钙和第二磷酸钙源的Ca/P摩尔比应当等于产物的摩尔比。PCA磷酸钙的Ca/P摩尔比在约1.1和约1.9之间。因此,根据至少某些本发明实施方案,无定形磷酸钙和第二磷酸钙源的Ca/P摩尔比应在约1.1和约1.9之间。在一些实施方案中,无定形磷酸钙和第二磷酸钙源的Ca/P摩尔比为约1.1-1.7。优选的是,无定形磷酸钙和第二磷酸钙源在组合时,形成Ca/P摩尔比小于1.67的低晶磷灰石(PCA)磷酸钙。在例如美国专利6,027,742、6,214,368、6,287,341、6,331,312和6,541,037中描述了优选的低晶磷灰石磷酸钙组合物,这些专利均并入本文作为参考文献。
一种低温、高机械强度磷酸钙组合物也能被用来制备含发泡剂和黏聚剂的磷酸钙组合物。这样一种低温高机械强度磷酸钙组合物描述于例如美国专利5,783,217中,该专利并入本文作为参考文献。
或者是,利用在足以使磷酸钙固体机械融化并将磷酸钙固体的晶畴减小到小于约100nm的力对磷酸钙固体进行高能研磨,所得到的无定形或纳米晶磷酸钙粉末可以用来制备多孔磷酸钙组合物。高能研磨可以用来制备结晶度和粒度减小和固态结构改变的单组分和多组分磷酸钙粉末。因为所形成的粉末具有小得多的结晶度,此过程被称作“非晶化”,该粉末被称作“非晶化粉末”。这些变化被用来控制硬化速率,固化、反应程度和/或最终产物的硬度。
在本发明这一方面的一项或多项实施方案中,将单独一种磷酸钙源进行非晶化并与发泡剂和生物相容性粘聚剂混合。可能最好是将单一的磷酸钙源非晶化(例如,高能研磨),以便提高其反应活性,或改变其在与其它磷酸钙化合物或其它试剂的反应中的性质。也可能发生粉末的相互作用和反应。组合物中的磷酸钙组分可以只包括非晶化的磷酸钙粉末,也可以包括一种非晶化的磷酸钙粉末与常规的磷酸钙、钙源和/或磷酸根源的组合以提供磷酸钙组分。然后将该磷酸钙组合物(由磷酸钙粉末、发泡剂和生物相容性黏聚剂组成)与水化介质混合,例如水、含水溶液(如盐水或磷酸盐缓冲液)或血清混合,形成硬化的多孔磷酸钙产物。
在本发明这一方面的另一实施方案中,将两种或多种粉末(其中至少一种是磷酸钙源)进行本发明的高能研磨过程。因此,在一项或多项实施方案中,粉末中可包含两种或多种磷酸钙。在一项或多项实施方案中,将磷酸钙源与第二种粉末,例如磷酸根源或钙源(或需要的其它试剂),混合并进行高能研磨以得到非晶化的粉末。除了上面对于单一组分粉末所述的作用,例如提高反应活性和降低结晶度以外,多组分粉末的高能研磨还能促进粉末之间的相互作用和反应。
非晶化程度可以用傅里叶变换红外光谱和/或X射线衍射法监测。两种谱图上的清楚明确的峰都随着结晶度下降变成宽和不清楚的峰,如下面更详细说明的那样。按照本发明的一个或多个实施方案的非晶化的粉末具有高于0.7g/cm2的振实密度(与之相比,常规粉末的振实密度小于0.6g/cm3)。研磨的效率还影响由水化的含有该非晶化磷酸钙粉末(糊体)制备的最终的硬化磷酸钙胶固材料的孔隙率。本发明的非晶化粉末比其常规的粉末对应物堆积得更有效,因此会形成紧密堆积的、但是多孔的磷酸钙产物。
在高能球磨中,一种或多种磷酸钙被置于容器中,利用在转动杆或臂的摇动下作无规运动的球研磨。可以使用例如商品名称Attritor Model01HD,Fritch Pulverisett 4,ASI Uni-Ball Mill II和Zoz的研磨机械。高能研磨将磷酸钙破碎成纳米结构颗粒,其量级小于约100纳米(nm),比表面积为约50-150m2/g。将这种纳米结构颗粒均匀混合,形成一种缺乏长程晶序的高密度均匀产物粉末。高能研磨方法,包括高能球磨,及其对磷酸钙源的影响,在2002年8月16日提交的题为“Synthesisof Calcium Phosphates by Mechano-Chemical Process”的同时待审美国专利申请10/222,670中有进一步的描叙,该申请并入本文作为参考文献。
在至少某些实施方案中,磷酸钙被研磨少于或等于约24小时。在一些实施方案中,磷酸钙被研磨约15小时。在其它实施方案中,磷酸钙被研磨约3小时。随着高能研磨时间增加,磷酸钙的非晶化程度提高,其X射线衍射图变得更宽和更弥散(例如见图1)。
磷酸钙粉末的用量将随植入材料的预定用途和所要求的特性而变。在某些实施方案中,磷酸钙粉末的用量为粉末组分的约20-99%重量(例如,至少约30%重量)。在其它实施方案中,磷酸钙粉末的含量为粉末组分的约50-99%重量(例如,至少约85%重量)。
发泡剂
本发明的多孔磷酸钙组合物还包含一种发泡剂。发泡剂可以是植入之前溶在磷酸钙组合物中的一种气体。该气体可以在压力下溶于磷酸钙组合物中,即,将组合物材料置于加压的气体气氛中,但该气体对于胶结反应呈惰性。然后在暴露于生理温度时(即,在注射或植入时),由于气体溶解度随温度升高而减小,气体被释放出来。在这些环境下,气体的和随后的孔形成仅在体内硬化期间发生,而不是在施用之前。这特别有吸引力,因为孔形成不希望在室温下于注射器内发生。合适的气体包括,但不限于,二氧化碳、空气、氮气、氦、氧和氩。
或者是,发泡剂可以是在溶解时释放气体的固体材料。例如,碳酸盐(如碳酸氢钠)放出二氧化碳,因为它转化成不稳定的碳酸中间体,它随后转化成二氧化碳和水。在一项实施方案中,发泡剂是碳酸氢钠,其在碳酸钙组合物中的含量为0.5-40%重量。在2002年5月31日提交,并于2002年12月12日作为美国专利申请出版物No.20020187104公布的题为“Calcium Phosphate Delivery Vehicles for Osteoinductive proteins”的U.S.S.N.10/160,607中,可以找到对发泡剂及其应用的更详细的描述。发泡剂也可以是两种或多种组分的联合,当它们在水化介质(例如水、pH缓冲盐水和血清)存在下结合时,由于该两组分或多组分之间的化学反应而释放出气体。最好是选择该两种或多种组分并按预定的摩尔比结合,从而在一段时间内产生一定量的气体。由发泡剂的两种或多种组分产生的气体以受控的速率释放,促进了硬化过程中磷酸钙组合物内相互交连孔的形成。
本发明的磷酸钙组合物中孔的形成优选通过加入发泡剂和黏度调节剂(例如生物相容性黏聚剂)来实现。选择发泡剂使其在生理温度如约37℃,或在约30-43℃的范围内,缓慢发泡,而黏度调节剂则改善胶固材料的黏聚性。得到的胶固材料是可塑和自硬化的。硬化的胶固材料显示为具有相互连通孔道的连续基质。
在其它实施方案中,硬化的磷酸钙组合物显示出至少约5-60%的孔隙率。优选该磷酸钙组合物的孔隙率为约5%,更优选为约10、20或30%,最优选为约40、50或60%。在一项优选的实施方案中,磷酸钙有至少约50%的孔隙率。该孔隙率是由于发泡剂的气体组分的受控释放作用而形成的。
在其它实施方案中,磷酸钙用预先确定的两种或多种组分的混合物作为发泡剂来制备,它在水化时反应产生气态副产物,气态副产物的释放促进了磷酸钙组合物内的互连孔的形成。例如,发泡剂可以包含按预定比例制备的两种组分;第一种组分具有化学式MxCO3,第二种组分具有化学式M’yHCO3,其中M和M’是一价阳离子,x=2,y=1。优选的一价阳离子包括钠(Na)、钾(K)、锂(Li)、铷(Rb)、铯(Cs)、银(Ag)、铊(Tl)和铵(NH4 +)。或者是,M和M’分别是二价和一价阳离子,x=1,y=1。优选的二价阳离子包括钡(Ba)、镉(Cd)、钙(Ca)、钴(Co)、铜(Cu)、铁(Fe)、镁(Mg)、锰(Mn)、镍(Ni)、锶(Sr)和锌(Zn),而优选的一价阳离子包括钠(Na)、钾(K)、锂(Li)、铷(Rb)、铯(Cs)、银(Ag)、铊(Tl)和铵(NH4 +)。磷酸钙组合物的孔隙率受CO2从这种发泡剂混合物中释放的速率控制。在溶剂化之前,发泡剂是稳定的固体形式。在溶剂化时,CO2从这些混合物中释放的速率取决于:合成混合物的总溶度积(Ksp)和MxCO3与M’yHCO3的摩尔比。优选的碳酸盐与碳酸氢盐的摩尔比在约1∶1至约1∶9的范围内。更优选为约1∶2,1∶3,1∶4,1∶5,1∶6,1∶7和1∶8。
在一种构造形式中,将Na2CO3与NaHCO3(摩尔比1∶9)的混合物加到磷酸钙粉末和黏聚剂中。当该混合物用非缓冲溶液水化时,能原位形成稳定的糊状物,填充许多临床缺损。当该糊状材料被置于缺损部位时,在体温下造成了受控的孔形成。孔形成过程通过CO2气的释放继续4-5分钟,形成硬化的形状吻合的固体,其中含有中值孔径标称10-100μm的相互连通的孔,抗压强度在至少约1MPa、更优选至少约10MPa或更高的量级。
在第二种构造形式中,将Na2CO3与NaHCO3(摩尔比1∶1)的混合物加到磷酸钙粉末和黏聚剂中。当该混合物用非缓冲液水化时,能原位形成稳定的糊状物,填充各式各样的临床缺损。当该糊状材料被置入缺损部位中时,在体温下引起受控的孔形成。孔形成过程通过CO2气的释放继续0-1分钟,形成硬化的、形状吻合的固体,其中含有中值孔径标称1-10μm的相互连通的孔,抗压强度至少为约1MPa,更优选至少为约10MPa或更高。
生物相容性黏聚剂
本发明的磷酸钙组合物包含一种生物相容性黏聚剂。合适的生物相容性黏聚剂的非限制性实例包括聚合物,选自:多糖类,核酸,碳水化合物,蛋白质,多肽,聚(α-羟基酸),聚(内酯),聚(氨基酸),聚(酸酐),聚(原酸酯),聚(酸酐-CO-酰亚胺),聚(原碳酸酯),聚(α-羟基烷酸酯),聚(二噁烷酮),聚(磷酸酯),聚(L-丙交酯)(PLLA),聚(D,L-丙交酯)(PDLLA),聚乙交酯(PGA),聚(丙交酯-CO-乙交酯)(PLGA),聚(L-丙交酯-CO-D,L-丙交酯),聚(D,L-丙交酯-CO-亚丙基碳酸酯),聚羟基丁酸酯(PHB),聚(ε-己内酯),聚(δ-戊内酯),聚(γ-丁内酯),聚(己内酯),聚丙烯酸,聚羧酸,聚(盐酸烯丙胺)。聚(氯化二烯丙基二甲铵),聚(亚乙基亚胺),聚富马酸丙二醇酯,聚乙烯醇,聚乙烯基吡咯烷酮,聚乙烯,聚甲基丙烯酸甲酯,碳纤维,聚乙二醇,聚氧乙醇,聚(乙烯基醇),聚(乙烯基吡咯烷酮),聚(乙基噁唑啉),环氧乙烷-CO-环氧丙烷嵌段共聚物,聚(对苯二甲酸乙二醇酯),聚酰胺,及它们的共聚物。优选的黏聚剂还包括藻酸,阿拉伯胶,瓜尔胶,黄原胶,明胶,壳多糖,脱乙酰壳多糖,乙酸脱乙酰壳多糖,乳酸脱乙酰壳多糖,硫酸软骨素,N,O-羧甲基脱乙酰壳多糖,葡聚糖(例如,α-环糊精,β-环糊精,γ-环糊精,或硫酸葡聚糖钠),纤维蛋白胶,甘油,透明质酸,透明质酸钠,纤维素(例如,甲基纤维素,羧甲基纤维素,羟丙基甲基纤维素或羟乙基纤维素),葡糖胺,蛋白聚糖,淀粉(例如,羟乙基淀粉或可溶性淀粉),乳酸,环氧乙烷与环氧丙烷共聚物,甘油磷酸钠,胶原,糖原,角蛋白,丝及它们的混合物。在一些实施方案中,生物相容性黏聚剂是水溶性的。水溶性黏聚剂在植入材料植入体内后不久就由其溶解出来,从而在骨植入材料中引入大孔隙。这种大孔隙通过增加了破骨细胞和成骨细胞在植入部位的通路并因此提高了重建活性,使骨植入材料的骨传导性增大。
生物相容性黏聚剂可以在粉末组分的制造期间的不同阶段以各种各样的数量加到多孔磷酸钙组合物中。生物相容性黏聚剂的用量为约1-50%重量。在本发明的几个实施方案中,生物相容性黏聚剂的用量少于或等于粉末组分重量的40%,优选少于或等于30%重量,更优选少于或等于20%重量,最优选少于或等于10%重量。在一项优选的实施方案中,生物相容性黏聚剂的用量为约5%重量。
在本发明的一项实施方案中,磷酸钙组合物中包含DBM。在一些情形,骨植入材料的DBM含量是如此之高,以致于尽管组合物的磷酸钙组分提供了成型能力和黏聚性,但可能还希望有一种黏聚剂用来进一步增大骨植入材料在植入期间的机械强度。在特定的实施方案中,生物相容性黏聚剂的用量为粉末组分的10%重量。在优选的实施方案中,磷酸钙组合物的DBM含量为约40-50%重量,磷酸钙组分的含量为约35-45%重量,黏聚剂的含量为约5-10%重量,发泡剂的含量为约5-10%重量,所有这些组分加起来为100%重量。生物相容性黏聚剂可以以溶液形式加到DBM颗粒中,例如,黏聚剂可以将DBM颗粒包覆。生物相容性黏聚剂可以加到包含DBM颗粒和磷酸钙粉末的本发明组合物粉末组分中。本领域技术人员能够决定对于指定用途所需要的黏聚剂的数量和加入方法。
生物活性剂
本发明的磷酸钙组合物还可以包含一种生物活性剂。通常,该生物活性剂应当在多孔磷酸钙的制造期间在糊状物内保持活性,或者能够在多孔磷酸钙的制造之后被激活或再活化。或者是,生物活性剂可以在多孔磷酸钙组合物(无论是可模制的糊状物或硬化的胶固材料的形式)植入到宿主中时加入,或者在该载体于含水环境中在37℃下硬化后加入。
可以掺加到本发明的组合物中的生物活性剂包括,但不限于,有机分子、无机材料、蛋白质、肽、核酸(例如,基因、基因片段、基因调节序列和反义分子)、核蛋白、多糖、糖蛋白和脂蛋白。可以掺加到本发明组合物中的各类生物活性化合物包括,但不限于,抗癌药物,抗生素,镇痛药,消炎药,免疫抑制剂,酶抑制剂,抗组胺药,抗惊厥药,激素,肌肉松驰药,解痉药,眼药,前列腺素,抗抑郁药,抗精神病药,营养因子,诱骨形成蛋白,生长因子和疫苗。
抗癌药物包括烷化剂,钠试剂,抗代谢药,拓扑异构酶抑制剂,抗肿瘤抗生素,抗有丝分裂药,芳化酶抑制剂,胸苷酸合成酶抑制剂,DNA拮抗剂,法尼基转移酶抑制剂,泵抑制剂,组蛋白乙酰转移酶抑制剂,金属蛋白酶抑制剂,核苷还原酶抑制剂,TNFα激动剂/拮抗剂,内皮素A受体拮抗剂,维甲酸受体激动剂,免疫调节剂,激素和抗激素药物,光动力学药物和酪氨酸激酶抑制剂。
列在表1中的任何生物活性剂均可使用。
表1
烷化剂 | 环磷酰胺白消安异环磷酰胺美法仑六甲蜜胺塞替派苯丁酸氮芥达卡巴嗪卡莫司汀 | 洛莫司汀丙卡巴肼六甲蜜胺磷酸雄莫司汀氮芥链佐星替莫唑胺司莫司汀 |
铂试剂 | 顺铂奥沙利铂螺铂羧基邻苯二甲酸合铂四铂奥马铂 | 卡铂ZD-0473(AnorMED)洛铂(Aeterna)沙铂(Johnson Matthey)BBR-3464(Hoffmann-La Roche)SM-11355(Sumitomo) |
异丙铂 | AP-5280(Access) | |
抗代谢药 | 阿扎胞苷吉西他滨卡培他滨5-氯尿嘧啶氟尿苷2-氯脱氧腺苷6-巯基嘌呤6-硫乌嘌呤阿糖胞苷2-氟脱氧胞苷甲氨蝶呤idatrexate | 拓优得三甲曲沙氧考福霉素氟达拉滨喷司他丁雷替曲塞羟基脲地西他滨(SuperGen)氯法拉滨(Bioenrision)伊罗夫文(MGI pharma)DMDC(Hoffmann-La Roche)乙炔基胞苷(Taiho) |
拓扑异构酶抑制剂 | 安吖啶表柔比星依托泊苷替尼泊苷或米托蒽醌伊立替康(CPT-11)7-乙基-10-羟基喜树碱托泊替康dexrazoxanet(Topo Target)匹蒽醌(Novuspharma)若贝霉素类似物(Exelixis)BBR-3576(Novuspharma) | 卢比替康(SuperGen)甲磺酸伊立替康(Daiichi)Quinamed(chemGenex)吉马替康(Sigma-Tau)二氟替康(Beaufour-Ipsen)TAS-103(Taiho)伊沙芦星(Spectrum)J-107088(Merck&Co)BNP-1350(BioNumerik)CKD-602(Chong Kun Dang)KW-2170(Kyowa Hakno) |
抗肿瘤抗生素 | 放线菌素D多柔比星脱氧比星戊柔比星柔红霉素表柔比星therarubicin伊达比星 | 氨萘非特azonafide蒽吡唑oxantrazole洛索蒽醌硫酸博来霉素(blenoxane)博来霉酸博来霉素A |
柔红霉素苯腙普卡霉素紫菜霉素氰基吧啉多柔比星米托蒽醌(诺安托) | 丝裂霉素B博来霉素CMEN-10755(Menarini)GPX-100(Gem pharmaceuticals) | |
抗有丝分裂药 | 紫杉醇多西他赛秋水仙碱长春碱长春新碱长春瑞滨长春地辛多拉司他汀10(NCI)利索新(Fujisawa)米伏布林(Warner-Lambert)西马多丁(BASF)RPR 109881A(Aventis)TXD 258(Aventis)埃坡霉素B(Novartis)T 900607(Tularik)T 138067(Tularik)含球藻环肽52(Eli Lilly)长春氟宁(Fabre)auristatin PE(Teikoku Hormone)BMS 247550(BMS)BMS 184476(BMS)BMS 188797(BMS)二十二碳六烯酸和紫杉醇轭合物(Protarga) | SB 408075(Glaxo Smithkline)E7010(Abbott)PG-TXL(Cell Therapeutics)IDN 5109(Bayer)A 105972(Abbott)A 204197(Abbott)Lu 223651(BASF)D 24851(ASTA Medica)ER-86526(Eisai)风车子抑碱A4(BMS)异高软海绵-B(PharmaMar)ZD 6126(AstraZeneca)PEG-紫杉醇(Enzon)AZ 10992(Asahi)IDN-5109(Indena)AVLB(Prescient NeuroPharma)Azaepothilone B(BMS)BNP-7787(BioNumerik)CA-4前药(OxiGENE)多拉司他汀-10(NIH)CA-4(OxiGENE) |
芳化酶抑制剂 | 氨鲁米特来曲唑阿那曲唑 | 伊西美坦阿他美坦(BioMedicines)YM-511(Yamanouchi) |
福美坦 | ||
