TW201834654A - 包含task-1與task-3通道抑制劑之醫藥劑型及其用於呼吸病症治療之用途 - Google Patents
包含task-1與task-3通道抑制劑之醫藥劑型及其用於呼吸病症治療之用途 Download PDFInfo
- Publication number
- TW201834654A TW201834654A TW106144530A TW106144530A TW201834654A TW 201834654 A TW201834654 A TW 201834654A TW 106144530 A TW106144530 A TW 106144530A TW 106144530 A TW106144530 A TW 106144530A TW 201834654 A TW201834654 A TW 201834654A
- Authority
- TW
- Taiwan
- Prior art keywords
- task
- nasal
- present
- stable pharmaceutical
- pharmaceutical formulation
- Prior art date
Links
- 208000023504 respiratory system disease Diseases 0.000 title claims abstract description 29
- 239000003112 inhibitor Substances 0.000 title claims description 69
- 239000002552 dosage form Substances 0.000 title abstract description 10
- 238000002560 therapeutic procedure Methods 0.000 title description 6
- 101001050878 Homo sapiens Potassium channel subfamily K member 9 Proteins 0.000 claims abstract description 67
- 208000001797 obstructive sleep apnea Diseases 0.000 claims abstract description 43
- 206010041235 Snoring Diseases 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 208000003417 Central Sleep Apnea Diseases 0.000 claims abstract description 16
- 230000002265 prevention Effects 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 118
- 238000009472 formulation Methods 0.000 claims description 111
- -1 Polyoxyethylene Polymers 0.000 claims description 63
- 150000003839 salts Chemical class 0.000 claims description 62
- 239000008194 pharmaceutical composition Substances 0.000 claims description 57
- 239000012453 solvate Substances 0.000 claims description 47
- 230000000694 effects Effects 0.000 claims description 46
- 210000003800 pharynx Anatomy 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 34
- 239000002207 metabolite Substances 0.000 claims description 28
- 239000000126 substance Substances 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 24
- 239000002671 adjuvant Substances 0.000 claims description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 239000011737 fluorine Substances 0.000 claims description 20
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 20
- 229920000053 polysorbate 80 Polymers 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 19
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 19
- 229940068968 polysorbate 80 Drugs 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 17
- 102100024986 Potassium channel subfamily K member 9 Human genes 0.000 claims description 16
- 230000006793 arrhythmia Effects 0.000 claims description 16
- 206010003119 arrhythmia Diseases 0.000 claims description 16
- 239000003002 pH adjusting agent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 239000003963 antioxidant agent Substances 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 13
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 229940125400 channel inhibitor Drugs 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 239000003755 preservative agent Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 230000002335 preservative effect Effects 0.000 claims description 9
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 239000007922 nasal spray Substances 0.000 claims description 7
- 230000001703 neuroimmune Effects 0.000 claims description 7
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- YDNWTNODZDSPNZ-UHFFFAOYSA-N 6-methoxypyridine-2-carbaldehyde Chemical compound COC1=CC=CC(C=O)=N1 YDNWTNODZDSPNZ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 239000000443 aerosol Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 5
- 229940097496 nasal spray Drugs 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 5
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- 229960004926 chlorobutanol Drugs 0.000 claims description 4
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003205 fragrance Substances 0.000 claims description 4
- 239000007923 nasal drop Substances 0.000 claims description 4
- 229940100662 nasal drops Drugs 0.000 claims description 4
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 4
- 229940068977 polysorbate 20 Drugs 0.000 claims description 4
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 238000010926 purge Methods 0.000 claims description 4
- 235000010199 sorbic acid Nutrition 0.000 claims description 4
- 239000004334 sorbic acid Substances 0.000 claims description 4
- 229940075582 sorbic acid Drugs 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 3
- 229960002216 methylparaben Drugs 0.000 claims description 3
- 239000006199 nebulizer Substances 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- CROTXORBJIXBSO-UHFFFAOYSA-N [4-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-(6-methoxypyridin-2-yl)methanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1=NC(=CC=C1)OC CROTXORBJIXBSO-UHFFFAOYSA-N 0.000 claims 2
- NABAWQRCDXXOMF-UHFFFAOYSA-N [4-[[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-(2-fluorophenyl)methanone Chemical compound BrC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1=C(C=CC=C1)F NABAWQRCDXXOMF-UHFFFAOYSA-N 0.000 claims 1
- RWCKYFYFNKRFHA-UHFFFAOYSA-N [4-[[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-cyclopentylmethanone Chemical compound BrC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1CCCC1 RWCKYFYFNKRFHA-UHFFFAOYSA-N 0.000 claims 1
- OJTQAPGPBFFNOG-UHFFFAOYSA-N [4-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-cyclopentylmethanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1CCCC1 OJTQAPGPBFFNOG-UHFFFAOYSA-N 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 229940100656 nasal solution Drugs 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 150000003016 phosphoric acids Chemical class 0.000 claims 1
- 230000000414 obstructive effect Effects 0.000 abstract description 15
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 4
- 230000003389 potentiating effect Effects 0.000 abstract description 4
- 235000002639 sodium chloride Nutrition 0.000 description 57
- 239000004480 active ingredient Substances 0.000 description 36
- 229920000642 polymer Polymers 0.000 description 21
- 230000000241 respiratory effect Effects 0.000 description 18
- 108091006146 Channels Proteins 0.000 description 17
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- 230000009471 action Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000005557 antagonist Substances 0.000 description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 239000011859 microparticle Substances 0.000 description 13
- 210000003205 muscle Anatomy 0.000 description 13
- 210000001331 nose Anatomy 0.000 description 12
- 235000006708 antioxidants Nutrition 0.000 description 11
- 239000002245 particle Substances 0.000 description 11
- 230000029058 respiratory gaseous exchange Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 210000002345 respiratory system Anatomy 0.000 description 9
- 201000002859 sleep apnea Diseases 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 241000282887 Suidae Species 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 7
- 208000008784 apnea Diseases 0.000 description 7
- 239000000227 bioadhesive Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 229920000136 polysorbate Polymers 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000009102 absorption Effects 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000003613 bile acid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229950008882 polysorbate Drugs 0.000 description 6
- 229940044601 receptor agonist Drugs 0.000 description 6
- 239000000018 receptor agonist Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 229960000686 benzalkonium chloride Drugs 0.000 description 5
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 5
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 5
- 238000001879 gelation Methods 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 229960005150 glycerol Drugs 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000002035 prolonged effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000009423 ventilation Methods 0.000 description 5
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 229920001661 Chitosan Polymers 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 206010021133 Hypoventilation Diseases 0.000 description 4
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 4
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 4
- 229940083712 aldosterone antagonist Drugs 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 239000012752 auxiliary agent Substances 0.000 description 4
- 239000002876 beta blocker Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 4
- 229960002748 norepinephrine Drugs 0.000 description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- 102100040214 Apolipoprotein(a) Human genes 0.000 description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 description 3
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 229940086609 Lipase inhibitor Drugs 0.000 description 3
- 108010033266 Lipoprotein(a) Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 description 3
- 229940122054 Peroxisome proliferator-activated receptor delta agonist Drugs 0.000 description 3
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- 102000004257 Potassium Channel Human genes 0.000 description 3
- 206010038669 Respiratory arrest Diseases 0.000 description 3
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 3
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 229940127218 antiplatelet drug Drugs 0.000 description 3
- 239000000480 calcium channel blocker Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 238000002567 electromyography Methods 0.000 description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002714 fluticasone Drugs 0.000 description 3
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000013160 medical therapy Methods 0.000 description 3
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 3
- 230000000420 mucociliary effect Effects 0.000 description 3
- 210000003097 mucus Anatomy 0.000 description 3
- 230000010352 nasal breathing Effects 0.000 description 3
- 210000002850 nasal mucosa Anatomy 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 3
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 3
- 108020001213 potassium channel Proteins 0.000 description 3
- 239000002461 renin inhibitor Substances 0.000 description 3
- 229940086526 renin-inhibitors Drugs 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229960002052 salbutamol Drugs 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229940031439 squalene Drugs 0.000 description 3
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 3