胸苷酸合成酶抑制剂 | 培美曲塞(EliLilly)ZD-9311(BTG) | 诺拉曲塞(Eximias)CoFactorTM(Biokeys) |
DNA拮抗剂 | 曲贝替定(phama Mar)葡磷酰胺(Baxter International)白蛋白+32P(Isotope Solutions)thymectacin(NewBiotics)依度曲肽(Novartis) | 马磷酰胺(Baxter International)阿帕奇醌(SpectrumPharmaceuticals)O6苄基鸟嘌呤(Paligent) |
法尼基转移酶抑制剂 | arglabin(NuOncology Labs)氯那法尼(Schering-Plough) | 替匹法尼(Johoson&Johnson)紫苏子醇(DOR Biopharma) |
泵抑制剂 | CBT-1(CBA Pharma)他立喹达(Xenova)MS-209(Schering AG) | 佐苏喹达三盐酸盐(Eli Lilly)比立考达(Vertex) |
组蛋白乙酰转移酶抑制剂 | 他地那兰(Pfizer)SAHA(Aton pharma)MS-275(ScheringAG) | 新戊酰氧甲基丁酸酯(Titan)缩肽(Fujisawa) |
金属蛋白酶抑制剂 | 新伐司他(Aeterna Laboratories)马立马司他(British Biotech) | CMT-3(CollaGenex)BMS-275291(Celltech) |
核苷还原酶抑制剂 | 麦芽酚镓(Titan)triapine(Vion) | tezacitabine(Aventis)didox (Molecules for Health) |
TNF α激动剂/拮抗剂 | Virulizin(Lorus Therapeutics)CDC-394(Celgene) | 来那度胺(Celgene) |
内皮素A受体拮抗剂 | 阿曲生坦(Abbott)ZD-4054(Astra Zeneca) | YM-598(Yamanouchi) |
维甲酸受体激动剂 | 芬维A胺(Johoson&Johnson)LGD-1550(Ligand) | 阿利维A酸(Ligand) |
免疫调节剂 | 干扰素个体化癌症疫苗(Antigenics)GMK(Progenics)腺癌疫苗(Biomira)CTP-37(AVI Biopharma)IRX-2(Immuno-Rx) | dexsome therapy(Anosys)pentrix(Australian cancer Technology)ISF-154(Tragen)癌症疫苗(Intercell)norelin(Biostar)BLP-25(Biomira) |
PEP-005(Peplin Biotech)Synchrovax疫苗(CTL Immuno)黑素瘤疫苗(CTL Immuno)p21RAS疫苗(Gem Vax) | MGV(Progenics)β-alethine(Dovetail)CLL疗法(Vasogen) | |
激素和抗激素药 | 雌激素缀合雌激素炔雌醇氯烯雌醚idenestrol己酸羟孕酮甲羟孕酮睾丸酮丙酸睾丸酮氟甲睾酮甲基睾丸酮己烯雌酚甲地孕酮他莫昔芬托瑞米芬地塞米松 | 泼尼松甲泼尼龙泼尼松龙氨鲁米特亮丙立德戈舍瑞林高丙瑞林比卡鲁胺氟他胺奥曲肽尼鲁米特米托坦P-04(Novogen)2-甲氧基雌二醇(EntreMed)阿佐昔芬(Eli Lilly) |
光动力学药物 | 他拉泊芬(Light Sciences)Theralux(Theratechnologies)莫特沙芬钆(pharmacyclics) | Pd-bacteriopheophorbide(Yeda)替沙林镥(pharmacyclics)金丝桃素 |
酪氨酸激酶抑制剂 | 伊马替尼(Norartis)来氟米特(Sygen/pharmacia)ZD 1839(AstraZeneca)厄洛替尼(Oncogene Science)卡纳替尼(Pfizer)角鲨胺(Genaera)SU 5416(Pharmacia)SU 6668(Pharmacia)ZD 4190(AstraZeneca) | 海蛞蝓提取物(pharmaMar)CEP-701(Cephalon)CEP-751(Cephalon)MLN518(Millenium)PKC412(Novarits)染料木黄酮类似物O曲妥珠单抗(Genen tech)C 225(ImClone)rhu-Mab(Genentech) |
ZD 644(AstraZeneca)伐他拉尼(Norartis)PKI 116(Novartis)GW 2016(Glaxo Smith Kline)EKB-509(Wyeth)EKB-569(Wyeth) | MDX-H210(Medarex)2C4(Genentech)MDX-447(Medarex)ABX-EGF(Abgenix)IMC-1C11(ImClone) |
抗生素包括氨基糖苷类(例如,庆大霉素、妥布霉素、奈替米星、链霉素、阿米卡星、新霉素)、杆菌肽、碳青霉烯类(例如,亚胺培南/cislastatin)、头孢菌素类、多黏菌素E、鸟洛托品、单环内酰胺(例如氨曲南)、青霉素类(例如,青霉素G、青霉素V、甲氧西林、natcillin、苯唑西林、氯唑西林、双氯西林、氨苄西林、阿莫西林、羧苄西林、替卡西林、哌拉西林、美洛西林、阿洛西林)、多黏菌素B、喹诺酮类和万古霉素;以及抑菌药,例如,氯霉素,克林霉素,大环内酯(例如红霉素、阿奇霉素、克拉霉素)、林可霉素、呋喃妥因、磺胺类药、四环素类(例如,四环素、多西环素、米诺环素、地美环素)和甲氧苄啶。还包括甲硝唑、氟喹诺酮类和ritampin。
酶抑制剂是抑制酶反应的物质。酶抑制剂的实例包括依酚氯铵,N-甲基毒扁豆碱,溴新斯的明,硫酸毒扁豆碱,他克林,1-羟基马来酸他克林,碘杀结核菌素,对溴四咪唑,10-(α-二乙基氨基丙酰)酚噻嗪盐酸盐,氯化卡米达佐,半胆碱-3,3,5-二硝基儿茶酚,二酰基甘油激酶抑制剂I,二酰基甘油激酶抑制剂II,3-苯基炔丙胺,N6-单甲基-L-精氨酸乙酸酯,卡比多巴,3-羟基苄基肼,肼屈嗪,氯吉兰,得普尼林,羟胺,磷酸异丙烟肼,6-甲氧基四氢-9H-吡啶并吲哚,尼亚拉胺,帕吉林,奎纳克林,氨基脲,反苯环丙胺,N,N-二乙基氨乙基-2,2-二苯基戊酸酯盐酸盐,3-异丁基-1-甲基呫吨酮,罂粟碱,吲哚美辛,2-环辛基-2-羟基乙胺盐酸盐,2,3-二氯-α-甲基苄胺(DCMB),8,9-二氯-2,3,4,5-四氢-1H-2-苯并盐酸盐,对氨鲁米特,酒石酸氨鲁米特,3-碘化酪氨酸,α-甲基酪氨酸,乙酰唑胺,双氯非那胺,6-羟基-2-苯并噻唑磺酰胺和别嘌醇。
抗组胺药包括美吡拉敏,氯苯那敏,四氢唑啉等。
消炎药包括皮质类固醇类,非甾类消炎药(例如,阿斯匹林,保泰松,吲哚美辛,舒林酸,托美丁,布洛芬,吡罗昔康和Fenamates),乙酰氨基酚,非那西丁,金盐,氯喹,D-青霉胺,甲氨蝶呤,秋水仙碱,别嘌醇,丙磺舒和磺吡酮。
肌肉松驰剂包括美芬新,美索巴莫,环苯扎林盐酸盐,盐酸苯海索,左旋多巴/卡比多巴和吡哌立登。
解痉剂包括阿托品,东莨菪碱,奥芬铵和罂粟碱。
镇痛药包括阿斯匹林,保泰松,吲哚美辛,舒林酸,托美丁,布洛芬,吡罗西康,fenamates,乙酰氨基酚,非那西丁,硫酸吗啡,硫酸可待因,麦啶,烯丙吗啡,阿片类(例如,硫酸可待因,柠檬酸芬太尼,氢可酮酒石酸氢盐,洛哌丁胺,硫酸吗啡,那可丁,去甲可待因,去甲吗啡,二甲基吗啡,nor-binaltorphimine,丁丙诺非,chlornaltrexamine,氟曲沙胺酮,纳布啡,纳洛酮,纳洛肼,纳曲酮和纳曲吲哚),普鲁卡因,利多卡因,丁卡因和地布卡因。
眼药包括荧光素钠,玫瑰红,醋甲胆碱,肾上腺素,可卡因,阿托品,α-糜蛋白酶,透明质酸酶,倍他洛尔,毛果芸香碱,噻吗洛尔,噻吗洛尔盐,以及它们的组合物。
前列腺素是本领域已知的,是一类天然存在的与长链脂肪酸化学上相关的化合物,它具有多种生物效应。
抗抑郁药是能够防止或减轻抑郁的物质。抗抑郁药的实例包括丙米嗪,阿米替林,去甲替林,普罗替林,地昔帕明,阿莫沙平,多塞平,马普替林,反苯环丙胺,苯乙肼和异卡波肼。
营养因子是其持续存在会改善细胞的存活力和寿命的那些因子。营养因子包括,但不限于,血小板衍生的生长因子(PDGP),嗜中性白红胞活化蛋白,单核细胞趋化蛋白,巨噬细胞炎性蛋白,血小板因子,血小板碱性蛋白和黑素瘤生长刺激因子;表皮生长因子,转化生长因子(α),成纤维细胞生长因子,血小板衍生的内皮细胞生长因子,胰岛素样生长因子,胶质衍生的生长神经营养因子,睫状神经营养因子,神经生长因子,骨生长/软骨诱发因子(α和β),骨形态发生蛋白,白介素(例如,白介素抑制剂或白介素受体,包括白介素1至白介素10),干扰素(例如干扰素α、β和γ),造血因子(包括促红细胞生成素),粒细胞集落刺激因子,巨噬细胞集落刺激因子和粒细胞-巨噬细胞集落刺激因子;肿瘤坏死因子,转化生长因子(β)(包括β-1、β-2、β-3),抑制素和活化素;以及骨形态发生蛋白,例如OP-1、BMP-2和BMP-7。
激素包括雌激素(例如,雌二醇,雌酮,雌三醇,己烯雌酚,炔雌醚,氯烯雌醚,炔雌醇,美雌醇),抗雌激素(例如,氯米芬,他莫昔芬),孕酮(例如,甲羟孕酮,炔诺酮,羟孕酮,炔诺孕酮),抗孕酮(米非司酮),雄激素(例如,环戊丙酸睾酮,氟甲睾酮,达那唑,睾内酯),抗雄激素(例如,醋酸环丙孕酮,氟他胺),甲状腺激素(例如,三碘甲状腺原氨酸,甲状腺素,丙硫氧嘧啶,甲巯咪唑和iodixode),和垂体激素(例如,促皮质激素,sumutotropin,缩宫素和加压素)。激素通常用于激素替代疗法和/或用于生育控制。甾体激素,例如泼尼松,也作为免疫抑制剂和消炎剂使用。
成骨蛋白
生物活性剂最好选自称作转化生长因子β(TGF-β)蛋白质超家族的蛋白质家族,这包括活化素、抑制素和骨形态生成蛋白(BMP)。最优选的是,该活性剂包含至少一种选自通常称作BMP的亚类蛋白的蛋白质,已发现BMP具有成骨活性和其它的生长及分化类型活性。这些BMP包括例如美国专利5,108,922、5,013,649、5,116,738、5,106,748、5,187,076和5,141,905中公开的BMP蛋白BMP-2、BMP-3、BMP-3b、BMP-4、BMP-5、BMP-6和BMP-7;PCT出版物WO 91/18098中公开的BMP-8;和PCT出版物WO 93/00432中公开的BMP-9,PCT申请WO 94/26893中公开的BMP-10;PCT申请WO 94/26892中公开的BMP-11,或PCT申请WO 95/16035中公开的BMP-12或BMP-13;BMP-14;美国专利5,635,372中公开的BMP-15;或美国专利5,965,403中公开的BMP-16。其它的BMP包括BMP-17和BMP-18。
可以在本发明的磷酸钙组合物中作为活性剂使用的其它TGF-β蛋白质包括Vgr-2,Jones et al.,Mol.Endocrinol.6:1961(1992),和任何生长及分化因子(GDFs),包括在PCT申请WO 94/15965,WO 94/15949,WO 95/01801,WO 95/01802,WO 94/21681,WO 94/15966,WO 95/10539,WO 96/01845,WO 96/02559及其它中所述的那些。可用于本发明中的还可以是WO 94/01557中公开的BIP,日本专利公布号7-250688中公开的HP00269,和PCT申请WO 93/16099中公开的MP52。以上所有申请的公开内容都并入本文作为参考文献。目前优选用在本发明中的一亚类BMP包括BMP-2,BMP-4,BMP-5,BMP-6,BMP-7,BMP-10,BMP-12,BMP-13,BMP-14和MP52。活性剂最优选是BMP-2,其序列公开在美国专利5,013,649中,其内容并入本文作为参考文献。本领域已知的其它成骨剂也可以使用,包括例如特立帕肽(ForteoTM),前列腺素E2或LIM蛋白。
生物活性剂可以重组产生,或是从蛋白组合物中纯化。生物活性剂,假设是TGF-β,例如BMP,或其它的二聚蛋白,可以是同源二聚的,也可以是与其它BMP(例如,由BMP-2和BMP-6各一个单体组成的异源二聚体),或与TGF-β超家族的其它成员,例如活化素、抑制素和TGF-β1,异源二聚的(例如,由BMP和TGF-β超家族相关成员各一个单体组成的异源二聚体)。这些异源二聚蛋白的实例描述于例如已公布的PCT专利申请WO 93/09229中,其说明书并入本文作为参考文献。
生物活性剂还可含有其它的试剂,例如,Hedgehog,Frazzled,脊索发生素,头发生素,Cerberus和抑滤泡素蛋白。这些蛋白质家族在Sasai等,Cell 79:779-790(1994)(脊索发生素),PCT专利出版物WO 94/05800(头发生素)和Fukui等,Devel.Biol.159:131(1993)(抑滤泡素)中有一般的描述。Hedgehog蛋白描述于WO 96/16668、WO 96/17924和WO 95/18856中。Frazzled家族蛋白是近来发现的蛋白家族,它与称作Frizzled的受体蛋白家族的胞外结合域具有高度同源性。Frizzled家族的基因和蛋白描述于Wang等,J.Biol.Chem.271:4468-4476(1996)中。活性剂还可以包括其它可溶性受体,例如PCT专利出版物WO 95/07982中公开的截短的可溶性受体。根据WO 95/07982的说明,本领域技术人员会认识到,对于很多其它的受体蛋白都能制备截短的可溶性受体。以上出版物被并入本文作为参考文献。
能有效刺激现有的或浸润的祖细胞或其它细胞的成骨活性提高的成骨蛋白的数量,将取决于所治疗的缺损的大小和本性,以及所使用的载体。
通常,包含在磷酸钙组合物中的生物活性剂的数量,在该磷酸钙组合物用于骨再生方面时,是以治疗或改善骨缺损或损伤;或者当该磷酸钙组合物作为释放生物活性剂的贮库载体使用时,足以治疗或防止疾病或障碍。“足够数量”是指为促进临床上相关作用,磷酸钙组合物中需要的生物活性剂的数量。为将本发明用于治疗所使用的生物活性化合物的足够数量与给药方式和患者的年龄、体重及一般健康状况有关。最终将由医师决定适当的数量和给药方案。对于本文中所述的任何单一疗法或联合疗法,合适的数量可以由动物模型、体外试验,和/或临床研究确定。
例如,磷酸钙组合物中包含的生物活性剂的数量可以是约0.1ng至约1.0g;优选约1.0μg至约100.0mg;最优选约10.0μg至约1.0mg。
生物活性剂可以在本发明的磷酸钙组合物配制期间或之后加入。可以方便地在组合物固化之前将活性剂混入其中。或者是,可以在载体成型和硬化后将其暴露在治疗药物的溶液中。这一特殊方法特别适合已知对磷灰石材料具有亲和性的蛋白质。可以使用含有生物活性剂的缓冲液代替水,作为自硬化糊体在植入前于其中灌注的水溶液。可以使用任何pH范围的缓冲液,但最常用的pH范围是5.0-8.0,在优选的实施方案中pH应与所要求的治疗药物的延长的稳定性及效力相匹配,在最优选的实施方案中,pH范围为5.5至7.4。合适的缓冲剂包括,但不限于,磷酸盐、磷酸盐(例如磷酸盐缓冲液)和有机缓冲剂,例如,Tris,HEPES和MOPS。最常见的是,缓冲剂应根据它与宿主组织的生物相容性和与治疗药物的相容性来选择。对于核酸、肽或抗生素的大多数应用,简单的磷酸盐缓冲液已经足够。
去矿化的骨基质
在一项优选实施方案中,生物活性剂是DBM。DBM是一种有机诱导成骨材料,常由用酸处理的去矿化长骨碎片得到。酸处理溶解了骨中的无机矿物组分和酸溶性蛋白,留下了胶原基质以及酸不溶性蛋白和生长因子(例如,见,Glowacki et al.(1985)Clin.Plast.Surg.12(2):233-241;Covey et al.(1989)Orthop.Rev.17(8):857-863)。在残留的酸不溶性蛋白和生长因子之中是诱导成骨因子,例如骨形态生成蛋白(BMPs)和转化生长因子(TGFs)。因此,DMB是诱骨生成的和可完全吸收的,当与本文所述的磷酸钙粉末联合使用时,生成骨植入材料,因其精密模拟了天然骨的化学成分,所以是高度生物相容的。优越的是,DMB的成本比很多其它现有的有机骨组合物添加剂(如分离的BMPs)都低。
本发明磷酸钙组合物中使用的DBM优选由自生的或异基因的来源衍生。如上所述,DBM可以通过用酸处理长骨碎片这样一种本领域普通技术人员熟知的方法得到。或者是,可以使用市售的DBM(例如,Allsource、American Red Cross、Musculoskeletal Transplant Foundation、Regeneration Technologies,Inc.,和Osteotech,Inc.供应的DBM)。
在至少某些实施方案中,骨植入材料中的DBM的含量为粉末组分重量的约10-70%。在特定的实施方案中,DBM的含量等于粉末组分重量的约60%。在其它实施方案中,DBM的含量为粉末组分重量的约1-50%。在另外的实施方案中,DBM含量少于或等于粉末组分重量的约1-20%。优选DBM含量少于或等于粉末组分重量的约15%。
在给定的组合物中,DBM的数量将随生物相容性黏聚剂的数量及磷酸钙组合物的预定用途和要求的特性而变。在特定的实施方案中,黏聚剂和DBM在磷酸钙组合物中的含量比为约1∶1(例如,在粉末组分的约0.5-20%重量的范围内),优选约1∶5,更优选约1∶10,最优选约1∶20。在优选的实施方案中,黏聚剂的含量为约5%重量或更少。
本领域技术人员能够确定对于特定用途所需的DBM、磷酸钙、发泡剂和黏聚剂的数量。例如,一种优选的磷酸钙粉末组合物包含约15%重量的DBM和约85%重量的磷酸钙粉末,后者含有约1-10%重量的黏聚剂和发泡剂。另一优选的磷酸钙粉末组合物包含约45%重量DBM,约45%重量的磷酸钙粉末,和约10%重量的生物相容性黏聚剂和发泡剂。
DBM颗粒可具有各式各样的尺寸和物理形式。如同DBM的数量一样,DBM颗粒的尺寸和形式将随骨植入材料的预定用途而变。在一些实施方案中,DBM颗粒的最长尺度在约35μm和约850μm之间,并可进一步具有小于约5的纵横比。在其它实施方案中,DBM颗粒的本性是纤维状的。在一些实施方案中,这些DBM纤维的长度约为50μm至3mm。在其它实施方案中,这些DBM纤维的长度约为250μm至2mm。在一些实施方案中,这些DBM纤维的纵横比大于4。在其它实施方案中,这些DBM纤维的纵横比大于10。这些DBM纤维可以是针形,平均宽度与平均厚度之比小于5。得到各种尺寸的DBM颗粒的方法是本领域技术人员熟知的,公开在例如2002年11月15日提交的题为“Cohesive Demineralized Bone Compositions”的同时待审美国专利申请10/298,112中,该申请被并入本文作为参考文献。值得注意的是,由长骨碎片或刮屑得到的针形、纤维状DBM,与由碎骨得到的DBM不同,当掺入到本发明的磷酸钙组合物中时提供增大的黏聚性。
由于DBM有降低它所掺入的植入材料的机械强度的倾向,所以向磷酸钙基骨植入材料中掺入DBM受到限制。因此,含有为使其诱导成骨能力达到最大所需数量DBM的植入材料难以操作,缺乏成型能力,并在植入体内后失去其黏聚性和形状。硬化的磷酸钙产物也弱得多。另外,DBM在含有无机骨传导组分(例如磷酸钙)的骨植入材料中不能有效地使用,因为该无机组分抑制DBM的诱导成骨作用。
本发明的磷酸钙组合物通过加入一种生物相容性黏聚剂克服了这些已知的缺点,这些黏聚剂为磷酸钙组合物在生物活性剂(如DBM)存在的情况下提供了优良的可成型性和黏聚性能。本发明的磷酸钙组合物还包含一种发泡剂,它促进了互相连通的孔的形成而不降低硬化的磷酸钙组合物的机械强度。这些孔促进了能分泌胞外骨基质的细胞向磷酸钙组合物内的迁移和渗透。这些孔还提供了血管形成的通路和高的表面积,从而增强了活性物质的吸收和释放以及细胞-基质相互作用。
释放以上列出的试剂的标准计划和方案是本领域已知的。将生物活性剂以能够向植入部位释放合适剂量的数量加入到磷酸钙载体中。在大多数情形,利用医师已知的适用于所研究的特定试剂的指导原则确定剂量。本发明的磷酸钙糊体中所包含的或是要加入到硬化的输送载体中的生物活性剂的典型数量,很可能与以下变量有关:病症的类型和程度,特定患者的总体健康状况,活性剂的制剂,以及所用的释药载体的生物吸收能力。可以使用标准的临床试验使得对任何特定的生物活性剂的剂量和用药频率最优化。
在至少某些实施方案中,向粉末组分中加入合适数量的生理上可接受的流体以得到自硬化的糊状或油灰状材料。合适的生理上可接受的流体的非限制性实例包括水,盐水,磷酸盐缓冲液和生物流体。生物流体包括与生命有机体有关的任何处理过或未处理的流体(包括悬浮液),特别是血液,包括全血,温血或冷血以及储存或新鲜的血液;处理过的血液,例如用至少一种生理溶液(包括但不限于盐水、营养液和/或抗凝药溶液)稀释的血液;血液组分,例如血小板浓集物(PC)、采集分离的血小板、富血小板血浆(PRP)、贫血小板血浆(PPP)、无血小板血浆、血浆、血清、新鲜冷冻血浆(FFP)、由血浆得到的组分、浓缩红细胞(PRC)、血沉棕黄层(BC);由血液或血液组分衍生的或由骨髓衍生的血液产物;与血浆分离并再悬浮于生理流体中的红细胞;和与血浆分离并再悬浮于生理流体中的血小板。生物流体还包括,例如,奶、尿、唾液、精液或阴道流体,滑液、淋巴液、羊水、卵的卵黄囊、卵壳或尿囊内的流体,汗和眼泪。
与大多数先前已知的植入材料相比,这些糊状组合物的流动特性改善,这归因为包含了无定形的磷酸钙和该磷酸钙粉的本性。可以向粉末中加入不同数量的流体以得到具有所要特性的糊体。例如,在至少一些实施方案中,使用每克粉末0.5-2.0cc的流体制备可成型的,即,能够模制并保持其形状的糊体。在至少某些实施方案中,糊状物是可注射的,即,能够通过16-18号注射器。
在加入生理上可接受的流体和适量的发泡剂之后,将该糊状物输送到植入部位。该糊状物可以被注射到植入部位中,或是形成所要的形状并装入到植入部位内。可以将糊状物形成所要求的形状,令其硬化,然后置于植入部位中。预成型装置可以是手工成型、模制或机械装置。本领域技术人员会了解适合给定用途的植入步骤。
本发明的磷酸钙组合物Ca/P摩尔比与天然存在的骨骼相近。Ca/P摩尔比在约1.1至约1.9之间。在一些实施方案中,Ca/P摩尔比为1.2-1.67。优选Ca/P摩尔比小于1.67,并可以小于约1.5。
糊状物向硬化的磷酸钙的转化在环境温度或体温下发生。此硬化过程不受加入生物活性剂(例如DBM)、生物相容性黏聚剂或发泡剂的不利影响。磷酸钙组合物的“自硬化”或“自固化”在环境温度下(即,在约20-25℃下)缓慢发生,在体温下(即,约32-37℃)则显著加快。例如,糊状物在环境温度下于大约20-60分钟后硬化,而在体温下,该糊状物在约3-15分钟后硬化。在例如美国专利6,214,368、6,027,742和5,650,176中进一步描述了磷酸钙的形成和固化特性,上述专利被并入本文作为参考文献。
硬化的本发明磷酸钙组合物,尽管包含着由发泡剂产生的孔,仍具有显著的抗压强度。抗压强度对于某些类型的骨植入物,例如脊柱植入物,是特别理想的特性。根据一些实施方案,磷酸钙骨植入材料的抗压强度大于约1MPa。在特定的实施方案中,抗压强度为1MPa-20MPa,并可高达30、40、50、60、70、80、90或100MPa。超过100MPa,例如120-150MPa的抗压强度也可以实现。在其它特定的实施方案中,抗压强度至少为2-10MPa。由于发泡剂的作用而具有约5-60%的孔隙率的组合物保持至少约1MPa的抗压强度,甚至能显示出高达100MPa的抗压强度。
一理糊状物转化成硬化的磷酸钙,则磷酸钙被重建到体内的骨中。如上所述,磷酸钙的化学成分和晶体结构与天然骨相似,并可在生物体内吸收。重建涉及磷酸钙的缓慢降解,和所形成的钙及磷酸根材料被身体利用生成新骨。按照本发明的一个或多个实施方案制备的骨植入材料的重建是一个长期过程,通常进行几个月至几年的时间。高密度的骨植入材料需要更长的重建周期,因为植入物的高密度和低孔性减慢了细胞和生物物质的渗透,造成重建以长期的向内扩散过程的形式发生。本发明的磷酸钙植入物的特征是由于孔隙率增大而重建加快。
本发明将用以下实施例示例说明,它们并非是用来限制本发明。
实施例
实施例1:去矿化骨基质纤维的制备
此实施例描述了实质上是纤维状的DBM颗粒的制备。
将长骨清洗,除去所有的结缔组织。去掉终板骨以便分离出长骨的皮质骨组分,除去骨髓。将中空的长骨在乙醇中洗涤,进一步清洁和去除脂肪。然后将骨在车床上旋削。利用将一个直缘的碳化硅切割工具压入骨的表面内进行刮削。该切割工具沿骨的长度前进以得到一段骨屑。骨的旋转速度与切割工具的运动速度一致,这可以由熟悉此工艺的人员控制,以便调节材料的去除速度。用此方法得到厚度为50-250μm、宽度2-10nm、长度无规的切屑。然后将这些切屑在乙醚中洗以除去剩余的脂肪。去矿化是通过在0.5M盐酸(HCl)中搅拌切屑1小时来完成。去矿化后,将纤维在去离子水中冲洗,直至除掉多余的酸。然后将纤维在乙醇和乙醚中冲洗,令乙醚蒸发,将纤维干燥。平均纤维长度无规地分布在约250μm和2mm之间,平均纤维厚度为约50-250μm。
实施例2:无定形磷酸钙的制备
此实施例描述了无定形磷酸钙粉末的制备。
制备1000g七水合磷酸氢二钠(Na2HPO4,7H2O)在14.4ml蒸馏水中的溶液并搅拌之。向此溶液中依次加入555g氢氧化钠(NaOH)、333g碳酸氢钠(NaHCO3)和2.2g十水合焦磷酸钠(Na4P2O7,10H2O),形成溶液1。
配制208g四水合硝酸钙(Ca(NO3)2·4H2O)在5.6L蒸馏水中的溶液并搅拌之。向此溶液加入11g六水合氯化镁(MaCl2·6H2O),形成溶液2。
在室温下将溶液2快速地倒入溶液1中,搅拌1分钟。无定形磷酸钙立即并完全沉淀。悬浮液的pH为13±0.5,保持该pH以防止沉淀转化成磷灰石或其它高晶度磷酸钙。
然后利用篮式离心过滤法将沉淀立即与其母液分离,用大约100L蒸馏水洗。最后洗涤液的离子电导率小于300μs证实洗涤完全。此过程产生约500g无定形磷酸钙的凝胶滤饼。
将无定形磷酸钙的湿饼立即冷冻干燥,以便在干燥期间保存其无定形结构。除去约80%的水。将约100g的冷冻干燥粉末在450℃煅烧1小时。
该无定形磷酸钙产物的Ca/P比小于1.5,通常为1.35-1.49。
实施例3:二水合磷酸二钙(DCPD)的制备
此实施例描述了二水合磷酸二钙粉末的制备。
20g磷酸氢二铵((NH4)2·HPO4)溶在1L蒸馏水中制备溶液3,它含有浓度为0.15M的可利用的磷酸根(PO4 -3)。溶液3的pH经检验为7.0-9.0。
将35.5g四水合硝酸钙(Ca(NO3)2·4H2O)溶在0.5L蒸馏水中,配制成可利用的钙(Ca+2)浓度为0.3M的溶液4。溶液4的pH经检验为5.0-8.0。
将溶液4倒入溶液3中,接着搅拌约2分钟。形成的悬浮液的pH经检验在5.2和6.2之间。将该悬浮液抽气过滤,形成均匀的滤饼。用750ml蒸馏水洗滤饼3次(总计2.25L)。洗完后,将滤饼与滤纸分离,在层流通风橱中干燥24小时。将干燥的粉末研磨通过一只标称120μm孔径的筛。
实施例4:磷酸钙粉末的制备
此实施例描述了含有无定形磷酸钙和第二种磷酸钙源的磷酸钙粉末的制备。
将按实施例2中所述制备的无定形磷酸钙和按实施例3中所述制备的晶态DCPD按1∶1的重量比(例如各25g)混合。将混合的粉末在一台球磨机中于100RPM下高能研磨约3小时。形成的粉末的平均晶畴大小小于约100nm。
实施例5:DBM/磷酸钙粉末的制备
此实施例描述了含有DBM颗粒和磷酸钙粉末的一种粉末的制备。
将如实施例1中所述制备的0.4g纤维状DBM颗粒和如实施例4中所述制备的0.6g磷酸钙粉末用Turbula混合机混合。
实施例6:DBM/磷酸钙/黏聚剂粉末的制备
此实施例描述含有DBM颗粒、磷酸钙粉和生物相容性黏聚剂的粉末的制备。
将0.5g如实施例1中所述制备的DBM颗粒,0.45g如实施例4中所述制备的磷酸钙粉,和0.05g羟甲基纤维素在混合罐中混合。形成的粉末含有约50%重量的DBM颗粒,约45%得量的磷酸钙粉末和约5%重量的羧甲基纤维素。
实施例7:DBM/磷酸钙/发泡剂/黏聚剂粉末的制备
此实施例描述了含有去矿化骨颗粒、磷酸钙粉、发泡剂和生物相容性黏聚剂的粉末的制备
0.50g从组织库得到的人的去矿化骨粉,0.40g按实施例4制备的磷酸钙粉,0.05g碳酸氢钠和0.05g羧甲基纤维素在一只硅橡胶混合机中混合。
实施例8:磷酸钙/发泡剂/黏聚剂粉末的制备
此实施例描述了含有磷酸钙粉、发泡剂和生物相容性黏聚剂的粉末的制备。
0.85g按实施例4中所述制备的磷酸钙粉,0.1g Effersoda(1∶9摩尔比的碳酸盐/碳酸氢盐)和0.05g羧甲基纤维素在一只硅橡胶混合机中混合。
实施例9:可成型的自硬化糊的制备
此实施例描述了从上述粉末制备可成型的自硬化糊状物。
将实施例4-8中所述粉末的各1.0g样品与足量的盐水(0.9%USP,0.2-2.0cc)混合,形成可模制的糊。
所形成的糊是可成型的,可经由注射器挤出,在湿环境中黏聚,并且在37℃下于20分钟之内硬化。
0.10cc糊状物经由具有平头针头的1cc Becton Dickinson滑动针头注射器挤出,形成一个0.1cc的糊状物圆柱体。
实施例10:可成型和自硬化糊状物的黏聚性
此实施例描述了对于按照本发明制备的可成型和自硬化糊状物的黏聚性的评价。
将1.0g按实施例9中所述制备的糊状物样品形成直径1.0cm的球,使球落在一烧杯水中。该球保持其原始形状至少10分钟,没有明显的可观察到的变形、溶胀或质量损失。从水中取出样品,滤除水,测定样品在浸入时的质量损失程度。未观察到可测量数量的质量损失。
实施例11:CaP/发泡剂/DBM组合物的抗压强度
此实施例描述了按照本发明制备的可成型和自硬化的糊状物的湿抗压强度的评价。
5g实施例8中所述粉末用每g粉末0.35cc的生理盐水水化,形成糊状物。
此糊状物可以均匀地加到直径6mm、高12mm的5只圆柱形不锈钢模具中。然后将模具在37℃的生理盐水浴中浸泡2小时。
从模具中取出5只硬化的样品,用一台万能试验机(Instron,Canton,MA)以5mm/分的滑块速度试验抗压强度。磷酸钙组合物的评价表明抗压强度至少为1MPa。
实施例12:骨植入材料的诱导或骨能力的测定
测定无胸腺大鼠肌内或皮下囊袋中植入后的异位骨形成是表征诱导成骨材料的现行标准。此实施例描述了应用无胸腺大鼠模型评价按本文所述制备的骨植入材料并将该组合物与其它DBM制剂相比较。
将6-7周龄雄性无胸腺大鼠(Rattus norvegicus,Crl:NIH-rnu nudes,Charles River laboratories)随机地植入四种不同的试验制品,两个在胸肌肉系统(胸大肌)中,两个在后肢(四头肌)中。每只动物接受腹膜内(IP)注射氯胺酮(100mg/kg)和塞拉嗪(10mg/kg)。在全麻醉后,用手术刀在第一植入部位作一小刀口,用剪刀将皮肤、皮下组织和筋膜对切。用尖头剪形成一个肌内囊以进入预定的肌肉。在与肌肉纤维相同的方向切第一刀,张开剪刀以形成小袋,保持袋张开,用镊子施加0.1ml试验制品。然后在其余三个植入部位重复此手术。如果需要,再施用半剂量的氯胺酮/塞拉嗪以保证麻醉足以完成植入步骤。
植入后,对每只动物逐日临床观察7天。随后进行双周临床观察。
植入6周后取出试验制品。将动物用超剂量的CO2麻醉,然后立即取出。收集的组织限于植入材料和大约0.5cm余量的骨骼肌和/或结缔组织。将组织样品在10%中性缓冲的福尔马林中固定至少12小时并转移至组织学等级的乙醇中。将组织样品在植入物中间截面横向对切,按常规加工进行石蜡包埋,切片置于玻璃载片上,用苏木精和伊红染色,放上盖玻片。如果需要,在组织分析之前将组织样品另外脱钙。
以对于施加的植入物单盲的方式将代表不同的肌内植入物切片的随机化的组织载玻片提供给病理学家。骨形成的数量用0-4级评分,0表示没有骨形成的迹象,1、2、3和4分别指示<25%、26-50%、51-75%和>75%的植入物表面参与新骨形成。衬有成骨细胞和/或腔隙内含有骨细胞和软骨细胞及其基质的新骨,以及被新骨的小梁包围的骨髓,都被认为是骨新生过程的一部分。还记下植入物的形状和尺寸(相对于原始的5mm圆柱体),新骨在植入物内的分布,以及植入物基质的性质。一旦完成对载玻片的评价,即将分组评价的关键数据提供给评估者以总结结果。
实施例13:骨植入材料的重建的评价
在尺寸严格的骨缺损中植入是表征骨移植材料愈合能力的标准方法。此实施例描述了本发明的磷酸钙组合物作为骨移植材料在兔模型的尺寸严格的缺损内的植入。
按以下方式,在4-5kg新西兰雌性白兔的远侧股髁中形成双侧圆柱形缺陷。将动物用氯胺酮30mg/kg、塞拉嗪5mg/kg、阿托品1-3mg/kg肌内注射麻醉,并在插管后用异氟烷维持。将双膝及以上面积处的皮肤除毛,用7.5%聚维酮碘和70%异丙醇清洗,并将手术场所适当用消毒布遮盖。通过侧向切口暴露出侧向股髁。利用在恒定的盐水灌注下打钻,在每个侧向股髁上形成直径5.0mm、深10mm的骨缺陷。然后将本发明的磷酸钙组合物作为骨移植材料装入到该缺损中。随后常规关闭和缝合。通常留下一些缺损不填充以作为负对照,另一些用取自兔的髂嵴的小片状自体骨移植物填充,作为正对照。
手术后监测动物发生感染的迹象,这不常见。所有显示疼痛或不适的动物均每12小时皮下注射丁丙诺非(每Kg体重0.02-0.05mg,必要时)。在恢复期以正常方式对其进行观察和治疗。不采用监禁方式。如果任何动物发生骨折,则立即将其安乐死。
在手术后的适当时刻,通过静脉内过量注射戊巴比妥(浓度:390mg/ml,每10磅体重1ml)将动物处死。这与美国兽医协会安乐死小组推荐的方法一致。所有各组手术移植的结果均用放射照相、组织学和组织形态学的方法进行评价。
AP放射照片在手术后按规则的间隔得到。将动物麻醉,以俯卧位置放置,拍摄单侧X光照片。在所有处置过程中要小心尽量减小缺损部位的负载。
对于组织学评价,将组织在10%中性缓冲的福尔马林中固定。对样品进行加工以用于常规的不脱钙的切片。将组织加工并包埋在甲基丙烯酸甲酯(MMA)中,切成矢状解剖平面。将切片用Stevenel蓝染色或Goldner三色染剂染色以用于组织分析。对组织切片进行新骨形成面积,未愈合的空洞或纤维状组织,以及残留的植入材料的评价。
实施例14:可模制的自固化大孔磷酸钙胶固材料的愈合能力评价
按照实施例9中所述,制备实施例8中所述的粉末,并按实施例13中所述植入,与取自髂嵴的小片状自体骨和空置的未处理的缺损相比较进行评价。12周后处死动物并收取组织。组织学样品显示出试验样品和自体骨都接近完全愈合。在未处理的缺损中未观察到愈合。
其它实施方案
本说明书中提到的所有出版物、专利和专利申请,均以各独立的出版物或专利申请专门和个别地被指出并入作为参考文献的同样程度,被并入本文作为参考文献。
虽然已联系具体的实施方案对本发明作了描述,但是应该理解,它能够作进一步的修改,本发明打算涵盖一般遵照本发明的原则的任何变化、应用和修改,包括在本发明所属领域中的已知或惯用作法的范围内与本发明内容的偏离,这些偏离可被应用于此前所述的基本特点,并遵从权利要求的范围。