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 108090000721 thyroid hormone receptors Proteins 0.000 description 3
- 102000004217 thyroid hormone receptors Human genes 0.000 description 3
- 230000001960 triggered effect Effects 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical class C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 102100031168 CCN family member 2 Human genes 0.000 description 2
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 229940127328 Cholesterol Synthesis Inhibitors Drugs 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101000777550 Homo sapiens CCN family member 2 Proteins 0.000 description 2
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 2
- 102100021711 Ileal sodium/bile acid cotransporter Human genes 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 description 2
- 101710149745 Lysophosphatidic acid receptor 1 Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 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 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- 239000004147 Sorbitan trioleate Substances 0.000 description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 2
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001348 alkyl chlorides Chemical class 0.000 description 2
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 description 2
- 229960002414 ambrisentan Drugs 0.000 description 2
- 230000001022 anti-muscarinic effect Effects 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229910052789 astatine Inorganic materials 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 229960003065 bosentan Drugs 0.000 description 2
- SXTRWVVIEPWAKM-UHFFFAOYSA-N bosentan hydrate Chemical compound O.COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 SXTRWVVIEPWAKM-UHFFFAOYSA-N 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229960004195 carvedilol Drugs 0.000 description 2
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- FEJVSJIALLTFRP-LJQANCHMSA-N darusentan Chemical compound COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 FEJVSJIALLTFRP-LJQANCHMSA-N 0.000 description 2
- 229950008833 darusentan Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 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
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- FUBBWDWIGBTUPQ-UHFFFAOYSA-N ethyl 2-[4-[3-[(4-fluorophenyl)-hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimethylanilino]-2-oxoacetate Chemical compound CC1=CC(NC(=O)C(=O)OCC)=CC(C)=C1OC1=CC=C(O)C(C(O)C=2C=CC(F)=CC=2)=C1 FUBBWDWIGBTUPQ-UHFFFAOYSA-N 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 102000052502 human ELANE Human genes 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 2
- 229960004083 methazolamide Drugs 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229960003073 pirfenidone Drugs 0.000 description 2
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 2
- 229960002797 pitavastatin Drugs 0.000 description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000003450 potassium channel blocker Substances 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 239000003368 psychostimulant agent Substances 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000003019 respiratory muscle Anatomy 0.000 description 2
- 239000003169 respiratory stimulant agent Substances 0.000 description 2
- 229940066293 respiratory stimulants Drugs 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 2
- 229960002578 sitaxentan Drugs 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 2
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 229940035044 sorbitan monolaurate Drugs 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 2
- 239000001570 sorbitan monopalmitate Substances 0.000 description 2
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 description 2
- 229960000391 sorbitan trioleate Drugs 0.000 description 2
- 235000011078 sorbitan tristearate Nutrition 0.000 description 2
- 239000001589 sorbitan tristearate Substances 0.000 description 2
- 229960004129 sorbitan tristearate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 229960000257 tiotropium bromide Drugs 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 1
- DZLOHEOHWICNIL-QGZVFWFLSA-N (2R)-2-[6-(4-chlorophenoxy)hexyl]-2-oxiranecarboxylic acid ethyl ester Chemical compound C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)OCC)CO1 DZLOHEOHWICNIL-QGZVFWFLSA-N 0.000 description 1
- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 description 1
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- DMYZJLOWGSRVKP-RTBURBONSA-N (2r,4r)-1-n-(4-chlorophenyl)-4-hydroxy-2-n-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-1,2-dicarboxamide Chemical compound N1([C@H](C[C@H](C1)O)C(=O)NC=1C=CC(=CC=1)N1C(COCC1)=O)C(=O)NC1=CC=C(Cl)C=C1 DMYZJLOWGSRVKP-RTBURBONSA-N 0.000 description 1
- ZXEIEKDGPVTZLD-NDEPHWFRSA-N (2s)-2-dodecylsulfanyl-n-(4-hydroxy-2,3,5-trimethylphenyl)-2-phenylacetamide Chemical compound O=C([C@@H](SCCCCCCCCCCCC)C=1C=CC=CC=1)NC1=CC(C)=C(O)C(C)=C1C ZXEIEKDGPVTZLD-NDEPHWFRSA-N 0.000 description 1
- LJCBAPRMNYSDOP-LVCYMWGESA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydron;chloride;pentahydrate Chemical compound O.O.O.O.O.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 LJCBAPRMNYSDOP-LVCYMWGESA-N 0.000 description 1
- AJBMORBNKXNZSF-COSHMZDQSA-N (2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxy-4,5-dimethoxy-6-[(2r,3r,4s,5r,6s)-6-methoxy-4,5-disulfooxy-2-(sulfooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-disulfooxy-2-(sulfooxymethyl)oxan-3-yl]oxy-4,5-dimethoxy-3-[(2r,3r,4s,5r,6r)-3,4 Chemical compound OS(=O)(=O)O[C@@H]1[C@@H](OS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](OC)[C@H](O[C@@H]4[C@@H]([C@@H](OC)[C@H](OC)[C@@H](COS(O)(=O)=O)O4)OC)[C@H](O3)C(O)=O)OC)[C@@H](COS(O)(=O)=O)O2)OS(O)(=O)=O)[C@H](C(O)=O)O1 AJBMORBNKXNZSF-COSHMZDQSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 description 1
- BTBHLEZXCOBLCY-QGZVFWFLSA-N (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Chemical compound C1([C@@H]2C(=C(C)NC=3C(C)=CN=C(C2=3)OCC)C(N)=O)=CC=C(C#N)C=C1OC BTBHLEZXCOBLCY-QGZVFWFLSA-N 0.000 description 1
- RWIUTHWKQHRQNP-ZDVGBALWSA-N (9e,12e)-n-(1-phenylethyl)octadeca-9,12-dienamide Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(=O)NC(C)C1=CC=CC=C1 RWIUTHWKQHRQNP-ZDVGBALWSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- XFDJYSQDBULQSI-QFIPXVFZSA-N (R)-doxapram Chemical compound C([C@H]1CN(C(C1(C=1C=CC=CC=1)C=1C=CC=CC=1)=O)CC)CN1CCOCC1 XFDJYSQDBULQSI-QFIPXVFZSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- 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 1
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 description 1
- ZUCFGSAENWHFPO-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-hydroxypropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;hydrate;hydrochloride Chemical compound O.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OCCCO)=C1 ZUCFGSAENWHFPO-UHFFFAOYSA-N 0.000 description 1
- PMGZJNCIQHGNLT-UHFFFAOYSA-N 1-[bis(2,2-dimethylpropanoyloxymethoxy)phosphoryl]-4-(3-phenoxyphenyl)butane-1-sulfonic acid Chemical compound CC(C)(C)C(=O)OCOP(=O)(OCOC(=O)C(C)(C)C)C(S(O)(=O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 PMGZJNCIQHGNLT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 1
- GUSVHVVOABZHAH-OPZWKQDFSA-N 1aw8p77hkj Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(OC[C@H](C)CC1)O5)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GUSVHVVOABZHAH-OPZWKQDFSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- DEMLYXMVPJAVFU-UHFFFAOYSA-N 2-(chloromethyl)oxirane;2-methyl-1h-imidazole Chemical compound ClCC1CO1.CC1=NC=CN1 DEMLYXMVPJAVFU-UHFFFAOYSA-N 0.000 description 1
- HQSRVYUCBOCBLY-XOOFNSLWSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2s,4r)-2-(4-chlorophenyl)-2-[(4-methyl-1,2,4-triazol-3-yl)sulfanylmethyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CSC=4N(C=NN=4)C)(OC3)C=3C=CC(Cl)=CC=3)=CC=2)C=C1 HQSRVYUCBOCBLY-XOOFNSLWSA-N 0.000 description 1
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 1
- CMLUGNQVANVZHY-POURPWNDSA-N 2-[1-[2-[(3r,5s)-1-(3-acetyloxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-5h-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-yl]acetic acid Chemical compound COC1=CC=CC([C@@H]2C3=CC(Cl)=CC=C3N(CC(C)(C)COC(C)=O)C(=O)[C@@H](CC(=O)N3CCC(CC(O)=O)CC3)O2)=C1OC CMLUGNQVANVZHY-POURPWNDSA-N 0.000 description 1
- FBMYKMYQHCBIGU-UHFFFAOYSA-N 2-[2-hydroxy-3-[[1-(1h-indol-3-yl)-2-methylpropan-2-yl]amino]propoxy]benzonitrile Chemical compound C=1NC2=CC=CC=C2C=1CC(C)(C)NCC(O)COC1=CC=CC=C1C#N FBMYKMYQHCBIGU-UHFFFAOYSA-N 0.000 description 1
- GKHIVNAUVKXIIY-UHFFFAOYSA-N 2-[3-[4-(1h-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-n-propan-2-ylacetamide Chemical compound CC(C)NC(=O)COC1=CC=CC(C=2N=C3C=CC=CC3=C(NC=3C=C4C=NNC4=CC=3)N=2)=C1 GKHIVNAUVKXIIY-UHFFFAOYSA-N 0.000 description 1
- UOJMJBUYXYEPFX-UHFFFAOYSA-N 2-[4-(4-hydroxy-3-propan-2-ylphenoxy)-3,5-dimethylanilino]-2-oxoacetic acid Chemical compound C1=C(O)C(C(C)C)=CC(OC=2C(=CC(NC(=O)C(O)=O)=CC=2C)C)=C1 UOJMJBUYXYEPFX-UHFFFAOYSA-N 0.000 description 1
- TXIIZHHIOHVWJD-UHFFFAOYSA-N 2-[7-(2,2-dimethylpropanoylamino)-4,6-dimethyl-1-octyl-2,3-dihydroindol-5-yl]acetic acid Chemical compound CC(C)(C)C(=O)NC1=C(C)C(CC(O)=O)=C(C)C2=C1N(CCCCCCCC)CC2 TXIIZHHIOHVWJD-UHFFFAOYSA-N 0.000 description 1
- QHVBWSIFLCIXBD-UHFFFAOYSA-N 2-[[2-[3-(diaminomethylidene)-6-oxocyclohexa-1,4-dien-1-yl]oxy-3,5-difluoro-6-[3-(1-methyl-4,5-dihydroimidazol-2-yl)phenoxy]pyridin-4-yl]-methylamino]acetic acid Chemical compound N=1C(OC=2C=C(C=CC=2)C=2N(CCN=2)C)=C(F)C(N(CC(O)=O)C)=C(F)C=1OC1=CC(=C(N)N)C=CC1=O QHVBWSIFLCIXBD-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- AUYYCJSJGJYCDS-UHFFFAOYSA-N 2/3/6893 Natural products IC1=CC(CC(N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-UHFFFAOYSA-N 0.000 description 1
- NCGICGYLBXGBGN-UHFFFAOYSA-N 3-morpholin-4-yl-1-oxa-3-azonia-2-azanidacyclopent-3-en-5-imine;hydrochloride Chemical compound Cl.[N-]1OC(=N)C=[N+]1N1CCOCC1 NCGICGYLBXGBGN-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NOBZETMXGVAWIM-UHFFFAOYSA-N 4-[(2-carbamimidoyl-3,4-dihydro-1h-isoquinolin-7-yl)oxymethyl]-1-pyridin-4-ylpiperidine-4-carboxylic acid;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=C2CN(C(=N)N)CCC2=CC=C1OCC(CC1)(C(O)=O)CCN1C1=CC=NC=C1 NOBZETMXGVAWIM-UHFFFAOYSA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- QFCXANHHBCGMAS-UHFFFAOYSA-N 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxymethyl]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(COC=2C=3OC=CC=3C(NC=3C=CC(Cl)=CC=3)=NN=2)=C1 QFCXANHHBCGMAS-UHFFFAOYSA-N 0.000 description 1
- KEWSCDNULKOKTG-UHFFFAOYSA-N 4-cyano-4-ethylsulfanylcarbothioylsulfanylpentanoic acid Chemical compound CCSC(=S)SC(C)(C#N)CCC(O)=O KEWSCDNULKOKTG-UHFFFAOYSA-N 0.000 description 1
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 1
- NEYKRKVLEWKOBI-UHFFFAOYSA-N 5-[2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonylphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N=2)=O)=C1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CCO)CC1 NEYKRKVLEWKOBI-UHFFFAOYSA-N 0.000 description 1
- RCJYGWGQCPDYSL-HZPDHXFCSA-N 7-[(3-bromo-4-methoxyphenyl)methyl]-1-ethyl-8-[[(1r,2r)-2-hydroxycyclopentyl]amino]-3-(2-hydroxyethyl)purine-2,6-dione Chemical compound C=1C=C(OC)C(Br)=CC=1CN1C=2C(=O)N(CC)C(=O)N(CCO)C=2N=C1N[C@@H]1CCC[C@H]1O RCJYGWGQCPDYSL-HZPDHXFCSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 229940110385 Benzodiazepine receptor antagonist Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000005461 Canertinib Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- 229940122820 Cannabinoid receptor antagonist Drugs 0.000 description 1
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 description 1
- 206010008469 Chest discomfort Diseases 0.000 description 1
- 102100037637 Cholesteryl ester transfer protein Human genes 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 229920002905 Colesevelam Polymers 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 102100027995 Collagenase 3 Human genes 0.000 description 1
- 108050005238 Collagenase 3 Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-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
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin 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
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- YARKMNAWFIMDKV-UHFFFAOYSA-N Epanolol Chemical compound C=1C=CC=C(C#N)C=1OCC(O)CNCCNC(=O)CC1=CC=C(O)C=C1 YARKMNAWFIMDKV-UHFFFAOYSA-N 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- YDBLKRPLXZNVNB-UHFFFAOYSA-N GW 501516 Chemical compound CC=1N=C(C=2C=CC(=CC=2)C(F)(F)F)SC=1CSC1=CC=C(OCC(O)=O)C(C)=C1 YDBLKRPLXZNVNB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- 108010072051 Glatiramer Acetate Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- 101000880514 Homo sapiens Cholesteryl ester transfer protein Proteins 0.000 description 1
- 101001049835 Homo sapiens Potassium channel subfamily K member 3 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020591 Hypercapnia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 101710156096 Ileal sodium/bile acid cotransporter Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-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
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib 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
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- XKLMZUWKNUAPSZ-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide Chemical compound COC1=CC=CC=C1OCC(O)CN1CCN(CC(=O)NC=2C(=CC=CC=2C)C)CC1 XKLMZUWKNUAPSZ-UHFFFAOYSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- HOKKHZGPKSLGJE-UHFFFAOYSA-N N-methyl-D-aspartic acid Natural products CNC(C(O)=O)CC(O)=O HOKKHZGPKSLGJE-UHFFFAOYSA-N 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 229920002651 Polysorbate 85 Polymers 0.000 description 1
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
- 102100023207 Potassium channel subfamily K member 3 Human genes 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 108091006335 Prostaglandin I receptors Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- RVOLLAQWKVFTGE-UHFFFAOYSA-N Pyridostigmine Chemical compound CN(C)C(=O)OC1=CC=C[N+](C)=C1 RVOLLAQWKVFTGE-UHFFFAOYSA-N 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 108091006614 SLC10A2 Proteins 0.000 description 1
- IGMKTIJBFUMVIN-UHFFFAOYSA-N Sabeluzole Chemical compound N=1C2=CC=CC=C2SC=1N(C)C(CC1)CCN1CC(O)COC1=CC=C(F)C=C1 IGMKTIJBFUMVIN-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 206010040978 Sleep apnoeas Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 101710108792 Stromelysin-2 Proteins 0.000 description 1
- 102100028847 Stromelysin-3 Human genes 0.000 description 1
- 108050005271 Stromelysin-3 Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 239000005463 Tandutinib Substances 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- KPWYNAGOBXLMSE-UHFFFAOYSA-N Tipelukast Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCOC1=CC=C(C(C)=O)C(OCCCC(O)=O)=C1CCC KPWYNAGOBXLMSE-UHFFFAOYSA-N 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 description 1
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 description 1
- 206010067775 Upper airway obstruction Diseases 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- CPGKMLVTFNUAHL-UHFFFAOYSA-N [Ca].[Ca] Chemical compound [Ca].[Ca] CPGKMLVTFNUAHL-UHFFFAOYSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- OJPSKWYIZCAQST-UHFFFAOYSA-N acetamide methoxymethane Chemical compound COC.C(C)(=O)N OJPSKWYIZCAQST-UHFFFAOYSA-N 0.000 description 1
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229950000221 adaprolol Drugs 0.000 description 1
- IPGLIOFIFLXLKR-AXYNENQYSA-N adaprolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CC(=O)OCCC1(C2)C[C@@H](C3)C[C@H]2C[C@@H]3C1 IPGLIOFIFLXLKR-AXYNENQYSA-N 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 108010003059 aggrecanase Proteins 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229960004601 aliskiren Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride 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
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940054053 antipsychotics butyrophenone derivative Drugs 0.000 description 1
- 239000003698 antivitamin K Substances 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 229960004823 armodafinil Drugs 0.000 description 1
- YFGHCGITMMYXAQ-LJQANCHMSA-N armodafinil Chemical compound C=1C=CC=CC=1C([S@](=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-LJQANCHMSA-N 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 229960000307 avanafil Drugs 0.000 description 1
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- 229950003799 axitirome Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine 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
- 229960004099 azithromycin Drugs 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 229960004495 beclometasone Drugs 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960002890 beraprost Drugs 0.000 description 1
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone 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-DVTGEIKXSA-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
- 230000002457 bidirectional effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 1
- 229960001500 bivalirudin Drugs 0.000 description 1
- 108010055460 bivalirudin Proteins 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000012661 block copolymerization Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 229950005341 bucindolol Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 229960000330 bupranolol Drugs 0.000 description 1
- HQIRNZOQPUAHHV-UHFFFAOYSA-N bupranolol Chemical compound CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 HQIRNZOQPUAHHV-UHFFFAOYSA-N 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- ZJKZKKPIKDNHDM-UHFFFAOYSA-L calcium;6-(5-carboxylato-5-methylhexoxy)-2,2-dimethylhexanoate Chemical compound [Ca+2].[O-]C(=O)C(C)(C)CCCCOCCCCC(C)(C)C([O-])=O ZJKZKKPIKDNHDM-UHFFFAOYSA-L 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 239000003536 cannabinoid receptor antagonist Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 108010089934 carbohydrase Proteins 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000001011 carotid body Anatomy 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 229960002320 celiprolol Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 210000000254 ciliated cell Anatomy 0.000 description 1
- ODQWQRRAPPTVAG-BOPFTXTBSA-N cis-doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)\C2=CC=CC=C21 ODQWQRRAPPTVAG-BOPFTXTBSA-N 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 1
- 229960003850 dabigatran Drugs 0.000 description 1
- 229950003418 dasantafil Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- CARVNSROHCBVAO-BUGJESOBSA-N depelestat Chemical compound O=C([C@H](C(C)C)NC(=O)CNC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H]2C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=3C4=CC=CC=C4NC=3)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@H]3CSSC[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=4C=CC(O)=CC=4)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC=4C=CC(O)=CC=4)NC(=O)[C@H]4N(CCC4)C(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC3=O)C(C)C)CSSC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(C)C)[C@@H](C)CC)C(C)C)=O)[C@@H](C)CC)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O)N1CCC[C@H]1C(O)=O CARVNSROHCBVAO-BUGJESOBSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 238000011161 development Methods 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
- 229960001767 dextrothyroxine Drugs 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- FPUQGCOBYOXAED-UHFFFAOYSA-N diethyl 2-[[2-[3-(dimethylcarbamoyl)-4-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]phenyl]acetyl]oxymethyl]-2-phenylpropanedioate Chemical compound C=1C=CC=CC=1C(C(=O)OCC)(C(=O)OCC)COC(=O)CC(C=C1C(=O)N(C)C)=CC=C1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 FPUQGCOBYOXAED-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
- 229960004419 dimethyl fumarate Drugs 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- XRKMNJXYOFSTBE-UHFFFAOYSA-N disodium;iron(4+);nitroxyl anion;pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+4].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] XRKMNJXYOFSTBE-UHFFFAOYSA-N 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- 229960001253 domperidone Drugs 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 229960002955 doxapram Drugs 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- PSMMNJNZVZZNOI-SJILXJHISA-N edoxaban tosylate hydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 PSMMNJNZVZZNOI-SJILXJHISA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229950005925 eflucimibe Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229950006127 embusartan Drugs 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960002711 epanolol Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229960001208 eplerenone Drugs 0.000 description 1
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-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
- 230000003628 erosive effect Effects 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- 229960003745 esmolol Drugs 0.000 description 1
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229950006213 etomoxir Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 1