其它的实施方案是在权利要求的范围之内。
Claims (48)
1.一种自固化的多孔磷酸钙组合物,其中含有与一种生理上可接受的流体混合的磷酸钙、发泡剂和生物相容性黏聚剂,其中所述发泡剂包含碳酸盐和碳酸氢盐,该碳酸盐和碳酸氢盐在所述组合物内存在的摩尔比在1:1和1:9之间,并且它们在所述组合物水合时反应从而产生作为气体组分的二氧化碳,其中从所述组合物释放出所述气体组分在组合物中产生至少5%的孔隙率,在硬化后该磷酸钙组合物是固体,其具有1MPa或更高的抗压强度。
2.根据权利要求1所述的组合物,其中所述磷酸钙选自无定形磷酸钙、低晶磷酸钙、羟基磷灰石、贫钙羟基磷灰石、磷酸一钙、偏磷酸钙、磷酸七钙、二水合磷酸二钙,磷酸四钙,磷酸八钙,焦磷酸钙和磷酸三钙,或它们的混合物。
3.根据权利要求1所述的组合物,其中所述磷酸钙用无定形磷酸钙和第二磷酸钙源制备。
4.根据权利要求3所述的组合物,其中所述第二磷酸钙源选自低晶磷酸钙、羟基磷灰石、贫钙羟基磷灰石、磷酸一钙、偏磷酸钙、磷酸七钙、二水合磷酸二钙,磷酸四钙,磷酸八钙,焦磷酸钙和磷酸三钙。
5.根据权利要求1所述的组合物,其中所述磷酸钙的平均晶畴大小小于100nm。
6.根据权利要求1所述的组合物,其中所述组合物的孔的直径为1-1000μm。
7.根据权利要求6所述的组合物,其中的孔径为10-100μm。
8.根据权利要求1所述的组合物,其中所述气体组分的释放产生至少10%的孔隙率。
9.根据权利要求8所述的组合物,其中所述气体组分的释放产生至少20%的孔隙率。
10.根据权利要求9所述的组合物,其中所述气体组分的释放产生至少40%的孔隙率。
11.根据权利要求10所述的组合物,其中所述气体组分的释放产生至少50%的孔隙率。
12.根据权利要求1所述的组合物,其中所述气体组分的释放产生5-60%的孔隙率。
13.根据权利要求1所述的组合物,其中所述碳酸盐和碳酸氢盐在该组合物内的摩尔比为1:1。
14.根据权利要求1所述的组合物,其中所述碳酸盐和碳酸氢盐在该组合物内的摩尔比为1:9。
15.根据权利要求1所述的组合物,其中所述发泡剂产生具有贯穿该组合物的相互交连孔的基质。
16.根据权利要求1所述的组合物,其中发泡剂的含量为1-40重量%。
17.根据权利要求1所述的组合物,其中生物相容性黏聚剂包括一种聚合物,选自:核酸,碳水化合物,蛋白质,多肽,聚(α-羟基酸),聚(内酯),聚(氨基酸),聚(酸酐),聚(原酸酯),聚(酸酐-CO-酰亚胺),聚(原碳酸酯),聚(α-羟基烷酸酯),聚(二烷酮),聚(磷酸酯),聚(L-丙交酯)(PLLA),聚(D,L-丙交酯)(PDLLA),聚乙交酯(PGA),聚(丙交酯-CO-乙交酯)(PLGA),聚(L-丙交酯-CO-D,L-丙交酯),聚(D,L-丙交酯-CO-亚丙基碳酸酯),聚羟基丁酸酯(PHB),聚羧酸,聚(盐酸烯丙胺),聚(氯化二烯丙基二甲铵),聚(亚乙基亚胺),聚富马酸丙二醇酯,聚乙烯醇,聚乙烯基吡咯烷酮,聚乙烯,聚甲基丙烯酸甲酯,碳纤维,聚乙二醇,聚氧乙醇,聚(乙烯基醇),聚(乙烯基吡咯烷酮),聚(乙基唑啉),环氧乙烷-CO-环氧丙烷嵌段共聚物,聚(对苯二甲酸乙二醇酯),聚酰胺,及它们的共聚物。
18.根据权利要求1所述的组合物,其中所述生物相容性黏聚剂包括选自多糖类和聚丙烯酸的聚合物。
19.根据权利要求17所述的组合物,其中所述聚(内酯)是聚(己内酯)。
20.根据权利要求17所述的组合物,其中所述聚(内酯)选自聚(ε-己内酯),聚(δ-戊内酯),聚(γ-丁内酯)。
21.根据权利要求1所述的组合物,其中生物相容性黏聚剂选自:藻酸,阿拉伯酸,瓜尔胶,黄原胶,明胶,壳多糖,脱乙酰壳多糖,乙酸脱乙酰壳多糖,乳酸脱乙酰壳多糖,硫酸软骨素,N,O-羧甲基脱乙酰壳多糖,葡聚糖,纤维蛋白胶,甘油,透明质酸,透明质酸钠,纤维素,葡糖胺,蛋白聚糖,淀粉,乳酸,环氧乙烷与环氧丙烷共聚物,甘油磷酸钠,胶原,糖原,角蛋白,丝,及它们的混合物。
22.根据权利要求21所述的组合物,其中该纤维素是甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素或羟乙基纤维素。
23.根据权利要求21所述的组合物,其中葡聚糖是α-环糊精、β-环糊精、γ-环糊精或葡聚糖硫酸钠。
24.根据权利要求21所述的组合物,其中淀粉是可溶性淀粉。
25.根据权利要求21所述的组合物,其中淀粉是羟乙基淀粉。
26.根据权利要求1所述的组合物,其中该生物相容性黏聚剂的含量为0.5-20重量%。
27.根据权利要求26所述的组合物,其中生物相容性黏聚剂的含量少于20重量%。
28.根据权利要求27所述的组合物,其中生物相容性黏聚剂的含量少于10重量%。
29.根据权利要求28所述的组合物,其中生物相容性黏聚剂的含量少于5重量%。
30.根据权利要求29所述的组合物,其中生物相容性黏聚剂的含量少于1重量%。
31.根据权利要求1所述的组合物,其中该组合物还含有一种生物活性剂。
32.根据权利要求31所述的组合物,其中该生物活性剂选自抗体、抗生素、聚核苷酸、多肽、蛋白质、抗癌药物、生长因子和疫苗。
33.根据权利要求32所述的组合物,其中蛋白质是成骨蛋白。
34.根据权利要求33所述的组合物,其中该成骨蛋白选自
BMP-2,BMP-3,BMP-3b,BMP-4,BMP-5,BMP-6,BMP-7,BMP-8,BMP-9,BMP-10,BMP-11,BMP-12,BMP-13,BMP-14,BMP-15,BMP-16,BMP-17,和BMP-18。
35.根据权利要求32所述的组合物,其中抗癌药物是选自烷化剂,铂试剂,抗代谢药,拓扑异构酶抑制剂,抗肿瘤抗生素,抗有丝分裂药,芳化酶抑制剂,胸苷酸合成酶抑制剂,DNA拮抗剂,法尼基转移酶抑制剂,泵抑制剂,组蛋白乙酰转移酶抑制剂,金属蛋白酶抑制剂,核苷还原酶抑制剂,TNFα激动剂/拮抗剂,内皮素A受体拮抗剂,维甲酸受体激动剂,免疫调节剂,激素和抗激素药物,光动力学药物和酪氨酸激酶抑制剂。
36.根据权利要求31所述的组合物,其中生物活性剂是去矿化的骨基质(DBM)。
37.根据权利要求1所述的组合物,其中磷酸钙的钙/磷酸根Ca/P摩尔比为1-1.67。
38.根据权利要求37所述的组合物,其中磷酸钙的Ca/P摩尔比为1.3-1.65。
39.根据权利要求38所述的组合物,其中磷酸钙的Ca/P摩尔比为1.4-1.6。
40.根据权利要求39所述的组合物,其中磷酸钙的Ca/P摩尔比为1.5。
41.根据权利要求1所述的组合物,其中该组合物在与生理上可接受的流体混合时形成自硬化的磷酸钙糊状物,该糊状物硬化后形成总Ca/P摩尔比小于1.67的低晶磷灰石磷酸钙。
42.根据权利要求1所述的组合物,其中生理上可接受上的流体选自水、盐水和磷酸盐缓冲液。
43.根据权利要求1所述的组合物,其中在硬化后,组合物的抗压强度至少为2MPa。
44.根据权利要求1所述的组合物,其中该组合物的抗压强度为1-150MPa。
45.根据权利要求44所述的组合物,其中该组合物的抗压强度为10MPa。
46.根据权利要求1所述的组合物,其中该组合物在37℃下于不到30分钟内硬化。
47.根据权利要求1所述的组合物,其中该组合物适合作为骨植入材料使用。
48.根据权利要求1-47中任一项所述的组合物在用于骨修复的药物制备中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/294,819 US8147860B2 (en) | 2005-12-06 | 2005-12-06 | Porous calcium phosphate bone material |
US11/294,819 | 2005-12-06 | ||
PCT/US2006/046435 WO2007067561A2 (en) | 2005-12-06 | 2006-12-06 | Porous calcium phosphate bone material |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101420922A CN101420922A (zh) | 2009-04-29 |
CN101420922B true CN101420922B (zh) | 2013-10-16 |
Family
ID=38119036
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006800520527A Active CN101420922B (zh) | 2005-12-06 | 2006-12-06 | 多孔磷酸钙骨材料 |
Country Status (8)
Country | Link |
---|---|
US (2) | US8147860B2 (zh) |
EP (2) | EP2992855B1 (zh) |
JP (1) | JP5416972B2 (zh) |
KR (1) | KR101395884B1 (zh) |
CN (1) | CN101420922B (zh) |
AU (1) | AU2006322025B2 (zh) |
CA (1) | CA2632785C (zh) |
WO (1) | WO2007067561A2 (zh) |
Families Citing this family (117)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7713297B2 (en) | 1998-04-11 | 2010-05-11 | Boston Scientific Scimed, Inc. | Drug-releasing stent with ceramic-containing layer |
DE10032220A1 (de) * | 2000-07-03 | 2002-01-24 | Sanatis Gmbh | Magnesium-ammonium-phosphat-Zemente, deren Herstellung und Verwendung |
US7273523B2 (en) * | 2002-06-07 | 2007-09-25 | Kyphon Inc. | Strontium-apatite-cement-preparations, cements formed therefrom, and uses thereof |
ES2396133T3 (es) | 2004-04-27 | 2013-02-19 | Kyphon SÀRl | Composiciones de sustitución osea y método de uso |
US20060127443A1 (en) * | 2004-12-09 | 2006-06-15 | Helmus Michael N | Medical devices having vapor deposited nanoporous coatings for controlled therapeutic agent delivery |
US7651701B2 (en) * | 2005-08-29 | 2010-01-26 | Sanatis Gmbh | Bone cement composition and method of making the same |
US8147860B2 (en) * | 2005-12-06 | 2012-04-03 | Etex Corporation | Porous calcium phosphate bone material |
CA2646486A1 (en) * | 2006-03-23 | 2007-09-27 | Citagenix Inc. | Reverse phase osteoconductive composition |
US20070224235A1 (en) | 2006-03-24 | 2007-09-27 | Barron Tenney | Medical devices having nanoporous coatings for controlled therapeutic agent delivery |
US8187620B2 (en) | 2006-03-27 | 2012-05-29 | Boston Scientific Scimed, Inc. | Medical devices comprising a porous metal oxide or metal material and a polymer coating for delivering therapeutic agents |
US7754005B2 (en) * | 2006-05-02 | 2010-07-13 | Kyphon Sarl | Bone cement compositions comprising an indicator agent and related methods thereof |
US7507286B2 (en) * | 2006-06-08 | 2009-03-24 | Sanatis Gmbh | Self-foaming cement for void filling and/or delivery systems |
US8815275B2 (en) | 2006-06-28 | 2014-08-26 | Boston Scientific Scimed, Inc. | Coatings for medical devices comprising a therapeutic agent and a metallic material |
EP2032091A2 (en) | 2006-06-29 | 2009-03-11 | Boston Scientific Limited | Medical devices with selective coating |
DE102006042142A1 (de) * | 2006-09-06 | 2008-03-27 | Curasan Ag | Phasen- und sedimentationsstabile, plastisch verformbare Zubereitung mit intrinsischer Porenbildung, bspw. zum Auffüllen von Knochendefekten bzw. zur Verwendung als Knochenersatzmaterial, und Verfahren zu deren Herstellung |
ATE508708T1 (de) | 2006-09-14 | 2011-05-15 | Boston Scient Ltd | Medizinprodukte mit wirkstofffreisetzender beschichtung |
AU2007300585A1 (en) * | 2006-09-21 | 2008-04-03 | Kyphon Sarl | Diammonium phosphate and other ammonium salts and their use in preventing clotting |
US20080195223A1 (en) * | 2006-11-03 | 2008-08-14 | Avram Allan Eddin | Materials and Methods and Systems for Delivering Localized Medical Treatments |
US7981150B2 (en) * | 2006-11-09 | 2011-07-19 | Boston Scientific Scimed, Inc. | Endoprosthesis with coatings |
US20080294236A1 (en) * | 2007-05-23 | 2008-11-27 | Boston Scientific Scimed, Inc. | Endoprosthesis with Select Ceramic and Polymer Coatings |
US8070797B2 (en) | 2007-03-01 | 2011-12-06 | Boston Scientific Scimed, Inc. | Medical device with a porous surface for delivery of a therapeutic agent |
US8431149B2 (en) * | 2007-03-01 | 2013-04-30 | Boston Scientific Scimed, Inc. | Coated medical devices for abluminal drug delivery |
US8067054B2 (en) | 2007-04-05 | 2011-11-29 | Boston Scientific Scimed, Inc. | Stents with ceramic drug reservoir layer and methods of making and using the same |
US7976915B2 (en) | 2007-05-23 | 2011-07-12 | Boston Scientific Scimed, Inc. | Endoprosthesis with select ceramic morphology |
US8002823B2 (en) | 2007-07-11 | 2011-08-23 | Boston Scientific Scimed, Inc. | Endoprosthesis coating |
US7942926B2 (en) | 2007-07-11 | 2011-05-17 | Boston Scientific Scimed, Inc. | Endoprosthesis coating |
EP2187988B1 (en) | 2007-07-19 | 2013-08-21 | Boston Scientific Limited | Endoprosthesis having a non-fouling surface |
US8815273B2 (en) | 2007-07-27 | 2014-08-26 | Boston Scientific Scimed, Inc. | Drug eluting medical devices having porous layers |
US7931683B2 (en) | 2007-07-27 | 2011-04-26 | Boston Scientific Scimed, Inc. | Articles having ceramic coated surfaces |
WO2009018340A2 (en) | 2007-07-31 | 2009-02-05 | Boston Scientific Scimed, Inc. | Medical device coating by laser cladding |
JP5210566B2 (ja) * | 2007-08-01 | 2013-06-12 | 日本特殊陶業株式会社 | 生体インプラント及びその製造方法 |
WO2009020520A1 (en) | 2007-08-03 | 2009-02-12 | Boston Scientific Scimed, Inc. | Coating for medical device having increased surface area |
EP2211920B1 (en) * | 2007-10-24 | 2017-12-06 | The University of Sydney | Biocompatible material and uses thereof |
US8029554B2 (en) | 2007-11-02 | 2011-10-04 | Boston Scientific Scimed, Inc. | Stent with embedded material |
US20090118821A1 (en) * | 2007-11-02 | 2009-05-07 | Boston Scientific Scimed, Inc. | Endoprosthesis with porous reservoir and non-polymer diffusion layer |
US7938855B2 (en) | 2007-11-02 | 2011-05-10 | Boston Scientific Scimed, Inc. | Deformable underlayer for stent |
US8216632B2 (en) | 2007-11-02 | 2012-07-10 | Boston Scientific Scimed, Inc. | Endoprosthesis coating |
ES2428263T3 (es) * | 2008-01-09 | 2013-11-06 | Oswestry Tissue Bank Ltd. | Método para fabricar una composición para la reparación ósea |
US20090286907A1 (en) * | 2008-01-23 | 2009-11-19 | Beltz Mark W | Fumaric Acid/Diol Polyesters and Their Manufacture and Use |
AU2015215892B2 (en) * | 2008-04-15 | 2017-11-30 | Life Science Enterprises, Inc. | Minimally invasive treatment of vertebra (mitv) using a calcium phosphate combination bone cement |
JP6324653B2 (ja) * | 2008-04-15 | 2018-05-16 | ライフ サイエンス エンタープライジズ インコーポレイテッド | リン酸カルシウム配合骨セメントを用いる脊椎骨の最小侵襲治療(mitv) |
US7968616B2 (en) * | 2008-04-22 | 2011-06-28 | Kyphon Sarl | Bone cement composition and method |
US8920491B2 (en) | 2008-04-22 | 2014-12-30 | Boston Scientific Scimed, Inc. | Medical devices having a coating of inorganic material |
US8932346B2 (en) | 2008-04-24 | 2015-01-13 | Boston Scientific Scimed, Inc. | Medical devices having inorganic particle layers |
EP2303350A2 (en) | 2008-06-18 | 2011-04-06 | Boston Scientific Scimed, Inc. | Endoprosthesis coating |
AU2009268781B2 (en) * | 2008-07-06 | 2015-05-07 | The Curators Of The University Of Missouri | Osteochondral implants, arthroplasty methods, devices, and systems |
KR100937736B1 (ko) * | 2008-09-23 | 2010-01-21 | 동국대학교 산학협력단 | 유도 조직 재생을 위한 다공성 지지체 및 그의 제조방법 |
CN101417149B (zh) * | 2008-10-22 | 2012-11-21 | 四川大学 | 含钙的磷酸盐成分的可降解生物活性复合材料及制备方法 |
US8231980B2 (en) | 2008-12-03 | 2012-07-31 | Boston Scientific Scimed, Inc. | Medical implants including iridium oxide |
US8409538B2 (en) | 2008-12-04 | 2013-04-02 | Skeletal Kinetics Llc | Tricalcium phosphate coarse particle compositions and methods for making the same |
US8673364B2 (en) | 2009-09-28 | 2014-03-18 | Skeletal Kinetics, Llc | Rapid setting high strength calcium phosphate cements comprising cyclodextrins |
US8071156B2 (en) | 2009-03-04 | 2011-12-06 | Boston Scientific Scimed, Inc. | Endoprostheses |
JPWO2010119897A1 (ja) * | 2009-04-17 | 2012-10-22 | Hoya株式会社 | 骨補填材用のリン酸カルシウム系セメント組成物及びそのキット |
US8287937B2 (en) | 2009-04-24 | 2012-10-16 | Boston Scientific Scimed, Inc. | Endoprosthese |
US20110243913A1 (en) * | 2010-04-06 | 2011-10-06 | Orthovita, Inc. | Biomaterial Compositions and Methods of Use |
WO2012062360A1 (en) | 2010-11-10 | 2012-05-18 | Stryker Trauma Gmbh | Polymeric bone foam composition and method |
EA031630B1 (ru) * | 2011-01-19 | 2019-01-31 | Лэборатори Скин Кер, Инк. | Композиции миноциклина для местного применения и способы их применения |
CN102133154B (zh) * | 2011-03-09 | 2012-09-19 | 东南大学 | 牙根根尖充填材料及其制备方法 |
KR101375828B1 (ko) * | 2011-03-31 | 2014-03-17 | 인제대학교 산학협력단 | 골-연골 재생용 복합 지지체, 이의 제조 방법 및 이를 유효성분으로 함유하는 골-연골 질환 치료용 조성물 |
JP5512887B2 (ja) | 2011-05-13 | 2014-06-04 | 学校法人北里研究所 | 成長因子アンカーリング型骨移植材料および成長因子アンカーリング型骨移植材料製造用キット |
KR101364312B1 (ko) * | 2011-07-15 | 2014-02-19 | 단국대학교 산학협력단 | 알지네이트 마이크로섬유의 제조방법 |
CN103127547B (zh) * | 2011-11-28 | 2015-04-01 | 成功大学 | 强化不崩解性的钙基骨水泥制剂 |
US10207027B2 (en) * | 2012-06-11 | 2019-02-19 | Globus Medical, Inc. | Bioactive bone graft substitutes |
US20150148292A1 (en) * | 2012-07-09 | 2015-05-28 | Emory University | Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto |
KR101309528B1 (ko) * | 2013-01-11 | 2013-09-24 | 군산대학교산학협력단 | 골 조성물의 제조방법, 이로써 제조된 골 조성물 및 이를 포함하는 인공골 |
EP2976111B1 (en) * | 2013-03-22 | 2018-11-14 | Psilox AB | Hollow calcium phosphate particles |
US9486483B2 (en) | 2013-10-18 | 2016-11-08 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US9539286B2 (en) | 2013-10-18 | 2017-01-10 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
CN103655209B (zh) * | 2013-12-04 | 2015-08-19 | 天津医科大学口腔医院 | 牙体硬组织再矿化的复合材料 |
CN104771782A (zh) * | 2014-01-10 | 2015-07-15 | 东莞博捷生物科技有限公司 | 一种骨修复用材料β-磷酸三钙及其制备方法 |
US9579421B2 (en) | 2014-02-07 | 2017-02-28 | Globus Medical Inc. | Bone grafts and methods of making and using bone grafts |
US9463264B2 (en) | 2014-02-11 | 2016-10-11 | Globus Medical, Inc. | Bone grafts and methods of making and using bone grafts |
CN104147641B (zh) * | 2014-07-11 | 2016-08-31 | 深圳职业技术学院 | 一种用于个性化的骨修复材料和其制备方法 |
WO2016084413A1 (ja) * | 2014-11-27 | 2016-06-02 | 東洋紡株式会社 | 多孔質複合体、骨再生材料、および、多孔質複合体の製造方法 |
CN104523341B (zh) * | 2014-12-18 | 2017-06-20 | 中国人民解放军第四军医大学 | 具有牙周生物活性的即刻种植牙的制造方法 |
CN104524630A (zh) * | 2015-01-25 | 2015-04-22 | 宁波开发区中心医院 | 可降解共聚物-硅酸钙复合骨修复材料及制备方法 |
US10219986B2 (en) | 2015-03-04 | 2019-03-05 | Modern Ideas LLC | Stabilized calcium phosphate and methods of forming same |
US10195305B2 (en) * | 2015-03-24 | 2019-02-05 | Orthovita, Inc. | Bioactive flowable wash-out resistant bone graft material and method for production thereof |
CN104771785B (zh) * | 2015-04-03 | 2017-06-20 | 周宏志 | 具有神经多肽诱导成骨活性的骨修复材料的制造方法 |
US10016529B2 (en) | 2015-06-10 | 2018-07-10 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
US11426489B2 (en) | 2015-06-10 | 2022-08-30 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
CN106334214B (zh) * | 2015-07-13 | 2019-11-12 | 中南大学 | 一种面向磷酸钙活性陶瓷骨支架制备的多重液相构建方法 |
CN105153612A (zh) * | 2015-08-31 | 2015-12-16 | 苏州莱特复合材料有限公司 | 用于矫形支架的复合材料及其制备方法 |
WO2017062737A1 (en) * | 2015-10-08 | 2017-04-13 | Zimmer Knee Creations, Inc. | Curable calcium phosphate compositions for use with porous structures and methods of using the same |
US9956314B2 (en) | 2016-01-26 | 2018-05-01 | Modern Ideas LLC | Adhesive for use with bone and bone-like structures |
JP2016209599A (ja) * | 2016-05-20 | 2016-12-15 | ライフ サイエンス エンタープライジズ インコーポレイテッド | リン酸カルシウム配合骨セメントを用いる脊椎骨の最小侵襲治療(mitv) |
EP3466905B1 (en) * | 2016-05-30 | 2021-12-15 | FUJIFILM Corporation | Method for producing calcium phosphate molded article, calcium phosphate molded article, and material for transplantation |
CN106178063B (zh) * | 2016-08-14 | 2019-09-27 | 山东省芙蓉堂制药有限公司 | 一种无免疫排斥创可贴 |
EP3532117B1 (en) | 2016-10-28 | 2023-08-02 | CELLINK Bioprinting AB | Preparation and applications of 3d bioprinting bioinks for repair of bone defects, based on cellulose nanofibrils hydrogels with natural or synthetic calcium phosphate particles |