- 229960002435 fasudil Drugs 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 229950010034 fidexaban Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229950004408 finerenone Drugs 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 229960004381 flumazenil Drugs 0.000 description 1
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- KANJSNBRCNMZMV-ABRZTLGGSA-N fondaparinux Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](OC)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O4)NS(O)(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS(O)(=O)=O)O2)NS(O)(=O)=O)[C@H](C(O)=O)O1 KANJSNBRCNMZMV-ABRZTLGGSA-N 0.000 description 1
- 229960001318 fondaparinux Drugs 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 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 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003776 glatiramer acetate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000002628 heparin derivative Substances 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229960002240 iloprost Drugs 0.000 description 1
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 1
- 229960002411 imatinib Drugs 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
- 229960004801 imipramine 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
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940125369 inhaled corticosteroids Drugs 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003434 inspiratory effect Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 229960003827 isosorbide mononitrate Drugs 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 229950005241 landiolol Drugs 0.000 description 1
- WMDSZGFJQKSLLH-RBBKRZOGSA-N landiolol Chemical compound O1C(C)(C)OC[C@H]1COC(=O)CCC(C=C1)=CC=C1OC[C@@H](O)CNCCNC(=O)N1CCOCC1 WMDSZGFJQKSLLH-RBBKRZOGSA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229950001845 lestaurtinib Drugs 0.000 description 1
- 208000002741 leukoplakia Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 210000000627 locus coeruleus Anatomy 0.000 description 1
- 229960003566 lomitapide Drugs 0.000 description 1
- QKVKOFVWUHNEBX-UHFFFAOYSA-N lomitapide mesylate Chemical compound CS(O)(=O)=O.C12=CC=CC=C2C2=CC=CC=C2C1(C(=O)NCC(F)(F)F)CCCCN(CC1)CCC1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 QKVKOFVWUHNEBX-UHFFFAOYSA-N 0.000 description 1
- 231100001252 long-term toxicity Toxicity 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 210000002698 mandibular nerve Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000000412 mechanoreceptor Anatomy 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 description 1
- 229960002137 melagatran Drugs 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 229960003134 mepindolol Drugs 0.000 description 1
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229960003739 methyclothiazide Drugs 0.000 description 1
- LYVGOAYMIAQLHI-UHFFFAOYSA-N methyl 2-butyl-1-[[2-fluoro-4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-6-oxopyridine-4-carboxylate Chemical compound CCCCC1=CC(C(=O)OC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1F LYVGOAYMIAQLHI-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960001344 methylphenidate Drugs 0.000 description 1
- 229960002704 metipranolol Drugs 0.000 description 1
- BLWNYSZZZWQCKO-UHFFFAOYSA-N metipranolol hydrochloride Chemical compound [Cl-].CC(C)[NH2+]CC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BLWNYSZZZWQCKO-UHFFFAOYSA-N 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 229960002817 metolazone Drugs 0.000 description 1
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960001785 mirtazapine Drugs 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 229960001165 modafinil Drugs 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 description 1
- 229960004027 molsidomine Drugs 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 108091008709 muscle spindles Proteins 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- VLUXBNSRYHXDBV-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-4,5-dihydro-1,3-thiazol-2-amine Chemical compound CC1=CC=CC(C)=C1NC1=NCCS1 VLUXBNSRYHXDBV-UHFFFAOYSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960004127 naloxone Drugs 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
- 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
- 229960005016 naphazoline Drugs 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 229960000619 nebivolol Drugs 0.000 description 1
- 229960002362 neostigmine 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
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 1
- 229960003226 nikethamide Drugs 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229960001609 oxitropium bromide Drugs 0.000 description 1
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 description 1
- 229960004570 oxprenolol Drugs 0.000 description 1
- 229960001528 oxymetazoline Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229950003510 pactimibe Drugs 0.000 description 1
- VWMZIGBYZQUQOA-QEEMJVPDSA-N pamaqueside Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC(=O)[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(OC[C@H](C)CC1)O5)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VWMZIGBYZQUQOA-QEEMJVPDSA-N 0.000 description 1
- 229950005482 pamaqueside Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229950006299 pelitinib Drugs 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
- 229960002035 penbutolol Drugs 0.000 description 1
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229960001697 physostigmine Drugs 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
- 238000013310 pig model Methods 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940113171 polysorbate 85 Drugs 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000000019 pro-fibrinolytic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229960002601 protriptyline 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
- IENZFHBNCRQMNP-UHFFFAOYSA-N prx-08066 Chemical compound C1=C(C#N)C(F)=CC=C1CN1CCC(NC=2C=3C=C(Cl)SC=3N=CN=2)CC1 IENZFHBNCRQMNP-UHFFFAOYSA-N 0.000 description 1
- 229960002290 pyridostigmine Drugs 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 229960000577 quinethazone Drugs 0.000 description 1
- AGMMTXLNIQSRCG-UHFFFAOYSA-N quinethazone Chemical compound NS(=O)(=O)C1=C(Cl)C=C2NC(CC)NC(=O)C2=C1 AGMMTXLNIQSRCG-UHFFFAOYSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960000213 ranolazine Drugs 0.000 description 1
- 210000001609 raphe nuclei Anatomy 0.000 description 1
- 229950010535 razaxaban Drugs 0.000 description 1
- 229960003770 reboxetine Drugs 0.000 description 1
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000012481 regulation of membrane potential Effects 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 1
- 210000001034 respiratory center Anatomy 0.000 description 1
- 230000036390 resting membrane potential Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 description 1
- 229940066675 ricinoleate Drugs 0.000 description 1
- 229960000529 riociguat Drugs 0.000 description 1
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229950008900 sabeluzole Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 229960003841 selexipag Drugs 0.000 description 1
- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 description 1
- 229950003647 semaxanib Drugs 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- BTGNGJJLZOIYID-UHFFFAOYSA-N sivelestat Chemical compound C1=CC(OC(=O)C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NCC(O)=O BTGNGJJLZOIYID-UHFFFAOYSA-N 0.000 description 1
- 229950009343 sivelestat Drugs 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- 229940124818 soft mist inhaler Drugs 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 108091007196 stromelysin Proteins 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 229940066767 systemic antihistamines phenothiazine derivative Drugs 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 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
- 229950009893 tandutinib Drugs 0.000 description 1
- 229950004186 telatinib Drugs 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000331 teriflunomide Drugs 0.000 description 1
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 description 1
- YIOFDLKFYQYWPU-UHFFFAOYSA-N tetratriacontyl hydrogen sulfate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCOS(O)(=O)=O YIOFDLKFYQYWPU-UHFFFAOYSA-N 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229950004996 tipelukast Drugs 0.000 description 1
- 229950004437 tiqueside Drugs 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 229960004631 tixocortol Drugs 0.000 description 1
- YWDBSCORAARPPF-VWUMJDOOSA-N tixocortol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CS)[C@@H]4[C@@H]3CCC2=C1 YWDBSCORAARPPF-VWUMJDOOSA-N 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 229960005461 torasemide Drugs 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 229960001262 tramazoline Drugs 0.000 description 1
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229960001177 trimetazidine Drugs 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960000438 udenafil Drugs 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229960002381 vardenafil Drugs 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
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229950005018 vericiguat Drugs 0.000 description 1
- QZFHIXARHDBPBY-UHFFFAOYSA-N vericiguat Chemical compound N1=C(N)C(NC(=O)OC)=C(N)N=C1C(C1=CC(F)=CN=C11)=NN1CC1=CC=CC=C1F QZFHIXARHDBPBY-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 229940019333 vitamin k antagonists Drugs 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Inorganic Chemistry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本申請案關於包含TASK-1及/或TASK-3通道的強效和選擇性抑制劑的新穎醫藥劑型及其用於治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症(obstructive and central sleep apnoeas)和打鼾。
Description
本申請案關於包含TASK-1及/或TASK-3通道的強效和選擇性抑制劑的新穎劑量投藥形式及其用於治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症(obstructive and central sleep apnoeas)和打鼾。
鉀通道是涉及大量不同生理過程的實質上普遍存在的膜蛋白。此亦包括神經元和肌肉細胞的膜電位和電興奮性的調控。鉀通道分為三個主要群組,其區別在於跨膜區域的數目(2、4或6)。其中兩個孔-形成區域的側面接有四個跨膜區域的鉀通道群組稱作K2P通道(兩-孔區域K +)。功能上,K2P通道係媒介-實質上和時間和電壓無關-K+背景電流及其對於維持靜息膜電位的貢獻至關重要。基於序列、結構和功能的相似性,K2P通道家族包括15個成員,分為6個亞族:TWIK(串聯孔區域氟烷抑制的K+通道)、TREK(TWIK相關的K+通道)、TASK(TWIK相關的酸敏性K+通道)、TALK(TWIK相關的鹼性pH活化的K+通道)、THIK(串聯孔區域氟烷抑制的K+通道)和 TRESK(TWIK相關的脊髓K+通道)。
特別感興趣的是TASK(TWIK相關的酸敏性K + 通道)亞族的TASK-1(KCNK3或K2P3.1)和TASK-3(KCNK9或K2P9.1)。功能上,該等通道的特徵在於,在維持與電壓無關的動力學期間,彼等具有流經該等的「洩漏」或「背景」流,而彼等藉由增加或減少其活性回應眾多生理和病理的影響。TASK通道的特徵是對細胞外pH變化的敏感反應:該等通道在酸性pH被抑制,而在鹼性pH被活化。
TASK-1與TASK-3通道在呼吸調節發揮作用。兩通道皆在腦幹呼吸中樞的呼吸神經中表現,尤其是在產生呼吸節律的神經元(腹側呼吸組與前-波茲格複合物(pre-Bötzinger complex))、以及在去甲腎上腺素能藍斑核(Locus caeruleus)中、還有在縫核(raphe nuclei)的血清素能神經元中表現。由於pH依賴性所致,在此該TASK通道具有感測器的功能,其將細胞外pH的變化轉譯成相應的細胞信號[Bayliss et al.,Pflugers Arch.467,917-929(2015)]。TASK-1和TASK-3亦在測量血液的pH和O2與CO2含量並將信號傳遞到腦幹的呼吸中樞以調節呼吸的周邊化學受體頸動脈球(Glomus caroticum)中表現。顯示TASK-1剔除小鼠對缺氧和常氧性高碳酸血症具有減少的通氣回應(呼吸速率和潮氣量增加)[Trapp et al.,J.Neurosci.28,8844-8850(2008)]。再者,已證實TASK-1和TASK-3通道在下頜下神經(Nervus hypoglossus)-第十二顱神經的的運動神經元中,其具有保持上部氣道開放的重要角色[Berg et al.,J.Neurosci.24,6693-6702(2004)]。
在麻醉豬的睡眠呼吸中止症模型中,鼻部投予毫微莫耳範圍內的阻斷TASK-1通道的鉀通道阻斷劑導致抑制咽部氣道肌肉群的可塌陷性和上呼吸道負壓反射的敏化。推論鉀通道阻斷劑的鼻部投藥使得上呼吸道中的機械受體去極化,並且,透過負壓反射的活化,導致上呼吸道肌肉群的活性 增加,於是穩定上呼吸道並防止塌陷。由於上呼吸道的此穩定化作用,TASK通道阻斷對於阻塞性睡眠呼吸中止症和打鼾可能是非常重要的[Wirth et al.,Sleep 36,699-708(2013);Kiper et al.,Pflugers Arch.467,1081-1090(2015)]。
阻塞性睡眠呼吸中止症(OSA)是一種睡眠相關的呼吸病症,其特徵是上呼吸道阻塞的反覆發作。在吸氣時,藉由兩個相反力的交互作用確保上呼吸道的通暢。上呼吸道肌肉群的擴張效應抵消負的腔內壓力,其使管腔收縮。隔膜和其他輔助性呼吸肌肉的主動收縮在氣道中產生負壓,於是構成呼吸的驅動力。上呼吸道的穩定性實質上係由上呼吸道的擴張肌的協調和收縮性質決定。
頦舌肌(Musculus genioglossus)在阻塞性睡眠呼吸中止症的發病機轉中扮演決定性角色。在擴張性補償機制的意義上,頦舌肌的活性係隨著咽部壓力減小而增加。由下頜下神經支配,它驅使舌頭向前和向下,於是擴寬咽部氣道[Verse et al.,Somnologie 3,14-20(1999)]。上呼吸道的擴張肌肉的張力尤其透過鼻腔/咽部的機械受體/拉伸受體來調節[Bouillette et al.,J.Appl.Physiol.Respir.Environ.Exerc.Physiol.46,772-779(1979)]。在患有嚴重的睡眠呼吸暫停的睡眠患者中,在上呼吸道的局部麻醉下,可以觀察到頦舌肌的活性更加降低[Berry et al.,Am.J.Respir.Crit.Care Med.156,127-132(1997)]。患有OSA的患者由於心血管病症,例如高血壓、心肌梗塞和中風而具有高死亡率和發病率[Vrints et al.,Acta Clin.Belg.68,169-178(2013)]。
在中樞性睡眠呼吸中止症的情況中,由於腦功能受損和呼吸調節受損的緣故,有呼吸驅動的偶發性抑制。中樞性呼吸道病症導致機械性呼吸驟停,即在該等發作期間,沒有呼吸活動;暫時地,包括隔膜在內的所有呼吸肌都靜止。在中樞性睡眠呼吸中止症的情況中,沒有上呼吸道的阻塞。
在原發性打鼾的情況中,同樣沒有上呼吸道的阻塞。然而,由於上呼吸道收縮的緣故,被吸入和呼出的空氣的流速增加了。此和鬆弛的肌肉群結合而導致口腔和咽部的軟組織在空氣流中顫動。此溫和的振動隨後產生典型的打鼾噪音。
阻塞性打鼾(上呼吸道阻力症候群、重度打鼾、低度呼吸症候群)是由睡眠期間上呼吸道的反覆局部阻塞所造成的。此導致呼吸阻力增加,於是增加呼吸的功,伴隨胸內壓力相當大的波動。在吸氣期間,胸內負壓可能達到類似於在OSA期間由於氣道完全阻塞而遭遇到的值。對於心臟、循環和睡眠品質的病理生理學後果係相當於阻塞性睡眠呼吸中止症的病理生理學後果。如同在OSA中,發病被推論為睡眠時的吸氣期間咽部擴張肌肉的反射機制受損。通常,阻塞性打鼾是OSA的初始階段[Hollandt et al.,HNO 48,628-634(2000)]。
打鼾和OSA的當前可用治療可能性是有限的。自1980s年代以來,就已知表面活性物質的混合物,其意圖降低上呼吸道的阻力和打鼾[Widdicombe and Davies,Eur Resp J 1,785-791(1988)]。該等混合物包含NaCl、甘油、聚山梨酯80和苯扎氯銨(benzalkonium chloride)。從藉由將該等混合物注射到咽內來投藥的狗的實驗,得出的結論是該等混合物在吸進和呼出時降低上呼吸道的阻力、增加頦舌肌的活動並減少打鼾噪音。在Widdicombe的文章中沒有提到OSA,在此模型中亦沒有顯示可以防止導致呼吸中止的上呼吸道塌陷。Widdicombe與Davies的模型因此不能預測OSA。
由0.26%甘油、0.2%聚山梨酯80、0.9%氯化鈉與0.15%山梨酸鉀(不含苯扎氯銨)所構成的組成物在市面上以Asonor®銷售作為打鼾療法。在哥本哈根的國立大學醫院的一項研究中,調查了鼻部投予Asonor®相較於不含聚山梨酯80的"Asonor®"對於改善打鼾的功效。Asonor®與不含聚山梨酯80的 "Asonor®"皆能顯著改善打鼾[Report from the Department of Neurology,University State Hospital,Copenhagen,Denmark.The effect of nasal application of Asonor® and Polyglycoside 80 on snoring and sleep apnoea,1989,http://www.chrapat.sk/img/klinicka-dokumentacia.pdf]。
EP 2595685 B1(美國專利號9,132,243 B1)主張一種醫藥產品,該醫藥產品包含一容器,該容器包含液體止鼾物質,其中該容器包含一液體出口部分,其被構形成將該液體止鼾物質以噴流的形式直接輸送至鼻腔通道。該液體止鼾物質是包含氯化鈉、甘油、聚山梨酯和乙二胺四乙酸鈉及作為防腐劑的任擇的山梨酸鉀的止鼾溶液。EP 2595685 B1和美國專利9,132,243 B1的原始提申申請案中並沒有揭露呼吸中止或OSA的療法。EP 2595685 B1係主張描述用於治療打鼾和呼吸驟停(呼吸中止)的止鼾物質。
目前沒有醫藥療法可用於治療OSA。手術和口腔器械的功效有限。治療標準為持續正壓氣道(CPAP)系統的療法。由於不適,此療法的遵囑率僅為50-70%,而且該系統平均每晚使用不超過4小時。
作為TASK-1及/或TASK-3通道的強效和選擇性抑制劑的新穎物質係因此尤其適用於治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾,還有由PCT/EP2016/079973和PCT/EP2016/07954(尚未公開)已知的其他病症。
EP 15199270.8和EP 15199268.2所揭露的TASK-1及/或TASK-3通道的強效和選擇性抑制劑在鼻部投藥上的作用持續時間並不總是足夠的,其使得有必要在夜間再次給藥且因此中斷夜間休息或睡眠。
因此,本發明的目的是提供用於治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的有效醫藥療 法,其代表以CPAP系統治療的替代方案。
本發明的另一個目的是,相較於當前療法標準(OSA的療法:CPAP系統),增加患者對治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的遵囑率。為此目的,此替代療法在使用上應該是簡單和舒適的,而不是擾人清眠。此外,此替代療法應該能夠藉由在入睡前的每日一次藥量而不用重複服藥來實現不受干擾的夜間休息。
因此,本發明的另一個目的是提供用於治療及/或預防治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的醫藥有效物質,該物質係為適用於在入睡前的每日一次鼻部或咽部投藥。尤其,本發明的目的是提供用於治療及/或預防治療及/或預防呼吸病症,包括睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的醫藥有效療法,其具有至少4小時的作用持續時間。
延長經鼻投予的活性成分的作用持續時間是困難的。由於生理條件所致,活性成分、顆粒、膠囊等等在上皮細胞中的停駐時間很短。上皮係由部分地具有毛髮狀結構,即纖毛的纖毛細胞構成。該等被黏膜層覆蓋,該黏膜層係藉由纖毛的協調運動而朝向喉部移離。在鼻部吸收後,異物顆粒和微生物仍黏附在黏膜層上,並藉由黏膜纖毛清除物與黏液一起運送到喉嚨和食道。該黏膜纖毛清除物因此抵消了活性成分的鼻部吸收並尤其是實現延長效果的挑戰。黏液流速約為每分鐘5mm,因此每15-20min更新一次。因此亦確定了經鼻投予的溶液和粉末的15min清除半衰期[Illum et al.,Int J Pharm.39,189-199(1987)],因此活性成分原則上僅短暫停留在黏膜上以達到效果。
實現鼻部投藥後之效果延長的方法是延長活性成分與鼻內吸收部位- 上皮細胞的接觸時間。鼻內的醫藥品吸收係藉由延長的接觸時間而增加。該活性成分吸收可在較長時間內發生,以便首先可實現延長的效果和作用持續時間,其次可增加吸收的醫藥品的總份量。增加活性成分和上皮細胞之間的接觸時間的方法尤其是使用生物黏附聚合物或使用微粒來增加黏性。
Pennington等人在1988年可能已經顯示,藉由用羥丙基甲基纖維素增加經鼻投予溶液的黏性來降低清除率[Pennington et al.,Int J Pharm.43,221-224(1988)]。隨著增加聚合物比例且於是增加黏性,半衰期從1小時增加至2.2小時。相較於Illum等人觀察到的15min的溶液半衰期[Illum et al.,Int J Pharm.39,189-199(1987)],增加黏性,於是導致半衰期明顯延長。然而,黏稠溶液和半固體系統,例如凝膠、乳霜和軟膏比低黏性調配物更難施用。藉由噴劑霧化不再是可能的,並且在半固體系統的情況下藉助於施用器的精確劑量是困難的。此外,經鼻施用的半固體系統可能導致堵塞,其可能破壞鼻腔呼吸。除了投予較高黏性溶液和即用型凝膠之外,也可考慮投予原位凝膠[Majithiya et al.,AAPS PharmSciTech 7(3),Article 67(2006)]。在此,舉例來說,藉由溫度變化、pH變化或離子的存在,凝膠化首先在鼻內被觸發。以此方式,可施用低黏性溶液,在沉積位點-鼻黏膜-凝膠化之後可得到黏稠的調配物,並具有正面效果。計量系統於是可用於投予,其能致使精確和簡單的投藥。然而,由於凝膠形成必須精確配合,所以彼等是複雜及精細的劑型。假使凝膠化是由溫度變化引起的,舉例來說,則必須確保凝膠化僅在生理溫度下觸發並且在儲存時仍受到抑止。因此,一方面對儲存和管理有特別要求,以防止過早凝膠化,而另一方面,此類敏感系統的開發和製造複雜度非常高。
澱粉和殼聚醣經常被用作生物黏附聚合物[Illum et al.,J Controlled Release 87,187-198(2003)]。殼聚醣是一種生物黏附性多醣,能與上皮細胞和黏液層顯著地相互作用。藉此產生更長的接觸時間,其允許活性成分經由該膜運輸。殼聚醣在文獻中廣泛使用,然而,主要用於體外實驗。殼聚醣目前尚未批准用於鼻部投藥(FDA Drug Databases,Inactive Ingredient Search for Approved Drug Products),而且尚未充分調查慢性鼻部投藥的潛在長期毒性。
延長鼻部活性成分投藥後的效果的另一可能性是將活性成分囊封在聚合物微粒內[Cerchiara et al.,Eur J Pharm Biopharm.61,195-200(2005)]]。為此目的,將活性成分埋置在具有低度水溶性的適宜聚合物內,或能夠額外地使載有活性成分的微粒黏附至鼻黏膜的聚合物組合內。在將此劑型引入鼻內後,取決於所使用的聚合物的性質,藉由擴散及/或聚合物降解/侵蝕,該活性成分係以時間延遲的方式從該微粒中釋放,其致使該活性成分在作用部位的作用持續時間延長了。假使所使用的構成該微粒的聚合物組合額外地具有黏附至鼻黏膜的性質,則預期經鼻引入的藥物的停駐時間延長了且是以作用持續時間延長了。微粒和生物黏附聚合物的組合因此代表了延長鼻部投藥作用持續時間的廣為描述方式,因為此處的兩個原則-延遲釋放和增加的接觸時間-被整合了。在此情況中,該等微粒可直接由生物黏附聚合物製備[Illum et al.,Int J Pharm.39,189-199(1987)]或可使用其他聚合物,例如聚(丙交酯-共-乙交酯)(PLGA)製造微粒,隨後在另外的步驟中以該生物黏附聚合物塗覆來製備[Pawar et al.,Am Assoc Pharmac Sci J 12,130-137(2010)]。
除了使用上述微粒之外,亦可藉由使用懸浮的而不是溶解的活性成分來延長活性成分的釋放。為此目的,舉例來說,將使用的活性成分微米化(粉碎成活性成分微粒)並摻入液相(懸浮的)中。在鼻內投藥後,在作用部位的 活性成分顆粒以延遲方式溶解。只有溶解的活性成分可經由鼻黏膜吸收且隨後有效。決定活性效果延長的溶解動力學係尤其取決於所使用活性成分的物理化學性質(譬如溶解度、顆粒尺寸)。藉由投予糖皮質激素的晶體懸浮液,可實現局部的延長效果,舉例來說[Rygg et al.,Pharm Res.33,909-921(2016)]。
為了延長鼻部投藥後的效果,在晶體懸浮液中處理活性成分並將活性成分囊封在聚合物微粒中係與許多缺點有關。
首先,舉例來說,相較於活性成分溶液,此類劑型的生產在技術上要複雜許多倍。舉例而言,晶體懸浮液和聚合物微粒的生產需要許多連續的方法步驟,其顯著影響所完成劑型的品質。由於缺乏儲存穩定性,該等複合劑型的功能性可能受到不利的影響。舉例而言,晶體懸浮液展現,舉例來說,在儲存期間的顆粒沉降(包括沉降物形成)及/或主要顆粒尺寸變化,其導致劑型內的不均勻性並因此導致給藥錯誤。
其次,晶體懸浮液和聚合物微粒的生產需要使用許多穩定劑和聚合物基質形成劑,其可能造成鼻部投藥後的局部不耐受/刺激感。舉例來說,已知許多穩定劑會導致對纖毛運動性、細胞裂解和酶失活的不良影響[Schinichiro et al.,Int J Pharm.9,173-184(1981)]。在經常用作微粒的基質形成劑的聚合物,例如生物可再吸收聚酯(譬如PLGA)的水解降解期間,發生降解產物(譬如乳酸和乙醇酸)的釋放,其可顯著降低局部pH,藉其可能發生局部刺激。局部刺激亦可藉由粒子本身觸發。
而且,僅使用伴隨著活性成分的延遲釋放和溶解的微粒系統,例如晶體懸浮液和聚合物微粒可能導致不可再現的藥量比例被輸出,並在吸收前由於黏液纖毛清除而以未溶解的顆粒被吞嚥。活性成分的吞嚥繼而可能導致暴露量的巨大變化[Malinovsky et al.,Br J Anaesthesia 77,203-207(1996)]。
再者,使用晶體懸浮液和聚合物微粒係聯結至複雜的說明手冊,這可能導致施用錯誤,繼而危害所欲的治療反應。
為了延長經鼻投予的活性成分的效果所描述的方式,例如黏性系統、晶體懸浮液和微粒的缺點據此是生產中的高支出、該等劑型的複雜性、暴露量的高變異性的風險及尤其是鼻部投藥所使用輔劑(譬如聚合物)的安全性不足。
出乎意料的是,本發明已經顯示,取決於劑量,包含溶於>2.5%至100% w/v聚乙二醇的治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑、或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽的調配物的鼻部投藥顯著延長該TASK-1及/或TASK-3通道抑制劑、或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽的作用持續時間。
本發明提供了用於鼻部或咽部投藥的穩定醫藥調配物,其包含溶於>2.5%至100% w/v聚乙二醇以及任擇地至少一種輔劑的治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽,其中該調配物具有4至8的pH。
鼻部或咽部投予在包含pH調節劑和增溶劑而無添加聚乙二醇的調配物中的治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽不會致使延長作用持續時間,即便增加TASK-1及/或TASK-3通道抑制劑的劑量。
出乎意料地,包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽並包含20% w/v丙二醇(而非聚乙二醇)、和pH調節劑與增溶劑的調配物並未顯示TASK-1及/或TASK-3通道抑制劑的作用持續時間有任何延長。
再者,包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑 或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽和1.25% w/v黏性-增強物質羧甲基纖維素鈉(Na-CMC)(而非PEG)、pH調節劑與增溶劑的調配物並未顯示TASK-1及/或TASK-3通道抑制劑的作用持續時間有任何延長,儘管帶有1.25% w/v Na-CMC的此調配物的黏性係相仿於包含20% w/v PEG 400的根據本發明之調配物的黏性。此指示由於添加PEG所致的黏性增加不可能是以根據本發明之調配物觀察到的作用持續時間延長的決定性原因。
包含溶於磷酸鹽緩衝液、pH 7之聚山梨酯80和至少5% w/v PEG 400、無TASK-1及/或TASK-3通道抑制劑的組成物在本發明中亦未顯示效果。
由於在未公開的PCT/EP2016/079973中首次描述了醫藥替代方案,所以本領域技術人員對於置換OSA的物理治療CPAP並無起始點。目前亦沒有或僅有非常有限的用於打鼾的醫藥療法,因此本領域技術人員甚至在此亦無起始點來實現本發明。即使PCT/EP2016/079973中描述的TASK-1及/或TASK-3抑制劑是已知的,本領域技術人員亦無理由認為為了延長TASK-1及/或TASK-3通道抑制劑的作用持續時間所概述的簡單易管理的解決方案是成功的。
在先前技術中並無指示,關於OSA,延長TASK-1及/或TASK-3通道抑制劑的效果幾個小時可藉由使用標準調配物輔劑聚乙二醇而非丙二醇來實現。在先前技術中亦無指示,數小時的延長效果可在不使用先前技術為了延長經鼻投予活性成分的效果所描述的複雜方式,例如微粒、晶體懸浮液或生物黏附系統來實現。
此外,在先前技術中並無指示藉助於根據本發明之調配物的效果的延長只能在調配物構分聚乙二醇的特定濃度範圍內實現。在先前技術中亦沒有發現調配物構分的適宜濃度範圍的指示。
在本發明上下文中,該穩定醫藥調配物係藉由鼻部或咽部途徑投予。
在本發明上下文中,術語「鼻部(nasal)」和「鼻內(intranasal)」係以同義使用。
在本發明上下文中,適用於鼻部投藥的穩定醫藥調配物為呈現液體、半固體或固體形式的調配物,舉例來說,鼻部滴劑、鼻部溶液、鼻部凝膠、鼻部軟膏、鼻部乳霜或粉狀劑型。
在本發明上下文中,鼻部投藥可藉由,舉例來說,鼻部噴劑、滴管、擠壓瓶、COMOD®系統、液體噴霧器(譬如壓電霧化器、噴嘴或超聲波氣霧發生器、軟霧吸入器)或計量型氣霧劑,或用於半固體調配物(注射管、抹刀)及/或固體調配物(粉末)的鼻部塗藥器來致效。根據本發明的一個具體例,該投藥係藉由鼻部噴劑來致效。
在本發明上下文中,適用於咽部投藥的穩定醫藥調配物為呈現液體、半固體或固體形式的調配物,舉例來說,溶液、凝膠或粉末。
在本發明上下文中,咽部投藥可藉由使用液體噴霧器(譬如壓電霧化器、噴嘴或超聲波氣霧發生器、幫浦噴劑)或計量型氣霧劑的吸入,或藉由使用支氣管鏡(滴注)、滴管、擠壓瓶或類似物的局部投藥來致效。
在本發明上下文中,治療效果被定義為患有睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的患者,在鼻部或咽部投予包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽的根據本發明的調配物之後的睡眠呼吸中止-低通氣指數(AHI)降低。
根據本發明的一個具體例,治療效果被定義患有睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的患者在鼻部或咽部投予包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合 物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽的根據本發明的調配物之後的睡眠呼吸中止-低通氣指數(AHI)降低了至少20%。
根據本發明的一個具體例,治療效果被定義患有睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的患者在鼻部或咽部投予包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽的根據本發明的調配物之後的睡眠呼吸中止-低通氣指數(AHI)降低了至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%或至少80%。
在本發明上下文中,作用持續時間被定義為在將包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽的根據本發明的調配物經鼻部或咽部投至患有睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的患者之後,該患者的睡眠呼吸中止-低通氣指數(AHI)降低的時間期。
根據本發明的一個具體例,作用持續時間被定義為在將包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽的根據本發明的調配物經鼻部或咽部投至患有睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症和打鼾的患者之後,該患者的睡眠呼吸中止-低通氣指數(AHI)降低至少20%的時間期。
根據本發明的一個具體例,作用持續時間被定義為在將包含治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽的根據本發明的調配物經鼻部或咽部投至患有睡眠相關的呼吸病症,例如阻塞性與中樞性睡眠呼吸中止症 和打鼾的患者之後,該患者的睡眠呼吸中止-低通氣指數(AHI)降低至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%或至少80%的時間期。
在本發明上下文中,該作用持續時間為至少3小時或至少3.5小時或至少4小時或至少4.5小時或至少5小時或至少5.5小時或至少6小時或至少6.5小時或至少7小時或至少7.5小時或至少8小時。根據本發明的一個實施例,該作用持續時間為至少3小時。根據本發明的一個實施例,該作用持續時間為至少4小時。根據本發明的一個實施例,該作用持續時間為至少5小時。
在本發明上下文中,治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽係定義為TASK-1及/或TASK-3通道的至少一種抑制劑、或其水合物、溶劑合物、多晶形物或其代謝物或其醫藥上可接受的鹽在鼻部或咽部投藥上顯示至少3小時或至少3.5小時或至少4小時或至少4.5小時或至少5小時或至少5.5小時或至少6小時或至少6.5小時或至少7小時或至少7.5小時或至少8小時之作用持續時間的份量。
在本發明上下文中,治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽係定義為TASK-1及/或TASK-3通道的至少一種抑制劑、或其水合物、溶劑合物、多晶形物或其代謝物或其醫藥上可接受的鹽在鼻部或咽部投藥上顯示至少3小時之作用持續時間的份量。
在本發明上下文中,治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽係定義為TASK-1及/或TASK-3通道的至少一種抑制劑、或其水合物、溶劑合物、多晶形物或其代謝物或其醫藥上可接受的鹽在鼻部或咽部投藥上 顯示至少4小時之作用持續時間的份量。