WO2018078130A1 (en) | 2016-10-28 | 2018-05-03 | Paul Gatenholm | Preparation and applications of 3d bioprinting bioinks for repair of bone defects, based on cellulose nanofibrils hydrogels with natural or synthetic calcium phosphate particles |
CN107551319A (zh) * | 2017-07-13 | 2018-01-09 | 吉林大学 | 一种抗骨肿瘤复合骨重建支架的制备方法 |
CN107648673B (zh) * | 2017-09-18 | 2020-12-11 | 暨南大学 | 一种复合型磷酸钙骨水泥及其制备方法与应用 |
CN108309517B (zh) * | 2018-01-25 | 2019-08-30 | 中国人民解放军新疆军区总医院 | 一种可吸收颈椎椎间融合器及其制备方法 |
KR101959523B1 (ko) * | 2018-01-30 | 2019-03-18 | 주식회사 파마리서치프로덕트 | 핵산, 골 이식재 및 양이온성 고분자를 포함하는 골 이식용 조성물 및 이를 제조하기 위한 골 이식용 키트 |
US20190314550A1 (en) * | 2018-04-16 | 2019-10-17 | Brahm Holdings, Llc | Bone substitute composition and related methods |
WO2020008555A1 (ja) * | 2018-07-04 | 2020-01-09 | オリンパス株式会社 | 骨補填材及び骨補填材の製造方法 |
WO2020008558A1 (ja) * | 2018-07-04 | 2020-01-09 | オリンパス株式会社 | 骨補填材及び骨補填材の製造方法 |
CN109260511A (zh) * | 2018-09-14 | 2019-01-25 | 广州润虹医药科技股份有限公司 | 一种可注射型多孔磷酸钙骨水泥及其制备方法 |
CN109316627A (zh) * | 2018-10-26 | 2019-02-12 | 中国医学科学院北京协和医院 | 一种新型人工骨材料及其制备方法和应用 |
CN109847095A (zh) * | 2018-12-28 | 2019-06-07 | 上海纳米技术及应用国家工程研究中心有限公司 | Peg包覆光敏剂ir780改性的可注射型磷酸钙骨水泥的制备及产品和应用 |
CN109980200B (zh) * | 2019-03-21 | 2021-01-15 | 北京工业大学 | 一种晶畴弥散分布非晶体磷基负极材料及其制备方法 |
CN109985277B (zh) * | 2019-03-27 | 2021-09-14 | 广东工业大学 | 一种骨组织工程用的多孔羟基磷灰石/壳聚糖复合材料支架及其制备方法 |
CN110201228A (zh) * | 2019-04-19 | 2019-09-06 | 湖北联结生物材料有限公司 | 一种含脱钙骨基质的磷酸钙骨水泥及其制备方法和应用 |
CN110101906B (zh) * | 2019-05-31 | 2021-08-06 | 西安理工大学 | 一种可注射型pmma抗生素骨水泥及其制备方法 |
US20220232821A1 (en) * | 2019-06-07 | 2022-07-28 | University Of Cincinnati | Red blood cell storage solutions, additives, and methods for improving the storage of red blood cells using inorganic pyrophosphates |
KR102307234B1 (ko) * | 2019-07-09 | 2021-10-01 | 나태용 | 치주용 골시멘트 조성물 |
WO2021029525A1 (ko) * | 2019-08-14 | 2021-02-18 | 주식회사 메드파크 | 골 이식재 조성물 및 이의 제조방법 |
KR102196235B1 (ko) * | 2019-08-14 | 2020-12-29 | (주)메드파크 | 골 이식재 조성물, 이의 제조 방법 및 골 이식재 조성물 키트 |
CN114096289B (zh) * | 2019-10-30 | 2023-09-01 | 爱恩斯生物科技(昆山)有限公司 | 含有骨无机质成分的复合脱钙骨组合物及其制备方法 |
CN113049839B (zh) * | 2019-12-27 | 2022-11-29 | 桂林英美特生物技术研究所 | 一种稳定的肝功能类复合质控品 |
CN113456886B (zh) * | 2020-03-31 | 2023-07-18 | 中国人民解放军第四军医大学 | 核酸-磷酸钙纳米颗粒复合物及其在生物矿化中的应用 |
US11896736B2 (en) | 2020-07-13 | 2024-02-13 | Globus Medical, Inc | Biomaterial implants and methods of making the same |
CN112028698B (zh) * | 2020-08-27 | 2022-08-12 | 中南林业科技大学 | 一种羟基磷灰石基底的纳米级缓释氮肥的制备方法 |
CN115068693B (zh) * | 2021-03-11 | 2024-04-12 | 东北林业大学 | 一种骨修复发泡复合材料及其制备方法 |
CN113368298B (zh) * | 2021-06-09 | 2022-07-15 | 刘长城 | 一种具有抗菌效果的骨科医用粘合材料及其制备方法 |
CN113350486A (zh) * | 2021-07-06 | 2021-09-07 | 深圳市人民医院 | 一种具有骨缺损修复功效的药物组合物及其应用 |
CN117339026A (zh) * | 2023-11-09 | 2024-01-05 | 广州医科大学附属口腔医院(广州医科大学羊城医院) | 用于植入人体牙槽骨中的可吸收支架的制备及应用 |
Family Cites Families (142)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2967802A (en) | 1957-12-02 | 1961-01-10 | Diamond Lab | Hydrated calcium phosphate gelantigen composition and method of preparing same |
FR1604134A (zh) | 1967-09-26 | 1971-07-12 | ||
US3577492A (en) | 1967-10-02 | 1971-05-04 | Miles Lab | Tableting lubricant |
US4016252A (en) | 1972-04-06 | 1977-04-05 | Institut Pasteur | Calcium phosphate gel for adsorbing vaccines |
FR2181426B1 (zh) | 1972-04-06 | 1974-12-20 | Pasteur Institut | |
US4157378A (en) | 1973-01-11 | 1979-06-05 | Colgate Palmolive Company | Process for preparing fluorapatite |
IL47412A0 (en) | 1974-06-04 | 1975-08-31 | Wellcome Found | Prostaglandin conjugates,their preparation and pharmaceutical compositions containing them |
CH611150A5 (zh) * | 1975-04-18 | 1979-05-31 | Sulzer Ag | |
US4108690A (en) | 1976-04-05 | 1978-08-22 | Amchem Products, Inc. | Method for producing an amorphous, light weight calcium phosphate coating on ferrous metal surfaces |
DE2843963A1 (de) | 1978-10-09 | 1980-04-24 | Merck Patent Gmbh | Im koerper resorbierbare geformte masse auf basis von kollagen und ihre verwendung in der medizin |
DE2965725D1 (en) | 1978-07-19 | 1983-07-28 | Patrick Couvreur | Biodegradable nanoparticles, pharmaceutical compositions containing them and process for their preparation |
JPS5654841A (en) | 1979-10-08 | 1981-05-15 | Mitsubishi Mining & Cement Co | Bone broken portion and filler for void portion and method of treating bone of animal using said filler |
US4346709A (en) | 1980-11-10 | 1982-08-31 | Alza Corporation | Drug delivery devices comprising erodible polymer and erosion rate modifier |
US4353888A (en) | 1980-12-23 | 1982-10-12 | Sefton Michael V | Encapsulation of live animal cells |
USRE33221E (en) | 1982-04-29 | 1990-05-22 | American Dental Association Health Foundation | Dental restorative cement pastes |
USRE33161E (en) | 1982-04-29 | 1990-02-06 | American Dental Association Health Foundation | Combinations of sparingly soluble calcium phosphates in slurries and pastes as mineralizers and cements |
US5286763A (en) | 1983-03-22 | 1994-02-15 | Massachusetts Institute Of Technology | Bioerodible polymers for drug delivery in bone |
JPS59170700U (ja) | 1983-04-30 | 1984-11-15 | 株式会社荏原製作所 | ストレ−ナ |
DE3325111A1 (de) | 1983-07-12 | 1985-01-24 | Merck Patent Gmbh, 6100 Darmstadt | Implantationsmaterialien |
US4612053A (en) | 1983-10-06 | 1986-09-16 | American Dental Association Health Foundation | Combinations of sparingly soluble calcium phosphates in slurries and pastes as mineralizers and cements |
JPS6117409A (ja) | 1984-07-02 | 1986-01-25 | Meishin Toryo Kk | 非晶質リン酸カルシウムの製法およびこれを主成分とする生体適応性組成物 |
US4620327A (en) | 1984-07-05 | 1986-11-04 | Caplan Arnold I | Process of adapting soluble bone protein for use in stimulating osteoinduction |
DE3433210C1 (de) | 1984-09-10 | 1986-06-05 | Hans Dr.med. Dr.med.dent. 8000 München Scheicher | Mittel zur Fuellung von Knochen- und Zahndefekten,zum Knochenaufbau,fuer Knochenkontaktschichten und fuer Knochen- und Zahnwurzelersatz und Verwendung von Carbonatapatit fuer diesen Zweck |
US5007930A (en) | 1985-02-19 | 1991-04-16 | The Dow Chemical Company | Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics |
JPS62182146A (ja) | 1985-10-11 | 1987-08-10 | 三井東圧化学株式会社 | 硬化性材料 |
US5187076A (en) | 1986-07-01 | 1993-02-16 | Genetics Institute, Inc. | DNA sequences encoding BMP-6 proteins |
ZA874681B (en) | 1986-07-01 | 1988-04-27 | Genetics Inst | Novel osteoinductive factors |
US5108922A (en) | 1986-07-01 | 1992-04-28 | Genetics Institute, Inc. | DNA sequences encoding BMP-1 products |
US5106748A (en) | 1986-07-01 | 1992-04-21 | Genetics Institute, Inc. | Dna sequences encoding 5 proteins |
US5013649A (en) | 1986-07-01 | 1991-05-07 | Genetics Institute, Inc. | DNA sequences encoding osteoinductive products |
US4778471A (en) | 1986-11-19 | 1988-10-18 | University Of Dayton | Zcap ceramics |
US5041138A (en) | 1986-11-20 | 1991-08-20 | Massachusetts Institute Of Technology | Neomorphogenesis of cartilage in vivo from cell culture |
US4737411A (en) | 1986-11-25 | 1988-04-12 | University Of Dayton | Controlled pore size ceramics particularly for orthopaedic and dental applications |
US5085861A (en) | 1987-03-12 | 1992-02-04 | The Beth Israel Hospital Association | Bioerodable implant composition comprising crosslinked biodegradable polyesters |
DE3709897A1 (de) | 1987-03-26 | 1988-10-06 | Ewers Rolf | Verfahren zur herstellung eines hydroxylapatitmaterials |
US4892538A (en) | 1987-11-17 | 1990-01-09 | Brown University Research Foundation | In vivo delivery of neurotransmitters by implanted, encapsulated cells |