在本發明上下文中,治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受的鹽係定義為TASK-1及/或TASK-3通道的至少一種抑制劑、或其水合物、溶劑合物、多晶形物或其代謝物或其醫藥上可接受的鹽在鼻部或咽部投藥上顯示至少5小時之作用持續時間的份量。
在本發明上下文中,輔劑為在該穩定醫藥調配物中用於,舉例來說,調節或穩定pH、增加活性成分的溶解度、微生物學和物理穩定該製劑、改變該調配物的黏性或改善味道或外觀的物質。
在本發明上下文中的輔劑的例子為pH調節劑、增溶劑、抗氧化劑、穩定劑、增稠劑、防腐劑、調整張力的物質、香氛、香料或染料。
本發明亦提供了根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一輔劑係選自由下列所構成之群組:至少一pH調節劑、至少一增溶劑、至少一抗氧化劑、至少一穩定劑、至少一增稠劑、至少一防腐劑、至少一用於調整張力的物質、至少一香氛、至少一香料和至少一染料。
在本發明上下文中,pH調節劑為,舉例來說,緩衝劑,例如檸檬酸及其鹽、乙酸及其鹽、磷酸及其鹽、或無機酸,例如氫氯酸、硼酸、羧酸、二羧酸、胺基酸或有機酸,例如一元羧酸,例如氧代羧酸或多元羧酸,或鹼,例如氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸氫鈉。
本發明亦提供了根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一pH調節劑係選自由下列所構成之群組:選自檸檬酸及其鹽、乙酸及其鹽、磷酸及其鹽、氫氯酸、硼酸、羧酸、二羧酸、胺基酸、氧代羧酸、多元羧酸、氫氧化鈉、氫氧化鉀、碳酸鈉和碳酸氫鈉。
根據本發明的一個具體例,該pH調節劑為磷酸鹽緩衝液。根據本發明的一個具體例,該pH調節劑是將本發明上下文中的溶液緩衝至介於4至8之間的pH的磷酸鹽緩衝液。較佳的pH範圍為介於7至8之間。根據一個具體例,根據本發明的調配物的pH為7。
在本發明上下文中,增溶劑為,舉例來說,螯合劑(舉例來說,環糊精和EDTA鈉(乙二胺四乙酸鈉))、共溶劑(舉例來說,乙醇、丙二醇、二甲基乙醯胺)、和表面活性劑。表面活性劑的群組包括,舉例來說,脂肪醇(舉例來說,鯨蠟醇)、磷脂(舉例來說,卵磷脂)、甾醇(舉例來說,膽固醇)、膽汁酸鹽、皂苷、甘油脂肪酸酯(舉例來說,甘油單硬脂酸酯)、聚氧乙烯脂肪酸酯(舉例來說,硬脂酸聚氧乙烯)、聚氧乙烯脫水山梨醇脂肪酸酯(例如Tween®,舉例來說,聚山梨酯20(聚氧乙烯(20)脫水山梨醇單月桂酸酯)、聚山梨酯21(聚氧乙烯(4)脫水山梨醇單月桂酸酯)、聚山梨酯40(聚氧乙烯(20)脫水山梨醇單棕櫚酸酯)、聚山梨酯60(聚氧乙烯(20)脫水山梨醇單硬脂酸酯)、聚山梨酯61(聚氧乙烯(4)脫水山梨醇單硬脂酸酯)、聚山梨酯65(聚氧乙烯(20)脫水山梨醇三硬脂酸酯)、聚山梨酯80(聚氧乙烯(20)脫水山梨醇單油酸酯)、聚山梨酯81(聚氧乙烯(5)脫水山梨醇單油酸酯)、聚山梨酯85(聚氧乙烯(20)脫水山梨醇三油酸酯)、聚山梨酯120(聚氧乙烯(20)脫水山梨醇單異硬脂酸酯))、脫水山梨醇脂肪酸酯(例如Span®,舉例來說,脫水山梨醇單月桂酸酯(Span® 20)、脫水山梨醇單棕櫚酸酯(Span® 40)、脫水山梨醇單硬脂酸酯(Span® 60)、脫水山梨醇三硬脂酸酯(Span® 65)、脫水山梨醇單油酸酯(Span® 80)、脫水山梨醇倍半油酸酯(Span® 83)、脫水山梨醇三油酸酯(Span® 85)、聚氧乙烯甘油脂肪酸酯(舉例來說,聚氧乙烯單硬脂酸甘油酯、聚氧乙烯甘油蓖麻油酸酯、聚氧乙烯甘油甘油三蓖麻油酸酯)、聚氧乙烯脂肪醇醚(舉例來說,聚氧乙烯月桂醚、聚氧乙烯鯨蠟基-硬脂基醚)、聚氧丙烯-聚氧 乙烯嵌段共聚物(舉例來說,泊洛沙姆(poloxamer))、烷基硫酸鹽(舉例來說,月桂基硫酸鈉、鯨蠟基-硬脂基硫酸鈉)、鹼皂(舉例來說,棕櫚酸鈉、硬脂酸鈉)和蔗糖脂肪酸酯。根據本發明的一個具體例,該增溶劑係選自由下列所構成之群組:乙醇、聚山梨酯20、聚氧乙烯(8)硬脂酸酯與聚山梨酯80。根據本發明的一個具體例,該增溶劑為聚山梨酯80。
本發明亦提供了根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一增溶劑選自乙醇、聚山梨酯20、聚氧乙烯(8)硬脂酸酯和聚山梨酯80。
假使表面活性劑係作為增溶劑存在於根據本發明的調配物中,則此表面活性劑的濃度係至少為其臨界微胞濃度(CMC),並且至多為鼻部或咽部投藥的最大批准量。聚山梨酯80的CMC為0.001% w/v,最大醫藥批准濃度為10% w/v。當使用聚山梨酯80作為增溶劑時,聚山梨酯80係以0.001-10% w/v、或0.1-10% w/v、或1-10% w/v或5-10% w/v的濃度存在於根據本發明的調配物中。或者,聚山梨酯80亦可以高達15% w/v或高達20% w/v的濃度存在於根據本發明的調配物中。
在本發明上下文中,抗氧化劑為,舉例來說,檸檬酸、丁基羥基茴香醚、丁基羥基甲苯、EDTA、用氮氣吹掃、生育酚、抗壞血酸、穀胱甘肽、半胱胺酸、亞硫酸鹽(舉例來說,亞硫酸鈉、亞硫酸氫鈉)、焦亞硫酸鹽(舉例來說,焦亞硫酸鈉)、抗壞血酸酯或沒食子酸酯。根據本發明的一個具體例,該抗氧化劑係選自由下列所構成之群組:檸檬酸、丁基羥基茴香醚、丁基羥基甲苯、EDTA和氮氣吹掃。根據本發明的一個具體例,該抗氧化劑是丁基羥基茴香醚。
本發明亦提供了根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一種抗氧化劑係選自由下列所構成之群組:檸檬酸、丁 基羥基茴香醚、丁基羥基甲苯、EDTA和用氮氣吹掃。
本發明的一個具體例關於用於鼻部或咽部投藥的穩定醫藥調配物,其包含:治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑、或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於>2.5%至100% w/v聚乙二醇,以及抗氧化劑與任擇地至少一種另外的輔劑,其中該調配物具有4至8的pH。
在本發明上下文中,防腐劑為,舉例來說,酚系物質,例如苯酚或甲酚,醇類,例如乙醇、氯丁醇、苯乙醇、或丙二醇,轉化皂類,例如苯扎氯銨或苄索氯銨(benzethonium chloride)、苯甲酸及其鹽、山梨酸及其鹽、脫氫乙酸和硫酸及其鹽、亞硫酸氫鈉、對羥基苯甲酸酯類(parabens),包括對羥基苯甲酸甲酯和對羥基苯甲酸丙酯或硫柳汞(thiomersal)。根據本發明的一個具體例,該防腐劑係選自由下列所構成之群組:C8-C18氯化烷、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、山梨酸、氯丁醇和苯扎氯銨。根據本發明的一個具體例,該防腐劑為苯扎氯銨。
本發明亦提供了根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一防腐劑係選自由下列所構成之群組:C8-C18氯化烷、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、山梨酸、氯丁醇和苯扎氯銨。
在本發明上下文中,用於調節張力的物質為,舉例來說,鹽(譬如具有生理上可耐受的平衡離子的血漿陽離子)、糖(譬如葡萄糖、蔗糖)、糖醇(譬如甘露醇、山梨醇)、二醇(譬如丙二醇)及其他非離子多元醇材料。
在本發明上下文中,增稠劑為,舉例來說,天然橡膠、海藻酸、果膠、澱粉和澱粉衍生物、明膠、泊洛沙姆(環氧乙烷和環氧丙烷的嵌段共聚物)、纖維素衍生物、丙烯酸聚合物或乙烯基聚合物。
根據本發明的一個具體例,根據本發明的調配物包含至少一種pH調節劑作為輔劑。根據本發明的一個具體例,根據本發明的調配物包含至少一種抗氧化劑作為輔劑。根據本發明的一個具體例,根據本發明的調配物包含至少一種增溶劑作為輔劑。根據本發明的一個具體例,根據本發明的調配物包含至少一種pH調節劑和至少一種增溶劑作為輔劑。根據本發明的一個具體例,根據本發明的調配物包含至少一種抗氧化劑和至少一種增溶劑作為輔劑。根據本發明的一個具體例,根據本發明的調配物包含至少一種pH調節劑、至少一種增溶劑和至少一種抗氧化劑作為輔劑。根據本發明的一個具體例,根據本發明的調配物包含至少一種pH調節劑、至少一種增溶劑、至少一種抗氧化劑和至少一種防腐劑作為輔劑。
本發明亦提供了根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該調配物包含5至100% w/v聚乙二醇400、0至10% wv增溶劑、0至95% w/v pH調節劑和任擇地至少一種另外的輔劑。
為了本發明的目的,聚乙二醇係定義為通式(II)的聚乙二醇,
其具有另佔併入水重量之每重複單元44g/mol的莫耳質量。聚乙二醇的實驗式為C2nH4n+2On+1。
在本發明上下文中,可使用具有200至3350Da之平均莫耳質量的聚乙二醇。根據另外的具體例,本發明使用具有200至600或300至400或400之分子量的聚乙二醇。該等被批准用於鼻部投藥。
本發明的一個具體例是根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該調配物包含>2.5% w/v至100% w/v的具有200至600之分子量的聚乙二醇,並且任擇地包含至少一種pH調節劑和任擇地至少一種增溶劑以 及任擇地至少一種另外的輔劑。
S PEG 400具有400glmol的平均莫耳質量,PEG 300具有300glmol的平均莫耳質量。
在本發明上下文中,根據本發明的調配物的動態黏性(在20℃)係介於0.5與1480mPa*s之間,較佳介於1.0與140mPa*s之間。根據本發明用於藉由鼻部噴劑經鼻投藥的調配物較佳具有介於1.0至140mPa*s之間的動態黏性(在20℃)。根據本發明用於藉由鼻部滴劑經鼻投藥的調配物較佳具有介於1.0與1480mPa*s之間的動態黏性(在20℃)。
本發明的一個具體例是根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該調配物在20℃具有黏性為0.5-200mPa*s,較佳為1-20mPa*s。
根據本發明的一個調配物-包含溶於磷酸鹽緩衝液中的20% w/v PEG 400和10% w/v聚山梨酯80-具有約6mPa*s的動態黏性。
在本發明上下文中,霧化調配物的較佳液滴尺寸(表明為中位數體積直徑)係介於5和300μm之間,較佳介於30和100μm之間。這與投藥是經鼻部或咽部無關。
本發明的一個具體例是根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其中該調配物係作為鼻部噴劑投予並具有中位數體積直徑為5-300μm,較佳30-100μm的液滴尺寸。
根據本發明的一個具體例,根據本發明的調配物包含>2.5% w/v至100% w/v或3% w/v至100% w/v或3% w/v至90% w/v或3% w/v至80% w/v或3% w/v至70% w/v或3% w/v至60% w/v或3% w/v至50% w/v或3% w/v至40% w/v或3% w/v至30% w/v或3% w/v至20% w/v或3% w/v至10% w/v或3% w/v至5% w/v或5% w/v至100% w/v或5% w/v至90% w/v或5% w/v至80% w/v或 5% w/v至70% w/v或5% w/v至60% w/v或5% w/v至50% w/v或5% w/v至40% w/v或5% w/v至50% w/v或5% w/v至20% w/v或5% w/v至10% w/v或5% w/v PEG200或PEG300或PEG400或PEG500或PEG600。
根據本發明的一個具體例,根據本發明的調配物包含>2.5% w/v至100% w/v或3% w/v至100% w/v或3% w/v至90% w/v或3% w/v至80% w/v或3% w/v至70% w/v或3% w/v至60% w/v或3% w/v至50% w/v或3% w/v至40% w/v或3% w/v至30% w/v或3% w/v至20% w/v或3% w/v至10% w/v或3% w/v至5% w/v或5% w/v至100% w/v或5% w/v至90% w/v或5% w/v至80% w/v或5% w/v至70% w/v或5% w/v至60% w/v或5% w/v至50% w/v或5% w/v至40% w/v或5% w/v至50% w/v或5% w/v至20% w/v或5% w/v至10% w/v或5% w/v PEG400。
根據本發明的一個具體例,根據本發明的調配物包含溶於>2.5至100% w/v PEG400的TASK-1及/或TASK-3通道抑制劑。根據本發明的一個具體例,根據本發明的調配物包含溶於5至100% w/v PEG400的TASK-1及/或TASK-3通道抑制劑。根據本發明的一個具體例,根據本發明的調配物包含溶於10至100% w/v PEG400的TASK-1及/或TASK-3通道抑制劑。根據本發明的一個具體例,根據本發明的調配物包含溶於20至100% w/v PEG400的TASK-1及/或TASK-3通道抑制劑。根據本發明的一個具體例,根據本發明的調配物包含溶於5至20% w/v PEG400的TASK-1及/或TASK-3通道抑制劑。根據本發明的一個具體例,根據本發明的調配物包含溶於20% w/v PEG400的TASK-1及/或TASK-3通道抑制劑。
在本發明上下文中,活性成分係定義為TASK-1及/或TASK-3通道的抑制劑、或其水合物、溶劑合物、多晶形物、或代謝物或其醫藥上可接受的鹽。
根據本發明的穩定醫藥調配物為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一抑制劑係選自PCT/EP2016/079973所述化合物的那些調配物。
根據本發明的穩定醫藥調配物為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自通式(I)之化合物的該等調配物,
其中R1 代表鹵素、氰基、(C1-C4)-烷基、環丙基或環丁基,以及R2 代表(C4-C6)-環烷基,其中一環CH2基團可被-O-置換,或代表式(a)苯基或式(b)吡啶基
其中*標記接至毗鄰羰基的鍵且R3 代表氟、氯、溴、氰基、(C1-C3)-烷基或(C1-C3)-烷氧基,其中(C1-C3)-烷基與(C1-C3)-烷氧基可經氟至多三次取代,R4 代表氫、氟、氯、溴或甲基,R5 代表氫、氟、氯、溴或甲基, 以及R6 為氫、(C1-C3)-烷氧基、環丁基氧基、氧雜環丁烷-3-基氧基、四氫呋喃-3-基氧基或四氫-2H-吡喃-4-基氧基,其中(C1-C3)-烷氧基可經氟至多三次取代,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自上文給予的通式(I)之化合物的該等調配物,其中R1 代表氟、氯、溴、甲基、異丙基、三級丁基或環丙基,以及R2 代表環丁基、環戊基或環己基,或代表式(a)苯基或式(b)吡啶基
其中*標記接至毗鄰羰基的鍵且R3 代表氟、氯、氰基、(C1-C3)-烷基、(C1-C3)-烷氧基或三氟甲氧基,R4 代表氫、氟或氯,R5 代表氫、氟、氯、溴或甲基,以及R6 代表氫或(C1-C3)-烷氧基,其可經氟至多三次取代,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自通式(I)之化合物的該等調配物,其中R1 代表氯或溴,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自通式(I)之化合物的該等調配物,其中R1 代表甲基、異丙基、三級丁基或環丙基,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自通式(I)之化合物的該等調配物,其中R2 代表環丁基、環戊基或環己基,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物亦為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自通式(I)之化合物的該等調配物,其中R2 代表式(a)苯基
其中**標記接至毗鄰羰基的鍵,R3 代表氟、氯、氰基、(C1-C3)-烷基或(C1-C3)-烷氧基,以及R4 代表氫、氟或氯,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物亦為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一抑制劑係選自通式(I)之化合物的該些調配物,其中R2 代表式(b)吡啶基
其中**標記接至毗鄰羰基的鍵,R5 代表氫、氯或溴以及R6 代表(C1-C3)-烷氧基,其可經氟至多三次取代,及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物亦為,舉例來說,當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自通式(I)之化合物的該等調配物,其中R1 代表氯、溴、異丙基或環丙基,以及R2 代表環丁基、環戊基或環己基,或代表式(a)苯基或式(b)吡啶基
其中*標記接至毗鄰羰基的鍵且R3 代表氟、氯、氰基、甲基、異丙基、甲氧基或乙氧基, R4 代表氫、氟或氯,R5 代表氫、氯或溴,以及R6 代表甲氧基、二氟甲氧基、三氟甲氧基或異丙氧基,及其鹽、溶劑合物與鹽之溶劑合物。
不論指明之基的分別組合,在基的分別組合或較佳組合中所指明之個別基定義亦視必要由其他組合的基定義置換。
極尤其偏好的是上述較佳範圍之兩或更多者的組合。
根據本發明的穩定醫藥調配物亦為當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自表1之化合物的該等調配物。該等化合物的合成係描述於PCT/EP2016/079973。
根據本發明的穩定醫藥調配物亦為當中的TASK-1及/或TASK-3通道的至少一種抑制劑係選自由下列所構成之群組的該等調配物:
及其鹽、溶劑合物與鹽之溶劑合物。
根據本發明的穩定醫藥調配物亦為當中TASK-1及/或TASK-3通道的至少一種抑制劑為(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮的該些調配物。
本發明的又一具體例為根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防疾病。
本發明的又一具體例為用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法。
本發明的又一具體例為用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法,其中該鼻部或咽部投藥係藉助於鼻腔或咽部投藥是藉由鼻部噴劑、鼻部滴劑、鼻部溶液、粉末吸入器、霧化器、計量氣霧劑或半固體凝膠。
本發明的又一具體例為用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法,其中該作用持續時間為至少3小時。
本發明的又一具體例為用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法,其中該作用持續時間為至少4小時。
本發明的又一具體例為用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法,其中該作用持續時間為至少5小時。
本發明的又一具體例為根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防阻塞性睡眠呼吸中止症或打鼾的方法,該調 配物包含:治療有效量之TASK-1及/或TASK-3通道抑制劑4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於20%至100% w/v PEG400以及0至10% w/v聚山梨酯80與具有7之pH的0至80% w/v磷酸鹽緩衝液,和任擇地至少一種另外的輔劑,其中在鼻部或咽部投藥之後,該穩定醫藥調配物的該作用持續時間為至少3小時或至少4小時或至少5小時或至少6小時或至少7小時或至少8小時。
本發明的又一具體例為根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防阻塞性睡眠呼吸中止症或打鼾的方法,該調配物包含治療有效量之TASK-1及/或TASK-3通道抑制劑4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於20%至100% w/v PEG400以及0至10% w/v聚山梨酯80與具有7之pH的0至80% w/v磷酸鹽緩衝液,和任擇地至少一種另外的輔劑,其中在鼻部或咽部投藥之後,該穩定醫藥調配物的該作用持續時間為至少3小時。
本發明的又一具體例為根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防阻塞性睡眠呼吸中止症或打鼾的方法,該調配物包含:治療有效量之TASK-1及/或TASK-3通道抑制劑4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於20%至100% w/v PEG400以及0至10% w/v聚山梨酯80與具有7之pH的0至80% w/v磷酸鹽緩衝液,和任擇地至少一種另外的輔劑,其中在鼻部或咽部投藥之後,該穩定 醫藥調配物的該作用持續時間為至少4小時。
本發明的又一具體例為根據本發明用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防阻塞性睡眠呼吸中止症或打鼾的方法,該調配物包含:治療有效量之TASK-1及/或TASK-3通道抑制劑4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於20%至100% w/v PEG400以及0至10% w/v聚山梨酯80與具有7之pH的0至80% w/v磷酸鹽緩衝液,和任擇地至少一種另外的輔劑,其中在鼻部或咽部投藥之後,該穩定醫藥調配物的該作用持續時間為至少5小時。