US5129905A (en) | 1988-04-20 | 1992-07-14 | Norian Corporation | Methods for in situ prepared calcium phosphate minerals |
US5178845A (en) | 1988-04-20 | 1993-01-12 | Norian Corporation | Intimate mixture of calcium and phosphate sources as precursor to hydroxyapatite |
US6002065A (en) | 1988-04-20 | 1999-12-14 | Norian Corporation | Kits for preparing calcium phosphate minerals |
US5047031A (en) | 1988-04-20 | 1991-09-10 | Norian Corporation | In situ calcium phosphate minerals method |
US5053212A (en) | 1988-04-20 | 1991-10-01 | Norian Corporation | Intimate mixture of calcium and phosphate sources as precursor to hydroxyapatite |
US5962028A (en) | 1988-04-20 | 1999-10-05 | Norian Corporation | Carbonated hydroxyapatite compositions and uses |
US6005162A (en) | 1988-04-20 | 1999-12-21 | Norian Corporation | Methods of repairing bone |
US4880610A (en) | 1988-04-20 | 1989-11-14 | Norian Corporation | In situ calcium phosphate minerals--method and composition |
US4849193A (en) | 1988-05-02 | 1989-07-18 | United States Gypsum Company | Process of preparing hydroxylapatite |
US5034059A (en) | 1989-02-17 | 1991-07-23 | Norian Corporation | Composition comprising octacalcium phosphate crystals and polypeptide |
US5037639A (en) | 1989-05-24 | 1991-08-06 | American Dental Association Health Foundation | Methods and compositions for mineralizing calcified tissues |
US5290558A (en) | 1989-09-21 | 1994-03-01 | Osteotech, Inc. | Flowable demineralized bone powder composition and its use in bone repair |
US5073373A (en) | 1989-09-21 | 1991-12-17 | Osteotech, Inc. | Flowable demineralized bone powder composition and its use in bone repair |
US5443832A (en) | 1990-04-16 | 1995-08-22 | Institut Swisse De Recherches Experimentales Sur Le Cancer | Hydroxyapatite-antigen conjugates and methods for generating a poly-Ig immune response |
EP0536186B1 (en) | 1990-05-16 | 2001-11-21 | Genetics Institute, Inc. | Bone and cartilage inductive proteins |
US5462751A (en) | 1990-06-22 | 1995-10-31 | The Regeants Of The University Of California | Biological and pharmaceutical agents having a nanomeric biodegradable core |
JP2621622B2 (ja) | 1990-09-27 | 1997-06-18 | 三菱マテリアル株式会社 | 水硬性リン酸カルシウムセメント |
US5486359A (en) | 1990-11-16 | 1996-01-23 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells |
US5226914A (en) | 1990-11-16 | 1993-07-13 | Caplan Arnold I | Method for treating connective tissue disorders |
US5197985A (en) | 1990-11-16 | 1993-03-30 | Caplan Arnold I | Method for enhancing the implantation and differentiation of marrow-derived mesenchymal cells |
US5149368A (en) | 1991-01-10 | 1992-09-22 | Liu Sung Tsuen | Resorbable bioactive calcium phosphate cement |
US5262166A (en) | 1991-04-17 | 1993-11-16 | Lty Medical Inc | Resorbable bioactive phosphate containing cements |
DK0592562T3 (da) | 1991-06-25 | 1999-08-30 | Genetics Inst | BMP-9-præparater |
EP0520690B1 (en) | 1991-06-26 | 1995-11-02 | Nitta Gelatin Inc. | Calcium phosphate type hardening material for repairing living hard tissue |
US5782971B1 (en) | 1991-06-28 | 1999-09-21 | Norian Corp | Calcium phosphate cements comprising amorophous calcium phosphate |
JP2686684B2 (ja) | 1991-08-27 | 1997-12-08 | 寅雄 大塚 | 水酸化アパタイトを充填し生体内溶解性繊維により編機されたチューブ網編成物 |
JP3504263B2 (ja) | 1991-11-04 | 2004-03-08 | ジェネティックス・インスチチュート・リミテッド・ライアビリティ・カンパニー | 組み換え型骨形態形成蛋白ヘテロダイマー、組成物および使用法 |
US5605713A (en) | 1991-11-22 | 1997-02-25 | Boltong; Maria G. | Process for the preparation of calcium phosphate cements and its application as bio-materials |
US5258044A (en) | 1992-01-30 | 1993-11-02 | Etex Corporation | Electrophoretic deposition of calcium phosphate material on implants |
US5306305A (en) | 1992-01-31 | 1994-04-26 | Etex Corporation | Methods of coating implants with bony structure |
US5281265A (en) | 1992-02-03 | 1994-01-25 | Liu Sung Tsuen | Resorbable surgical cements |
US5314476A (en) | 1992-02-04 | 1994-05-24 | Osteotech, Inc. | Demineralized bone particles and flowable osteogenic composition containing same |
CA2129820C (en) | 1992-02-12 | 2003-06-17 | Helge Neidhardt | Dna sequences encoding novel growth/differentiation factors |
ATE208217T1 (de) | 1992-02-28 | 2001-11-15 | Cohesion Tech Inc | Injektierbare, keramische verbindungen sowie verfahren zur deren herstellung und anwendung |
IL106278A0 (en) | 1992-07-13 | 1993-11-15 | Sumitomo Metal Ind | Bone formation-inducing protein |
AU5125693A (en) | 1992-09-03 | 1994-03-29 | Regents Of The University Of California, The | Dorsal tissue affecting factor and compositions |
US5399665A (en) | 1992-11-05 | 1995-03-21 | Massachusetts Institute Of Technology | Biodegradable polymers for cell transplantation |
EP0679163A4 (en) | 1993-01-12 | 1997-07-16 | Univ Johns Hopkins Med | FACTOR-3 OF GROWTH AND DIFFERENTIATION. |
EP0690871A4 (en) | 1993-01-12 | 1999-10-20 | Univ Johns Hopkins Med | GROWTH AND DIFFERENTIATION FACTOR-5 |
JP3482207B2 (ja) | 1993-01-12 | 2003-12-22 | ジョーンズ ホプキンス ユニバーシティー スクール オブ メディシン | 増殖分化因子−9 |
US5514378A (en) | 1993-02-01 | 1996-05-07 | Massachusetts Institute Of Technology | Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures |
US5522893A (en) | 1993-03-12 | 1996-06-04 | American Dental Association Health Foundation | Calcium phosphate hydroxyapatite precursor and methods for making and using the same |
DE69432815T2 (de) | 1993-03-19 | 2003-12-11 | Univ Johns Hopkins Med | Wachstumsfaktor-8 |
US5565502A (en) | 1993-03-24 | 1996-10-15 | Children's Medical Center Corporation | Isolation of the calcium-phosphate crystals of bone |
WO1994025637A1 (en) | 1993-04-23 | 1994-11-10 | Etex Corporation | Method of coating medical devices and devices coated thereby |
DE69433530T2 (de) | 1993-05-12 | 2005-01-05 | Genetics Institute, LLC, Cambridge | Bmp-11 zusammensetzungen |
AU677849B2 (en) | 1993-05-12 | 1997-05-08 | Genetics Institute, Llc | BMP-10 compositions |
GB9310321D0 (en) | 1993-05-19 | 1993-06-30 | Queen Mary & Westfield College | Method for the preparation of carbonated hydroxyapatite compositions |
WO1995001802A1 (en) | 1993-07-09 | 1995-01-19 | The Johns Hopkins University School Of Medicine | Growth differentiation factor-7 |
JPH09503903A (ja) | 1993-07-09 | 1997-04-22 | ザ ジョーンズ ホプキンス ユニバーシティー スクール オブ メディシン | 増殖分化因子−6 |
RU2077329C1 (ru) | 1993-07-21 | 1997-04-20 | Акционерное общество закрытого типа "ОСТИМ" | Средство для стимуляции роста костной ткани |
JP3773254B2 (ja) | 1993-07-22 | 2006-05-10 | ノリアン コーポレイション | 貯蔵安定性の部分中和化酸組成物及び利用 |
US5763092A (en) | 1993-09-15 | 1998-06-09 | Etex Corporation | Hydroxyapatite coatings and a method of their manufacture |
US6291206B1 (en) | 1993-09-17 | 2001-09-18 | Genetics Institute, Inc. | BMP receptor proteins |
US5525148A (en) | 1993-09-24 | 1996-06-11 | American Dental Association Health Foundation | Self-setting calcium phosphate cements and methods for preparing and using them |
US6204047B1 (en) | 1993-10-08 | 2001-03-20 | The Johns Hopkins University School Of Medicine | Growth differentiation factor-10 |
ES2255059T3 (es) | 1993-12-07 | 2006-06-16 | Genetics Institute, Llc | Bmp-12, bmp-13 y composiciones suyas inductoras de tendon. |
CA2179029C (en) | 1993-12-30 | 2009-02-24 | Philip W. Ingham | Vertebrate embryonic pattern-inducing hedgehog-like proteins |
JPH07250688A (ja) | 1994-01-28 | 1995-10-03 | Sagami Chem Res Center | TGF−βスーパーファミリー蛋白質をコードするヒト新規cDNA |
US5508342A (en) | 1994-02-01 | 1996-04-16 | The United States Of America As Represented By The Secretary Of Commerce | Polymeric amorphous calcium phosphate compositions |