本發明的調配物可單獨使用或如有需要時和一或多個其他藥理活性物質合併使用,前提是此組合不會導致非所欲與不可接受的副作用。本發明因此更提供包含本發明調配物之至少一者和一或多個另外活性成分的醫藥品,尤其是用於治療及/或預防前述病症。適用於此目的之組合活性成分的較佳例子包括:˙呼吸刺激劑,舉例且偏好的是,茶鹼(theophylline)、多沙普崙(doxapram)、尼卡巴胺(nikethamide)或咖啡因(caffeine);˙精神興奮劑,舉例且偏好的是,莫達非尼(modafinil)或愛達非尼(armodafinil);˙安非他命(amphetamines)與安非他命衍生物,舉例且偏好的是,安非他命、甲基安非他命或利他能(methylphenidate);˙血清素再吸收抑制劑,舉例且偏好的是,氟西汀(fluoxetine)、帕羅西丁(paroxetine)、西酞普蘭(citalopram)、艾司普蘭(escitalopram)、舍曲林(sertraline)、氟伏沙明(fluvoxamine)或曲唑酮(trazodone); ˙血清素前驅物,舉例且偏好的是,L-色胺酸;˙選擇性血清素去甲腎上腺素能再吸收抑制劑,舉例且偏好的是,文拉法辛(venlafaxine)或度洛西汀(duloxetine);˙去甲腎上腺素能和特異性血清素能抗抑鬱藥,舉例且偏好的是,米氮平(mirtazapine);˙選擇性去甲腎上腺素能再吸收抑制劑,舉例且偏好的是,瑞波西汀(reboxetine);˙三環類抗抑鬱藥,舉例且偏好的是,阿米替林(amitriptyline)、普羅替林(protriptyline)、多塞平(doxepine)、曲米帕明(trimipramine)、丙咪嗪(imipramine)、氯米帕明(clomipramine)或地昔帕明(desipramine);˙α2-腎上腺素能促效劑,舉例且偏好的是,可樂定(clonidine);˙GABA促效劑,舉例且偏好的是,巴氯芬(baclofen);˙α擬交感神經藥,舉例且偏好的是,木糖唑啉(xylometazoline)、羥甲唑啉(oxymetazoline)、苯腎上腺素(phenylephrine)、萘甲唑啉(naphazoline)、四唑啉(tetryzoline)或曲馬唑啉(tramazoline);˙糖皮質激素,舉例且偏好的是,氟替卡松(fluticasone)、布地奈德(budesonide)、倍氯米松(beclometasone)、莫米松(mometasone)、替可的酮(tixocortol)或曲安奈德(triamcinolone);˙大麻素(cannabinoid)受體促效劑;˙碳水化酶抑制劑,舉例且偏好的是,乙醯偶氮胺(acetazolamide)、甲醋唑胺(methazolamide)或雙氯非那胺(diclofenamide);˙鴉片類(opioid)與苯二氮平(benzodiazepine)受體拮抗劑,舉例且偏好的是,氟馬西尼(flumazenil)、納洛酮(naloxone)或納曲酮(naltrexone);˙膽鹼酯酶抑制劑,舉例且偏好的是,新斯的明(neostigmine)、吡斯的明 (pyridostigmine)、毒扁豆鹼(physostigmine)、多奈哌齊(donepezil)、加蘭他敏(galantamine)或利伐斯的明(rivastigmine);˙N-甲基-D-天門冬胺酸和穀胺酸拮抗劑,舉例且偏好的是,金剛烷胺(amantadine)、美金剛(memantine)或沙貝魯唑(sabeluzole);˙尼古丁受體促效劑;˙白三烯受體拮抗劑,舉例且偏好的是,孟魯司特(montelukast)或崔魯司特(tripelukast);˙多巴胺受體拮抗劑,舉例且偏好的是,多潘立酮(dromperidone)、甲氧氯普胺(metoclopramide)或苄醯胺(benzamide)、苯丁酮(butyrophenone)或吩噻嗪(phenothiazine)衍生物;˙食慾抑制劑,舉例且偏好的是,西布曲明(sibutramin)、托吡酯(topiramate)、芬特明(phentermine)、脂肪酶抑制劑或大麻素受體拮抗劑;˙質子幫浦抑制劑,舉例且偏好的是,泮托拉唑(pantoprrazole)、奧美拉唑(omeprrazole)、伊莫拉唑(esomeprrazole)、蘭索拉唑(lansoprrazole)或雷貝拉唑(rabeprrazole);˙有機硝酸鹽和NO供體,舉例來說,硝普鈉(sodium nitroprusside)、硝化甘油、異山梨醇單硝酸酯、二硝酸異山梨酯、嗎莫地平(molsidomine)或SIN-1,與吸入式NO;˙抑制環鳥苷單磷酸酯(cGMP)及/或環腺苷單磷酸酯(cAMP)降解的化合物,舉例來說,磷酸二酯酶(PDE)1、2、3、4及/或5的抑制劑,尤其是PDE 5抑制劑,例如西地那非(sildenafil)、伐地那非(vardenafil)、他達拉非(tadalafil)、烏地那非(udenafil)、達沙他非(dasantafil)、阿伐那非(avanafil)、米羅那非(mirodenafil)或洛地那非(lodenafil);˙可溶性鳥苷酸環化酶(sGC)的NO-及血紅素-獨立性活化劑,例如尤其是 說明於WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462與WO 02/070510的化合物;˙可溶性鳥苷酸環化酶(sGC)的NO-獨立性但是血紅素依賴性刺激劑,例如尤其是利奧西呱(riociguat)、威利西呱(vericiguat)與說明於WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647與WO 2012/059549的化合物;˙前列環素類似物與IP受體促效劑,舉例且偏好的是,依洛前列素(iloprost)、貝前列素(beraprost)、曲前列素(treprostinil)、依前列醇(epoprostenol)或賽樂西帕(selexipag);˙內皮素受體拮抗劑,舉例且偏好的是,波生坦(bosentan)、達盧生坦(darusentan)、安貝生坦(ambrisentan)或西他生坦(sitaxsentan);˙抑制人類嗜中性細胞彈性蛋白酶(HNE)的化合物,舉例且偏好的是,西維來司(sivelestat)或DX-890(瑞創(reltran));˙抑制細胞外基質的降解和變動的化合物,舉例且偏好的是,基質金屬蛋白酶(MMPs)的抑制劑,尤其是基質溶素(stromelysin)、膠原酶、明膠酶和聚集蛋白聚醣酶(aggrecanases)(就此上下文而言,尤其是MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11與MMP-13)與金屬蛋白酶(MMP-12)的抑制劑;˙阻斷血清素結合至其受體的化合物,舉例且偏好的是,5-HT2B受體的拮抗劑,例如PRX-08066;˙生長因子、細胞介質和趨化介質的拮抗劑,舉例且偏好的是,TGF-β、CTGF、IL-1、IL-4、IL-5、IL-6、IL-8、IL-13與整合素的拮抗劑;˙ρ激酶-抑制化合物,舉例且偏好的是,法舒地爾(fasudil)、Y-27632、 SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095或BA-1049;˙影響心臟能量代謝的化合物,舉例且偏好的是,依托莫司(etomoxir)、二氯乙酸、雷諾嗪(ranolazine)或曲美他嗪(trimetazidine);˙抑制信號傳導級聯的化合物,舉例且偏好的是,來自激酶抑制劑群組,尤其來自酪胺酸激酶及/或絲胺酸/蘇胺酸激酶抑制劑群組,舉例且偏好的是,尼達尼布(nintedanib)、達沙替尼(dasatinib)、尼羅替尼(nilotinib)、波束替尼(bosutinib)、瑞果尼布(regorafenib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、西地尼布(cediranib)、阿西替尼(axitinib)、替拉替尼(telatinib)、伊馬替尼(imatinib)、布伐尼布(brivanib)、帕唑帕尼(pazopanib)、伐他拉尼(vatalanib)、吉非替尼(gefitinib)、埃羅替尼(erlotinib)、拉帕替尼(lapatinib)、卡奈替尼(canertinib)、來他替尼(lestaurtinib)、泰息安(pelitinib)、司馬沙尼(semaxanib)或坦度替尼(tandutinib);˙抗阻塞劑係用於,舉例來說,治療慢性阻塞性肺病(COPD)或支氣管哮喘,舉例且偏好的是,來自以下群組:吸入性或全身性投予的β-腎上腺素能受體促效劑(β-模擬物)與吸入性投予的抗毒蕈鹼能物質;˙抗炎性、免疫調節、免疫抑制及/或細胞毒性劑,舉例且偏好的是,來自以下群組:全身性或吸入性投予的皮質類固醇與富馬酸二甲酯、芬戈莫德(fingolimod)、乙酸格拉默(glatiramer acetate)、β-干擾素、那他珠單抗(natalizumab)、特立氟胺(teriflunomide)、米托蒽醌(mitoxantrone)、免疫球蛋白、乙醯半胱胺酸、孟魯司特(montelukast)、提披路卡(tipelukast)、硫唑嘌呤(azathioprine)、環磷醯胺(cyclophosphamide)、羥基脲(hydroxycarbamide)、阿奇黴素(azithromycin)、干擾素-γ、吡非尼酮(pirfenidone)或依那西普(etanercept); ˙抗纖維化劑,舉例且偏好的是,溶血磷脂酸受體1(LPA-1)拮抗劑'、CTGF抑制劑、IL-4拮抗劑、IL-13拮抗劑、TGF-β拮抗劑或吡非尼酮(pirfenidone);˙抗血栓劑,舉例且偏好的是,來自以下群組:血小板凝集抑制劑、抗凝血劑和纖維蛋白溶解物質;˙降壓活性成分,舉例且偏好的是,來自以下群組:鈣鈣拮抗劑、血管緊張素AII拮抗劑、ACE抑制劑、血管肽酶抑制劑、內皮素拮抗劑、腎素抑制劑、α受體阻斷劑、β受體阻斷劑、鹽皮質激素受體拮抗劑,還有利尿劑;及/或˙改變脂質代謝的活性成分,舉例且偏好的是,來自以下群組:甲狀腺受體促效劑、膽固醇合成抑制劑,舉例且較佳的是,HMG-CoA還原酶抑制劑或角鯊烯合成抑制劑、ACAT抑制劑、CETP抑制劑、MTP抑制劑、PPAR-α、PPAR-γ及/或PPAR-δ促效劑、膽固醇吸收抑制劑、脂肪酶抑制劑、聚合膽汁酸吸附劑、膽汁酸再吸收抑制劑與脂蛋白(a)拮抗劑。
在本發明的較佳具體例中,本發明的調配物係和以下合併投予:β-腎上腺素能受體促效劑,舉例且偏好的是,阿布叔醇(albuterol)、異丙腎上腺素(isoproterenol)、奥西那林(metaproterenol)、特布他林(terbutalin)、非諾特羅(fenoterol)、福莫特羅(formoterol)、瑞特醇(reproterol)、沙丁胺醇(salbutamol)或沙美特羅(salmeterol)。
在本發明的較佳具體例中,本發明的調配物係和以下合併投予:抗毒蕈鹼能物質,舉例且偏好的是,異丙托溴銨(ipratropium bromide)、噻托溴銨(tiotropium bromide)或氧托溴銨(oxitropium bromide)。
在本發明的較佳具體例中,本發明的調配物係和以下合併投予:皮質類固醇,舉例且偏好的是,潑尼松(prednisone)、潑尼松龍(prednisolone)、甲 基潑尼松龍(methylprednisolone)、曲安西龍(triamcinolone)、地塞米松(dexamethasone)、倍氯米松(beclomethasone)、倍他米松(betamethasone)、氟尼縮松(flunisolide)、布地奈德(budesonide)或氟替卡松(fluticasone)。
抗血栓劑係較佳理解為意指來自血小板凝集抑制劑、抗凝血劑與前纖維蛋白溶解物質群組的化合物。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:血小板凝集抑制劑,舉例且偏好的是,阿斯匹靈(aspirin)、氯吡格雷(clopidogrel)、噻氯匹定(ticlopidine)或雙嘧達莫(dipyridamole)。
在本發明的較佳具體例中,本發明的調配物係和以下合併投予:纖維蛋白酶抑制劑,舉例且偏好的是,希美加群(ximelagatran)、美拉加群(melagatran)、達比加群(dabigatran)、比伐盧定(bivalirudin)或克立生(clexane)。
在本發明的較佳具體例中,本發明的調配物係和以下合併投予:GPIIb/IIIa拮抗劑,舉例且偏好的是,替羅非班(tirofiban)或阿昔單抗(abciximab)。
在本發明的較佳具體例中,本發明的調配物係和以下合併投予:第Xa因子抑制劑,舉例且偏好的是,拜瑞妥(rivaroxaban)、阿哌沙班(apixaban)、非地沙班(fidexaban)、雷扎沙班(razaxaban)、磺達肝癸(fondaparinux)、艾屈肝素(idraparinux)、DU-176b、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV 803、SSR-126512或SSR-128428。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:肝素或低分子量(LMW)肝素衍生物。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:維生素K拮抗劑,舉例且偏好的是,香豆素(coumarin)。
降壓劑係較佳理解為意指來自以下群組的化合物:鈣拮抗劑血管緊張素AII拮抗劑、ACE抑制劑、內皮素拮抗劑、腎素抑制劑、α-受體阻斷劑、β-受體阻斷劑、鹽皮質激素受體拮抗劑、與利尿劑。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:鈣拮抗劑,舉例且偏好的是,硝苯地平(nifedipine)、氨氯地平(amlodipine)、維拉帕米(verapamil)或地爾硫(diltiazem)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:α-1-受體阻斷劑,舉例且偏好的是,哌唑嗪(prazosin)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:β-受體阻斷劑,舉例且偏好的是,普萘洛爾(propranolol)、阿替洛爾(atenolol)、噻嗎洛爾(timolol)、吲哚洛爾(pindolol)、阿普洛爾(alprenolol)、氧烯洛爾(oxprenolol)、噴布洛爾(penbutolol)、布普洛爾(bupranolol)、美替洛爾(metipranolol)、納多洛爾(nadolol)、甲吲洛爾(mepindolol)、卡拉洛爾(carazalol)、索他洛爾(sotalol)、美托洛爾(metoprolol)、倍他洛爾(betaxolol)、塞利洛爾(celiprolol)、比索洛爾(bisoprolol)、卡替洛爾(carteolol)、艾司洛爾(esmolol)、拉貝洛爾(labetalol)、卡維地洛(carvedilol)、阿達洛爾(adaprolol)、蘭地洛爾(landiolol)、奈必洛爾(nebivolol)、依泮洛爾(epanolol)或布新洛爾(bucindolol)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:血管緊張素AII拮抗劑,較佳例子是洛沙坦(losartan)、坎地沙坦(candesartan)、纈沙坦(valsartan)、替米沙坦(telmisartan)或恩布沙坦(embusartan)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:ACE抑制劑,舉例且偏好的是,依那普利(enalapril)、卡托普利(captopril)、 賴諾普利(lisinopril)、雷米普利(ramipril)、地拉普利(delapril)、福辛普利(fosinopril)、喹那普利(quinopril)、培哚普利(perindopril)或川多普利(trandopril)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:內皮素拮抗劑,舉例且偏好的是,波生坦(bosentan)、達盧生坦(darusentan)、安貝生坦(ambrisentan)或西他生坦(sitaxsentan)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:腎素抑制劑,舉例且偏好的是,阿利吉崙(aliskiren)、SPP-600或SPP-800。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:鹽皮質激素受體拮抗劑,舉例且偏好的是,螺內酯(spironolactone)、依普利酮(eplerenone)或芬內利酮(finerenone)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:利尿劑,舉例且偏好的是,呋塞米(furosemide)、布美他尼(bumetanide)、托塞米(torsemide)、苯曲威噻嗪(bendroflumethiazide)、氯噻嗪(chlorothiazide)、氫氯噻嗪(hydrochlorothiazide)、氫氟噻嗪(hydroflumethiazide)、甲基噻嗪(methyclothiazide)、聚噻嗪(polythiazide)、三氯甲基噻嗪(trichlormethiazide)、氯噻酮(chlorthalidone)、吲達帕胺(indapamide)、美托拉宗(metolazone)、喹那黴素(quinethazone)、乙醯唑胺(acetazolamide)、雙氯非那胺(dichlorphenamide)、醋甲唑胺(methazolamide)、甘油、異山梨醇、甘露醇、阿米洛利(amiloride)或氨苯蝶啶(triamterene)。
脂質代謝調節劑係較佳理解為意指來自以下群組的化合物:CETP抑制劑、甲狀腺受體促效劑、膽固醇合成抑制劑,例如HMG-CoA還原酶抑制劑或角鯊烯合成抑制劑、ACAT抑制劑、MTP抑制劑、PPAR-α、PPAR-γ及/或PPAR-δ促效劑、膽固醇吸收抑制劑、聚合膽汁酸吸附劑、膽汁酸再吸收 抑制劑、脂肪酶抑制劑與脂蛋白(a)拮抗劑。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:CETP抑制劑,舉例且偏好的是,托徹普(torcetrapib)(CP-529 414)、JJT-705或CETP疫苗(Avant)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:甲狀腺受體促效劑,例如,舉例來說且較佳地,D-甲狀腺素、3,5,3'-三碘基甲狀腺原胺酸(T3)、CGS 23425或愛米提(axitirome)(CGS 26214)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:來自他汀類的HMG-CoA還原酶抑制劑,舉例且偏好的是,洛伐他汀(lovastatin)、辛伐他汀(simvastatin)、普伐他汀(pravastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、瑞舒伐他汀(rosuvastatin)或匹伐他汀(pitavastatin)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:角鯊烯合成抑制劑,舉例且偏好的是,BMS-188494或TAK-475。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:ACAT抑制劑,舉例且偏好的是,阿伐麥布(avasimibe)、美利胺(melinamide)、帕替麥布(pactimibe)、愛氟麥布(eflucimibe)或SMP-797。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:MTP抑制劑,舉例且偏好的是,英普他派(implitapide)、BMS-201038、R-103757或JTT-130。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:PPAR-γ促效劑,舉例且偏好的是,吡格列酮(pioglitazone)或羅格列酮(rosiglitazone)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予: PPAR-δ促效劑,舉例且偏好的是,GW 501516或BAY 68-5042。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:膽固醇吸收抑制劑,舉例且偏好的是,依澤替米貝(ezetimibe)、替奎安(tiqueside)或帕馬苷(pamaqueside)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:脂肪酶抑制劑,舉例且偏好的是,奧利司他(orlistat)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:聚合膽汁酸吸附劑,舉例且偏好的是,消膽胺(cholestyramine)、考來替泊(colestipol)、考來索凡(colesolvam)、考來斯塔(CholestaGel)或考來替米(colestimide)。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:膽汁酸再吸收抑制劑,舉例且偏好的是,ASBT(=IBAT)抑制劑,舉例來說,AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在本發明的較佳具體例中,根據本發明的調配物係和以下合併投予:脂蛋白(a)拮抗劑,舉例且偏好的是,沾卡平鈣(gemcabene calcium)(CI-1027)或菸鹼酸。
尤其偏好的是根據本發明的調配物和選自由下列所構成群組的一或多個另外活性成分之組合:呼吸刺激劑、精神興奮劑、血清素再吸收抑制劑、去甲腎上腺素能、血清素能與三環類抗抑鬱藥、sGC刺激劑、鹽皮質激素受體拮抗劑、抗炎性藥劑、免疫調節劑、免疫抑制劑與細胞毒性劑。
若有必要,根據本發明的調配物亦可連同使用一或多個醫療科技裝置或輔劑運用,前提是此不導致非所欲與不可接受的副作用。適用於此類合併應用的醫療裝置與輔劑為,舉例且偏好的是:˙正壓氣道通氣裝置,舉例且偏好的是,CPAP(持續性正壓氣道)裝置、 BiPAP(雙向正壓氣道)裝置與IPPV(間歇性正壓通氣)裝置;˙下頜下神經的神經刺激劑;˙口腔內輔劑,舉例且偏好的是,突出牙套;˙鼻用拋棄式閥;˙鼻用支架。
在一個具體例中,就鼻內投藥而言的劑量為每日約0.1μg至500μg。在一另外的具體例中,就鼻內投藥而言的劑量為每日約1μg至250μg。在一另外的具體例中,就鼻內投藥而言的劑量為每日約1μg至120μg。在一另外的具體例中,每日約0.1μg至500μg、或每日約1μg至250μg、或每日約1μg至120μg的劑量係一天一次在睡前以鼻內途徑投予。在一個具體例中,每日約0.1μg至500μg、或每日約1μg至250μg、或每日約1μg至120μg的劑量係一天一次以一半投予每個鼻孔。在一個具體例中,每日約0.1μg至500μg、或每日約1μg至250μg、或每日約1μg至120μg的劑量係一天一次在睡前以一半投予每個鼻孔。
儘管如此,在一些情況下,可能有必要的是,明確地說,以體重、投藥途徑、對活性成分的個別反應、製劑本質以及投藥發生的時間或區間的函數偏離所述之份量。於是,在一些情況下,低於前述最小量可能是足夠的,而在其他情況下,必須超過所提及之上限。在投予較大份量的情況下,將該等分為一天數份個別劑量可能是明智的。
存在於根據本發明的調配物的TASK-1及/或TASK-3通道抑制劑的藥理活性已藉由PCT/EP2016/079973中的體外實驗證實。
根據本發明的調配物的藥理活性可藉由本領域技術人員已知的體內研究來證實。下文的應用實施例說明了本發明化合物的生物學作用,但本發明不限於該等實施例。
在用於阻塞性睡眠呼吸中止症的豬模型中,調查了根據本發明的調配物的TASK-1及/或TASK-3通道抑制劑藉由負壓及上呼吸道的塌陷性對頦舌肌活化閾值的效應。
使用負壓,有可能引發已麻醉、自主呼吸的豬的上呼吸道的塌陷且於是阻塞[Wirth et al.,Sleep 36,699-708(2013)]。
德國藍瑞斯豬(German Landrace pigs)係用作模型。由於在人類,鼻軸在水平睡姿中處於幾乎垂直的位置,實驗中的豬被固定在坐姿(70度),其中鼻子朝上。在鼻部投藥後,調配物因此向下流過上呼吸道的所有區域。豬被 麻醉和氣管切開。將各別一個插管插入氣管的前部與尾部。使用T型連接器,將頭端插管一方面連接到產生負壓的裝置,另一方面連接到尾管。使用T型連接器,將尾部插管連接到前側插管及連接至允許繞過上呼吸道的自主呼吸的管子。藉由適當地關閉和打開該管子,於是在上呼吸道被隔離並連接到用於產生負壓的裝置期間,豬有可能從正常的鼻呼吸改變成透過尾部插管的呼吸。藉由肌電圖(EMG)記錄頦舌肌的肌肉活性。
在某些時間點,藉由讓豬透過尾部插管呼吸並向上呼吸道施加-50、-100與-150mbar(相當於-50、-100與-150cm水柱(cm H2O))的負壓來測試上呼吸道的可塌陷性。此導致上呼吸道塌陷,其本身表現為氣流的中斷和管系統的壓力降。此測試在投予測試物質之前和在投予測試物質之後的某些間隔進行。適當有效的測試物質可防止吸氣相中的氣道的此塌陷。
在從鼻部呼吸轉換到透過尾部套管呼吸之後,不可能測量麻醉豬的頦舌肌的任何EMG活性。作為進一步的測試,隨後測定EMG活性重新開始時的負壓。假使測試物質有效,此閾值係轉移至更正向的值。該測試同樣在投予測試物質之前以及投予測試物質之後的某些間隔進行。該測試物質係藉由鼻部途徑投予。
下文表格所顯示的結果是用表1列為實施例1、實施例3和實施例4的化合物進行。除另有指明外,該等數據是在上呼吸道上以-100mbar(對應於-100cm水柱(cm H2O))的負壓測量。
將表1列為實施例1、實施例3與實施例4的活性成分溶於下表2所列示的各式調配物中,並以每隻豬0μg、3μg、10μg、30μg或100μg的份量投予。該活性成分調配物或純載劑係各別用400μl體積的移液管投予至各個鼻孔中。
表2:用於鼻部投藥的調配物的組成,其中投予表1所列示的實施例3化合物:
表2的調配物任擇地額外包含濃度為0.02% w/v的丁基羥基茴香醚。
磷酸鹽緩衝液pH 7、0.063M係根據歐洲藥典8.7製備:將5.18g無水磷酸氫二鈉與3.65g磷酸二氫鈉單水合物溶於950mL水中,用磷酸調整pH,並將溶液補水至1000mL,或者,磷酸鹽緩衝液係使用磷酸氫二鈉二水合物與磷酸二氫鈉二水合物取代無水磷酸氫二鈉與磷酸二氫鈉單水合物來製備。為此目的,將6.49g磷酸氫二鈉二水合物與4.13g磷酸二氫鈉二水合物溶於950mL水中,用磷酸調整pH,並將溶液補水至1000mL。
在此豬模型中的作用持續時間被定義為在任何動物中沒有觀察到上呼吸道塌陷的時間[min],其係如同指明數量的動物的平均值。指明為“>" Xmin的作用持續時間表示實驗在Xmin終止,並且直到此時點,在任何動物中仍未觀察到上呼吸道的塌陷。
Claims (15)
- 一種用於鼻部或咽部投藥的穩定醫藥調配物,該調配物包含:治療有效量之TASK-1及/或TASK-3通道的至少一種抑制劑或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於>2.5%至100% w/v聚乙二醇以及任擇地至少一種輔劑,其中該調配物具有4至8的pH。
- 根據請求項1之用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一種輔劑係選自由下列所構成之群組:至少一種pH調節劑、至少一種增溶劑、至少一種抗氧化劑、至少一種穩定劑、至少一種增稠劑、至少一種防腐劑、至少一種用於調整張力的物質、至少一種香氛、至少一種香料和至少一種染料。
- 根據請求項1或2之用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一種pH調節劑係選自由下列所構成之群組:檸檬酸及其鹽、乙酸及其鹽、磷酸及其鹽、氫氯酸、羧酸、二羧酸、胺基酸、氧代羧酸、多元羧酸、氫氧化鈉、氫氧化鉀、碳酸鈉與碳酸氫鈉。
- 根據請求項1至3中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一種增溶劑係選自由下列所構成之群組:乙醇、聚山梨酯20、聚氧乙烯(8)硬脂酸酯和聚山梨酯80。
- 根據請求項1至4中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一種抗氧化劑係選自由下列所構成之群組:檸檬酸、丁基羥基茴香醚、丁基羥基甲苯、EDTA與用氮氣吹掃。
- 根據請求項1至5中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其中該任擇的至少一種防腐劑係選自由下列所構成之群組:C 8-C 18氯化 烷、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、山梨酸、氯丁醇和苯扎氯銨(benzalkonium chloride)。
- 根據請求項1至6中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其中該調配物包含5至100% w/v聚乙二醇400、0至10% w/v增溶劑、0至95% w/v pH調節劑和任擇地至少一種另外的輔劑。
- 根據請求項1至7中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其中該TASK-1及/或TASK-3通道的至少一種抑制劑係選自式(I)化合物,
- 根據請求項1至8中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其中該TASK-1及/或TASK-3通道的至少一抑制劑係選自(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮,(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(2-氟苯基)甲酮,(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(環戊基)甲酮,以及(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(環戊基)甲酮,以及其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽。
- 根據請求項1至9中任一項之穩定醫藥調配物,其中該TASK-1及/或TASK-3通道的至少一抑制劑為(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽。
- 根據請求項1至9中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防疾病。
- 根據請求項1至9中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠 呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法。
- 根據請求項1至9中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法,其中該鼻部或咽部投藥係藉助於鼻腔或咽部投藥是藉由鼻部噴劑、鼻部滴劑、鼻部溶液、粉末吸入器、霧化器、計量氣霧劑或半固體凝膠。
- 根據請求項1至9中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防呼吸病症、睡眠相關的呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、節律不齊、神經退化病症、神經炎性病症與神經免疫病症的方法,其中該作用持續時間為至少4小時。
- 根據請求項1至9中任一項之用於鼻部或咽部投藥的穩定醫藥調配物,其係用於治療及/或預防阻塞性睡眠呼吸中止症或打鼾的方法,該調配物包含:治療有效量之TASK-1及/或TASK-3通道抑制劑4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}哌嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或其水合物、溶劑合物、多晶形物或代謝物或其醫藥上可接受之鹽,其溶於20%至100% w/v PEG400以及0至10% w/v聚山梨酯80與具有7之pH的0至80% w/v磷酸鹽緩衝液,和任擇地至少一種另外的輔劑,其中在鼻部或咽部投藥之後,該穩定醫藥調配物的該作用持續時間為至少5小時。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16205686.5A EP3338803A1 (de) | 2016-12-21 | 2016-12-21 | Pharmazeutische darreichungsformen enthaltend inhibitoren von task-1 und task-3 kanälen und deren verwendung für die therapie von atemstörungen |
??16205686.5 | 2016-12-21 | ||
??17157800.8 | 2017-02-24 | ||
EP17157800 | 2017-02-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201834654A true TW201834654A (zh) | 2018-10-01 |
Family
ID=60812051
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106144530A TW201834654A (zh) | 2016-12-21 | 2017-12-19 | 包含task-1與task-3通道抑制劑之醫藥劑型及其用於呼吸病症治療之用途 |
Country Status (23)
Country | Link |
---|---|
US (1) | US20200085734A1 (zh) |
EP (1) | EP3558379A1 (zh) |
JP (1) | JP2020502206A (zh) |
KR (1) | KR20190099211A (zh) |
CN (1) | CN110114091A (zh) |
AU (1) | AU2017379247A1 (zh) |
BR (1) | BR112019012569A2 (zh) |
CA (1) | CA3047428A1 (zh) |
CL (1) | CL2019001727A1 (zh) |
CO (1) | CO2019006654A2 (zh) |
CR (1) | CR20190300A (zh) |
CU (1) | CU20190060A7 (zh) |
DO (1) | DOP2019000171A (zh) |
EC (1) | ECSP19044508A (zh) |
IL (1) | IL267344A (zh) |
JO (1) | JOP20190141A1 (zh) |
MA (1) | MA47069A (zh) |
MX (1) | MX2019007378A (zh) |
PE (1) | PE20191241A1 (zh) |
PH (1) | PH12019501408A1 (zh) |
TW (1) | TW201834654A (zh) |
UY (1) | UY37542A (zh) |
WO (1) | WO2018114503A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2016365676A1 (en) | 2015-12-10 | 2018-06-07 | Bayer Pharma Aktiengesellschaft | 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives as blockers of TASK-1 and TASK-2 channels, for the treatment of sleep-related breathing disorders |
TWI795381B (zh) | 2016-12-21 | 2023-03-11 | 比利時商健生藥品公司 | 作為malt1抑制劑之吡唑衍生物 |
WO2018227427A1 (en) | 2017-06-14 | 2018-12-20 | Bayer Aktiengesellschaft | Substituted bridged diazepane derivatives and use thereof |
JOP20190284A1 (ar) | 2017-06-14 | 2019-12-11 | Bayer Pharma AG | مركبات إيميدازوبيريميدين مستبدلة بديازا ثنائي الحلقة واستخدامها للمعالجة من اضطرابات التنفس |
ES2966457T3 (es) | 2018-06-18 | 2024-04-22 | Janssen Pharmaceutica Nv | Derivados de pirazol como inhibidores de MALT1 |
PE20211285A1 (es) * | 2018-11-27 | 2021-07-19 | Bayer Ag | Proceso para la produccion de formas farmaceuticas que contienen inhibidores de los canales task-1 y task-3 y su uso para la terapia de trastornos respiratorios |
CA3139298A1 (en) * | 2019-05-09 | 2020-11-12 | Bayer Aktiengesellschaft | Combination of an a2-adrenoceptor subtype c (alpha-2c) antagonists with a task1/3 channel blocker for the treatment of sleep apnea |
TW202108139A (zh) * | 2019-05-09 | 2021-03-01 | 德商拜耳廠股份有限公司 | 用於治療睡眠呼吸中止之α2—腎上腺素受體亞型C(α—2C)拮抗劑與TASK1/3通道阻斷劑之組合 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19834044A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19834047A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
DE19943635A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE19943636A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE19943634A1 (de) | 1999-09-13 | 2001-04-12 | Bayer Ag | Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE19943639A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Dicarbonsäurederivate mit neuartigen pharmazeutischen Eigenschaften |
CN1303674A (zh) * | 1999-12-02 | 2001-07-18 | 山东省医药工业研究所 | 阿普唑仑鼻喷剂 |
AR031176A1 (es) | 2000-11-22 | 2003-09-10 | Bayer Ag | Nuevos derivados de pirazolpiridina sustituidos con piridina |
DE10110749A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte Aminodicarbonsäurederivate |
DE10110750A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE10220570A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
JP5161871B2 (ja) * | 2006-04-27 | 2013-03-13 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Task−1およびtask−3イオンチャンネルの阻害剤 |
DE102010021637A1 (de) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung |
EP2682394A1 (de) | 2010-07-09 | 2014-01-08 | Bayer Intellectual Property GmbH | 1H-Pyrazolo[3,4-b]pyridin-Triazine Verbindungen und ihre Verwendung zur Behandlung bzw. Prophylaxe von Herz-Kreislauf-Erkrankungen |
US9132243B2 (en) | 2010-07-23 | 2015-09-15 | Tannermedico A/S | Method of administering a substance to the throat |
DE102010040233A1 (de) | 2010-09-03 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Bicyclische Aza-Heterocyclen und ihre Verwendung |
DE102010043379A1 (de) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung |
AU2016365676A1 (en) * | 2015-12-10 | 2018-06-07 | Bayer Pharma Aktiengesellschaft | 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives as blockers of TASK-1 and TASK-2 channels, for the treatment of sleep-related breathing disorders |
-
2017
- 2017-06-16 JO JOP/2019/0141A patent/JOP20190141A1/ar unknown
- 2017-12-13 BR BR112019012569A patent/BR112019012569A2/pt not_active Application Discontinuation
- 2017-12-13 JP JP2019533394A patent/JP2020502206A/ja active Pending
- 2017-12-13 AU AU2017379247A patent/AU2017379247A1/en not_active Abandoned
- 2017-12-13 WO PCT/EP2017/082545 patent/WO2018114503A1/de unknown
- 2017-12-13 KR KR1020197017397A patent/KR20190099211A/ko unknown
- 2017-12-13 PE PE2019001284A patent/PE20191241A1/es unknown
- 2017-12-13 CU CU2019000060A patent/CU20190060A7/es unknown
- 2017-12-13 EP EP17821532.3A patent/EP3558379A1/de not_active Withdrawn
- 2017-12-13 CA CA3047428A patent/CA3047428A1/en not_active Abandoned
- 2017-12-13 CR CR20190300A patent/CR20190300A/es unknown
- 2017-12-13 CN CN201780079708.2A patent/CN110114091A/zh active Pending
- 2017-12-13 MX MX2019007378A patent/MX2019007378A/es unknown
- 2017-12-13 US US16/471,263 patent/US20200085734A1/en not_active Abandoned
- 2017-12-13 MA MA047069A patent/MA47069A/fr unknown
- 2017-12-19 TW TW106144530A patent/TW201834654A/zh unknown
- 2017-12-21 UY UY0001037542A patent/UY37542A/es not_active Application Discontinuation
-
2019
- 2019-06-13 IL IL267344A patent/IL267344A/en unknown
- 2019-06-19 DO DO2019000171A patent/DOP2019000171A/es unknown
- 2019-06-19 PH PH12019501408A patent/PH12019501408A1/en unknown
- 2019-06-20 CL CL2019001727A patent/CL2019001727A1/es unknown
- 2019-06-21 CO CONC2019/0006654A patent/CO2019006654A2/es unknown
- 2019-06-21 EC ECSENADI201944508A patent/ECSP19044508A/es unknown
Also Published As
Publication number | Publication date |
---|---|
AU2017379247A8 (en) | 2019-07-18 |
BR112019012569A2 (pt) | 2019-11-26 |
KR20190099211A (ko) | 2019-08-26 |
AU2017379247A1 (en) | 2019-06-13 |
CL2019001727A1 (es) | 2019-11-29 |
MX2019007378A (es) | 2019-09-18 |
UY37542A (es) | 2018-07-31 |
PH12019501408A1 (en) | 2020-02-10 |
PE20191241A1 (es) | 2019-09-16 |
US20200085734A1 (en) | 2020-03-19 |
MA47069A (fr) | 2021-04-21 |
CR20190300A (es) | 2019-09-23 |
IL267344A (en) | 2019-08-29 |
CO2019006654A2 (es) | 2019-06-28 |
JP2020502206A (ja) | 2020-01-23 |
CN110114091A (zh) | 2019-08-09 |
DOP2019000171A (es) | 2019-07-15 |
CU20190060A7 (es) | 2020-02-04 |
CA3047428A1 (en) | 2018-06-28 |
JOP20190141A1 (ar) | 2019-06-12 |
ECSP19044508A (es) | 2019-06-30 |
WO2018114503A1 (de) | 2018-06-28 |
EP3558379A1 (de) | 2019-10-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW201834654A (zh) | 包含task-1與task-3通道抑制劑之醫藥劑型及其用於呼吸病症治療之用途 | |
TW201834653A (zh) | 包含task-1與task-3通道抑制劑之醫藥劑型及其於呼吸道疾病治療之用途 | |
AU2008259864B2 (en) | Methods and compositions for administration of Oxybutynin | |
TW202034920A (zh) | 用於治療睡眠呼吸中止之α2-腎上腺素受體亞型C(α-2C)拮抗劑 | |
JP5362151B2 (ja) | Pgd2拮抗剤及びヒスタミン拮抗剤からなるアレルギー性鼻炎治療用医薬 | |
JP7474760B2 (ja) | Task-1およびtask-3チャンネル阻害剤を含有する医薬投薬形態の製造方法、ならびに呼吸障害治療におけるその使用 | |
EP3338764A1 (de) | Pharmazeutische darreichungsformen enthaltend inhibitoren von task-1 und task-3 kanälen und deren verwendung für die therapie von atemstörungen | |
EP3338803A1 (de) | Pharmazeutische darreichungsformen enthaltend inhibitoren von task-1 und task-3 kanälen und deren verwendung für die therapie von atemstörungen | |
US20220016113A1 (en) | ?2-adrenoceptor subtype c (alpha-2c) antagonists for the treatment of sleep apnea | |
JP2016504358A (ja) | オキシブチニンを投与するための方法および組成物 | |
EA045860B1 (ru) | АНТАГОНИСТЫ α2-АДРЕНОРЕЦЕПТОРОВ ПОДТИПА С (АЛЬФА-2С АДРЕНОРЕЦЕПТОРОВ) ДЛЯ ЛЕЧЕНИЯ АПНОЭ ВО СНЕ |