DK0776337T3 (da) | 1994-07-08 | 2005-12-12 | Univ Johns Hopkins Med | Vækstdifferentieringsfaktor-11 |
PT770089E (pt) | 1994-07-13 | 2001-02-28 | Univ Johns Hopkins Med | Factor 12 de diferenciacao do crescimento |
US5516532A (en) | 1994-08-05 | 1996-05-14 | Children's Medical Center Corporation | Injectable non-immunogenic cartilage and bone preparation |
US5496399A (en) | 1994-08-23 | 1996-03-05 | Norian Corporation | Storage stable calcium phosphate cements |
US5569442A (en) | 1994-11-04 | 1996-10-29 | Norian Corporation | Reactive tricalcium phosphate compositions and uses |
US6281332B1 (en) | 1994-12-02 | 2001-08-28 | The Johns Hopkins University School Of Medicine | Hedgehog-derived polypeptides |
US5904716A (en) | 1995-04-26 | 1999-05-18 | Gendler; El | Method for reconstituting cartilage tissue using demineralized bone and product thereof |
US5635372A (en) | 1995-05-18 | 1997-06-03 | Genetics Institute, Inc. | BMP-15 compositions |
US6132463A (en) | 1995-05-19 | 2000-10-17 | Etex Corporation | Cell seeding of ceramic compositions |
US6287341B1 (en) | 1995-05-19 | 2001-09-11 | Etex Corporation | Orthopedic and dental ceramic implants |
US5676976A (en) | 1995-05-19 | 1997-10-14 | Etex Corporation | Synthesis of reactive amorphous calcium phosphates |
US6027742A (en) | 1995-05-19 | 2000-02-22 | Etex Corporation | Bioresorbable ceramic composites |
US6541037B1 (en) | 1995-05-19 | 2003-04-01 | Etex Corporation | Delivery vehicle |
US6117456A (en) | 1995-05-19 | 2000-09-12 | Etex Corporation | Methods and products related to the physical conversion of reactive amorphous calcium phosphate |
US5700289A (en) | 1995-10-20 | 1997-12-23 | North Shore University Hospital Research Corporation | Tissue-engineered bone repair using cultured periosteal cells |
US5702717A (en) | 1995-10-25 | 1997-12-30 | Macromed, Inc. | Thermosensitive biodegradable polymers based on poly(ether-ester)block copolymers |
US5783217A (en) | 1995-11-07 | 1998-07-21 | Etex Corporation | Low temperature calcium phosphate apatite and a method of its manufacture |
US6033582A (en) | 1996-01-22 | 2000-03-07 | Etex Corporation | Surface modification of medical implants |
US5843289A (en) | 1996-01-22 | 1998-12-01 | Etex Corporation | Surface modification of medical implants |
US5965403A (en) | 1996-09-18 | 1999-10-12 | Genetics Institute, Inc. | Nucleic acids encoding bone morphogenic protein-16 (BMP-16) |
US5795330A (en) | 1996-10-10 | 1998-08-18 | Etex Corporation | Mixing device |
US6953594B2 (en) | 1996-10-10 | 2005-10-11 | Etex Corporation | Method of preparing a poorly crystalline calcium phosphate and methods of its use |
CA2268156C (en) | 1996-10-16 | 2007-05-29 | Etex Corporation | Bioceramic compositions |
EP0873145A2 (en) | 1996-11-15 | 1998-10-28 | Advanced Bio Surfaces, Inc. | Biomaterial system for in situ tissue repair |
US20020098222A1 (en) | 1997-03-13 | 2002-07-25 | John F. Wironen | Bone paste |
US6071982A (en) | 1997-04-18 | 2000-06-06 | Cambridge Scientific, Inc. | Bioerodible polymeric semi-interpenetrating network alloys for surgical plates and bone cements, and method for making same |
US20020076429A1 (en) | 1998-01-28 | 2002-06-20 | John F. Wironen | Bone paste subjected to irradiative and thermal treatment |
US6030635A (en) | 1998-02-27 | 2000-02-29 | Musculoskeletal Transplant Foundation | Malleable paste for filling bone defects |
US5968253A (en) | 1998-07-31 | 1999-10-19 | Norian Corporation | Calcium phosphate cements comprising antimicrobial agents |
CA2362046A1 (en) | 1999-02-04 | 2000-08-10 | Sdgi Holdings, Inc. | Osteogenic paste compositions and uses thereof |
US6461631B1 (en) | 1999-11-16 | 2002-10-08 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
US6340477B1 (en) | 2000-04-27 | 2002-01-22 | Lifenet | Bone matrix composition and methods for making and using same |
US6599516B1 (en) | 2000-09-14 | 2003-07-29 | Etex Corporation | Malleable implant containing solid element that resorbs or fractures to provide access channels |
US6547866B1 (en) * | 2000-10-30 | 2003-04-15 | Howmedica Osteonics Corp. | Porous calcium phosphate cement |
TWI267378B (en) * | 2001-06-08 | 2006-12-01 | Wyeth Corp | Calcium phosphate delivery vehicles for osteoinductive proteins |
GB2377285A (en) * | 2001-07-02 | 2003-01-08 | Ubinetics Ltd | State machine |
US6840961B2 (en) | 2001-12-21 | 2005-01-11 | Etex Corporation | Machinable preformed calcium phosphate bone substitute material implants |
WO2003057137A2 (en) | 2001-12-21 | 2003-07-17 | Etex Corporation | Synthesis of calcium phosphates by mechano-chemical process |
US20030180344A1 (en) | 2002-02-05 | 2003-09-25 | Cambridge Scientific, Inc. | Bioresorbable osteoconductive compositions for bone regeneration |
US7582309B2 (en) | 2002-11-15 | 2009-09-01 | Etex Corporation | Cohesive demineralized bone compositions |
EP3254710B1 (en) | 2003-04-11 | 2019-05-22 | Etex Corporation | Osteoinductive bone material |
JP3935122B2 (ja) | 2003-08-06 | 2007-06-20 | 日本航空電子工業株式会社 | コネクタ |
US7252833B2 (en) | 2003-11-18 | 2007-08-07 | Skeletal Kinetics, Llc | Calcium phosphate cements comprising an osteoclastogenic agent |
US7252841B2 (en) | 2004-05-20 | 2007-08-07 | Skeletal Kinetics, Llc | Rapid setting calcium phosphate cements |
US7175858B2 (en) | 2004-07-26 | 2007-02-13 | Skeletal Kinetics Llc | Calcium phosphate cements and methods for using the same |
US8147860B2 (en) * | 2005-12-06 | 2012-04-03 | Etex Corporation | Porous calcium phosphate bone material |
-
2005
- 2005-12-06 US US11/294,819 patent/US8147860B2/en active Active
-
2006
- 2006-12-06 EP EP15153139.9A patent/EP2992855B1/en active Active
- 2006-12-06 CA CA2632785A patent/CA2632785C/en active Active
- 2006-12-06 KR KR1020087016283A patent/KR101395884B1/ko active IP Right Grant
- 2006-12-06 AU AU2006322025A patent/AU2006322025B2/en active Active
- 2006-12-06 CN CN2006800520527A patent/CN101420922B/zh active Active
- 2006-12-06 EP EP06844849.7A patent/EP1962716B1/en active Active
- 2006-12-06 WO PCT/US2006/046435 patent/WO2007067561A2/en active Application Filing
- 2006-12-06 JP JP2008544447A patent/JP5416972B2/ja active Active
-
2012
- 2012-04-03 US US13/438,207 patent/US8545858B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
WO2007067561A3 (en) | 2007-10-11 |
EP1962716B1 (en) | 2015-03-04 |
CA2632785A1 (en) | 2007-06-14 |
US20070128245A1 (en) | 2007-06-07 |
KR101395884B1 (ko) | 2014-05-21 |
CN101420922A (zh) | 2009-04-29 |
JP5416972B2 (ja) | 2014-02-12 |
EP2992855A1 (en) | 2016-03-09 |
KR20080113013A (ko) | 2008-12-26 |
EP1962716A2 (en) | 2008-09-03 |
US8147860B2 (en) | 2012-04-03 |
US8545858B2 (en) | 2013-10-01 |
JP2009519052A (ja) | 2009-05-14 |
AU2006322025A1 (en) | 2007-06-14 |
EP1962716A4 (en) | 2010-11-03 |
WO2007067561A2 (en) | 2007-06-14 |
CA2632785C (en) | 2015-02-24 |
AU2006322025B2 (en) | 2013-08-15 |
EP2992855B1 (en) | 2017-11-29 |
US20120282301A1 (en) | 2012-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101420922B (zh) | 多孔磷酸钙骨材料 | |
KR101161784B1 (ko) | 골 유도성 골 물질 | |
US20220072204A1 (en) | Platelet-Derived Growth Factor Compositions and Methods of Use Thereof | |
KR101218454B1 (ko) | 세팅 지연 칼슘 포스페이트 페이스트 | |
US20180311402A1 (en) | Minimally invasive treatment of vertebra (mitv) using a calcium phosphate combination bone cement | |
AU2015215892A1 (en) | Minimally invasive treatment of vertebra (mitv) using a calcium phosphate combination bone cement |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |