CN106061494A - 可用于治疗阿片样物质诱导的功能障碍的鸟苷酸环化酶的激动剂 - Google Patents
可用于治疗阿片样物质诱导的功能障碍的鸟苷酸环化酶的激动剂 Download PDFInfo
- Publication number
- CN106061494A CN106061494A CN201480067381.3A CN201480067381A CN106061494A CN 106061494 A CN106061494 A CN 106061494A CN 201480067381 A CN201480067381 A CN 201480067381A CN 106061494 A CN106061494 A CN 106061494A
- Authority
- CN
- China
- Prior art keywords
- peptide
- opioid
- aminoacid
- acid
- compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 31
- 108010078321 Guanylate Cyclase Proteins 0.000 title claims abstract description 11
- 102000014469 Guanylate cyclase Human genes 0.000 title claims abstract description 11
- 239000000556 agonist Substances 0.000 title claims description 42
- 230000004064 dysfunction Effects 0.000 title abstract description 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 174
- 239000000203 mixture Substances 0.000 claims abstract description 93
- 238000000034 method Methods 0.000 claims abstract description 54
- 239000000018 receptor agonist Substances 0.000 claims abstract description 9
- 229940044601 receptor agonist Drugs 0.000 claims abstract description 9
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 94
- 239000003814 drug Substances 0.000 claims description 54
- 229960005181 morphine Drugs 0.000 claims description 47
- 230000006698 induction Effects 0.000 claims description 45
- 238000002360 preparation method Methods 0.000 claims description 41
- 229920000642 polymer Polymers 0.000 claims description 36
- 210000001630 jejunum Anatomy 0.000 claims description 28
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 claims description 27
- 239000003112 inhibitor Substances 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 20
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 19
- 230000008685 targeting Effects 0.000 claims description 14
- 239000002775 capsule Substances 0.000 claims description 13
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 12
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 230000008859 change Effects 0.000 claims description 9
- 210000003405 ileum Anatomy 0.000 claims description 8
- 208000024891 symptom Diseases 0.000 claims description 8
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims description 7
- 210000001072 colon Anatomy 0.000 claims description 7
- 230000001419 dependent effect Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 7
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 6
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 claims description 6
- 229960001113 butorphanol Drugs 0.000 claims description 6
- 229960004126 codeine Drugs 0.000 claims description 6
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 6
- 229960002428 fentanyl Drugs 0.000 claims description 6
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims description 6
- 229960000240 hydrocodone Drugs 0.000 claims description 6
- 229960002085 oxycodone Drugs 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 6
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 5
- 229960004380 tramadol Drugs 0.000 claims description 5
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 210000001198 duodenum Anatomy 0.000 claims description 4
- 238000005457 optimization Methods 0.000 claims description 4
- NSPHQWLKCGGCQR-DLJDZFDSSA-N (2s)-2-[[(1r,4s,7s,10s,13s,16r,21r,27s,34r,37s,40s)-10-(2-amino-2-oxoethyl)-34-[[(2s)-4-carboxy-2-[[(2s)-3-carboxy-2-[[(2s)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]amino]butanoyl]amino]-37-(2-carboxyethyl)-27-[(1r)-1-hydroxyethyl]-4-methyl-40-(2-methylp Chemical compound N1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(N)=O)CSSC[C@@H]2NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)[C@H]([C@@H](C)O)NC2=O NSPHQWLKCGGCQR-DLJDZFDSSA-N 0.000 claims description 3
- 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 claims description 3
- 210000001815 ascending colon Anatomy 0.000 claims description 3
- 230000004888 barrier function Effects 0.000 claims description 3
- 229960001571 loperamide Drugs 0.000 claims description 3
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 claims description 3
- 108010018859 plecanatide Proteins 0.000 claims description 3
- 229950008515 plecanatide Drugs 0.000 claims description 3
- 229960002381 vardenafil Drugs 0.000 claims description 3
- REZGGXNDEMKIQB-UHFFFAOYSA-N zaprinast Chemical compound CCCOC1=CC=CC=C1C1=NC(=O)C2=NNNC2=N1 REZGGXNDEMKIQB-UHFFFAOYSA-N 0.000 claims description 3
- 229950005371 zaprinast Drugs 0.000 claims description 3
- NPFVRBCDMFKOPY-UHFFFAOYSA-N 3-(4-imidazol-1-ylthiophen-2-yl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC(N2C=NC=C2)=CS1 NPFVRBCDMFKOPY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 230000006870 function Effects 0.000 claims description 2
- 229950002910 motapizone Drugs 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 29
- 229940024606 amino acid Drugs 0.000 description 193
- 235000001014 amino acid Nutrition 0.000 description 167
- 150000001413 amino acids Chemical class 0.000 description 159
- 230000002496 gastric effect Effects 0.000 description 78
- 239000003795 chemical substances by application Substances 0.000 description 62
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 61
- 229960001797 methadone Drugs 0.000 description 61
- 230000032258 transport Effects 0.000 description 55
- -1 propoxyhene Chemical compound 0.000 description 54
- 241000700159 Rattus Species 0.000 description 51
- 210000004027 cell Anatomy 0.000 description 47
- 239000000463 material Substances 0.000 description 39
- 230000000694 effects Effects 0.000 description 36
- 239000002253 acid Substances 0.000 description 35
- 206010010774 Constipation Diseases 0.000 description 30
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 24
- 229920001184 polypeptide Polymers 0.000 description 24
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 23
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 23
- 201000010099 disease Diseases 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 230000000968 intestinal effect Effects 0.000 description 23
- 229960001153 serine Drugs 0.000 description 23
- 235000004400 serine Nutrition 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 23
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 21
- 229960004441 tyrosine Drugs 0.000 description 19
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 description 18
- 229920002472 Starch Polymers 0.000 description 18
- 229940016286 microcrystalline cellulose Drugs 0.000 description 18
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 18
- 239000008108 microcrystalline cellulose Substances 0.000 description 18
- 229940032147 starch Drugs 0.000 description 18
- 235000019698 starch Nutrition 0.000 description 18
- 239000008107 starch Substances 0.000 description 18
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 17
- 235000002374 tyrosine Nutrition 0.000 description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- 239000002202 Polyethylene glycol Substances 0.000 description 16
- 229920001223 polyethylene glycol Polymers 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 102100034605 Atrial natriuretic peptide receptor 3 Human genes 0.000 description 15
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 15
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 15
- 101000924488 Homo sapiens Atrial natriuretic peptide receptor 3 Proteins 0.000 description 15
- 239000011248 coating agent Substances 0.000 description 15
- 238000000576 coating method Methods 0.000 description 15
- 229940029575 guanosine Drugs 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 229960005190 phenylalanine Drugs 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 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 13
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 13
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 13
- 229930195725 Mannitol Natural products 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 230000003203 everyday effect Effects 0.000 description 13
- 229960003136 leucine Drugs 0.000 description 13
- 235000010355 mannitol Nutrition 0.000 description 13
- 239000000594 mannitol Substances 0.000 description 13
- 229960001855 mannitol Drugs 0.000 description 13
- 229920001206 natural gum Polymers 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 229910021529 ammonia Inorganic materials 0.000 description 12
- 235000010980 cellulose Nutrition 0.000 description 12
- 229920002678 cellulose Polymers 0.000 description 12
- 239000001913 cellulose Substances 0.000 description 12
- 229920001577 copolymer Polymers 0.000 description 12
- 238000004132 cross linking Methods 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 229920000159 gelatin Polymers 0.000 description 12
- 235000019322 gelatine Nutrition 0.000 description 12
- 230000000670 limiting effect Effects 0.000 description 12
- 230000004048 modification Effects 0.000 description 12
- 238000012986 modification Methods 0.000 description 12
- 239000008188 pellet Substances 0.000 description 12
- 230000001629 suppression Effects 0.000 description 12
- 238000012384 transportation and delivery Methods 0.000 description 12
- 108010010803 Gelatin Proteins 0.000 description 11
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 11
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 11
- 235000010443 alginic acid Nutrition 0.000 description 11
- 229920000615 alginic acid Polymers 0.000 description 11
- 239000008273 gelatin Substances 0.000 description 11
- 235000011852 gelatine desserts Nutrition 0.000 description 11
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 10
- 229920003134 Eudragit® polymer Polymers 0.000 description 10
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
- 241001597008 Nomeidae Species 0.000 description 10
- 208000002193 Pain Diseases 0.000 description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 description 10
- 235000014113 dietary fatty acids Nutrition 0.000 description 10
- 229930195729 fatty acid Natural products 0.000 description 10
- 239000000194 fatty acid Substances 0.000 description 10
- 239000003292 glue Substances 0.000 description 10
- 229960001375 lactose Drugs 0.000 description 10
- 239000008101 lactose Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 238000003305 oral gavage Methods 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- 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 9
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 9
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 9
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 9
- 239000008896 Opium Substances 0.000 description 9
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 9
- 239000004473 Threonine Substances 0.000 description 9
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 230000003213 activating effect Effects 0.000 description 9
- 239000002270 dispersing agent Substances 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 9
- 229960001027 opium Drugs 0.000 description 9
- 229940126701 oral medication Drugs 0.000 description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 235000010356 sorbitol Nutrition 0.000 description 9
- 239000000600 sorbitol Substances 0.000 description 9
- 229960002898 threonine Drugs 0.000 description 9
- 235000008521 threonine Nutrition 0.000 description 9
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229920002907 Guar gum Polymers 0.000 description 8
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 8
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 8
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 8
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 8
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical group Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 description 8
- 238000011284 combination treatment Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000002702 enteric coating Substances 0.000 description 8
- 238000009505 enteric coating Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 235000013922 glutamic acid Nutrition 0.000 description 8
- 239000004220 glutamic acid Substances 0.000 description 8
- 235000010417 guar gum Nutrition 0.000 description 8
- 239000000665 guar gum Substances 0.000 description 8
- 229960002154 guar gum Drugs 0.000 description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 8
- 230000003834 intracellular effect Effects 0.000 description 8
- 239000007928 intraperitoneal injection Substances 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- 229960002160 maltose Drugs 0.000 description 8
- 235000012054 meals Nutrition 0.000 description 8
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 8
- 239000004014 plasticizer Substances 0.000 description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 210000002700 urine Anatomy 0.000 description 8
- 239000004474 valine Substances 0.000 description 8
- 229960004295 valine Drugs 0.000 description 8
- 229920001285 xanthan gum Polymers 0.000 description 8
- 235000004279 alanine Nutrition 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 235000010418 carrageenan Nutrition 0.000 description 7
- 229920001525 carrageenan Polymers 0.000 description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 7
- 235000018417 cysteine Nutrition 0.000 description 7
- 229960002433 cysteine Drugs 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 229960000310 isoleucine Drugs 0.000 description 7
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 7
- 239000000314 lubricant Substances 0.000 description 7
- 229920000609 methyl cellulose Polymers 0.000 description 7
- 235000010981 methylcellulose Nutrition 0.000 description 7
- 239000001923 methylcellulose Substances 0.000 description 7
- 229960002900 methylcellulose Drugs 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 108020004707 nucleic acids Proteins 0.000 description 7
- 102000039446 nucleic acids Human genes 0.000 description 7
- 150000007523 nucleic acids Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 235000010493 xanthan gum Nutrition 0.000 description 7
- 239000000230 xanthan gum Substances 0.000 description 7
- 229940082509 xanthan gum Drugs 0.000 description 7
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 6
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 6
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 6
- 206010015548 Euthanasia Diseases 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 6
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 6
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000000783 alginic acid Substances 0.000 description 6
- 229960001126 alginic acid Drugs 0.000 description 6
- 150000004781 alginic acids Chemical class 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- 235000003704 aspartic acid Nutrition 0.000 description 6
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 6
- 229940105329 carboxymethylcellulose Drugs 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- 230000002354 daily effect Effects 0.000 description 6
- 239000003405 delayed action preparation Substances 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229960000482 pethidine Drugs 0.000 description 6
- 229920001282 polysaccharide Polymers 0.000 description 6
- 239000005017 polysaccharide Substances 0.000 description 6
- 150000004804 polysaccharides Chemical class 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 210000000582 semen Anatomy 0.000 description 6
- 230000008961 swelling Effects 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 5
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 5
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 5
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 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 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 5
- 229920002774 Maltodextrin Polymers 0.000 description 5
- 239000005913 Maltodextrin Substances 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 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 5
- 230000009471 action Effects 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000008272 agar Substances 0.000 description 5
- 229940023476 agar Drugs 0.000 description 5
- 235000010419 agar Nutrition 0.000 description 5
- 229910052782 aluminium Inorganic materials 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 230000037396 body weight Effects 0.000 description 5
- 229960000846 camphor Drugs 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000013553 cell monolayer Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 238000005253 cladding Methods 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 5
- 239000010408 film Substances 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 5
- 235000004554 glutamine Nutrition 0.000 description 5
- 229960002885 histidine Drugs 0.000 description 5
- 229940035034 maltodextrin Drugs 0.000 description 5
- 229940063557 methacrylate Drugs 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229920001277 pectin Polymers 0.000 description 5
- 235000010987 pectin Nutrition 0.000 description 5
- 239000001814 pectin Substances 0.000 description 5
- 230000000149 penetrating effect Effects 0.000 description 5
- 238000010647 peptide synthesis reaction Methods 0.000 description 5
- 229920001983 poloxamer Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000029058 respiratory gaseous exchange Effects 0.000 description 5
- 210000005070 sphincter Anatomy 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 4
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 239000001856 Ethyl cellulose Substances 0.000 description 4
- 229930091371 Fructose Natural products 0.000 description 4
- 239000005715 Fructose Substances 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 4
- 229920000161 Locust bean gum Polymers 0.000 description 4
- 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 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229940072056 alginate Drugs 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 230000013872 defecation Effects 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 235000019325 ethyl cellulose Nutrition 0.000 description 4
- 229920001249 ethyl cellulose Polymers 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000008141 laxative Substances 0.000 description 4
- 230000002475 laxative effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000010420 locust bean gum Nutrition 0.000 description 4
- 239000000711 locust bean gum Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229960001639 penicillamine Drugs 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 235000010413 sodium alginate Nutrition 0.000 description 4
- 239000000661 sodium alginate Substances 0.000 description 4
- 229940005550 sodium alginate Drugs 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 150000005846 sugar alcohols Polymers 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- XLEKQZHPKBRJNB-BKLSDQPFSA-N (2r)-3-sulfanylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1NCCC1S XLEKQZHPKBRJNB-BKLSDQPFSA-N 0.000 description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 3
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 description 3
- LGFMXOTUSSVQJV-NEYUFSEYSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;1-[(3,4-dimethoxyphenyl)methyl]-6 Chemical compound Cl.Cl.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 LGFMXOTUSSVQJV-NEYUFSEYSA-N 0.000 description 3
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 3
- 206010000087 Abdominal pain upper Diseases 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 3
- 244000063299 Bacillus subtilis Species 0.000 description 3
- 235000014469 Bacillus subtilis Nutrition 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 3
- 102000011045 Chloride Channels Human genes 0.000 description 3
- 108010062745 Chloride Channels Proteins 0.000 description 3
- 208000000094 Chronic Pain Diseases 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 102000001189 Cyclic Peptides Human genes 0.000 description 3
- 108010069514 Cyclic Peptides Proteins 0.000 description 3
- 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 3
- 108020004414 DNA Proteins 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229920002148 Gellan gum Polymers 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 241000219480 Mesembryanthemum Species 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 3
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 108010009736 Protein Hydrolysates Proteins 0.000 description 3
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 3
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229960001391 alfentanil Drugs 0.000 description 3
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 3
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000000605 aspartame Substances 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 3
- 229960003438 aspartame Drugs 0.000 description 3
- 235000010357 aspartame Nutrition 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 3
- 229960001736 buprenorphine Drugs 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 235000001465 calcium Nutrition 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 239000008119 colloidal silica Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229960003461 dezocine Drugs 0.000 description 3
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 210000001842 enterocyte Anatomy 0.000 description 3
- 239000003797 essential amino acid Substances 0.000 description 3
- 235000020776 essential amino acid Nutrition 0.000 description 3
- 229940051147 fd&c yellow no. 6 Drugs 0.000 description 3
- 210000003608 fece Anatomy 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 229940060037 fluorine Drugs 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 3
- 235000010492 gellan gum Nutrition 0.000 description 3
- 239000000216 gellan gum Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000007453 hemicolectomy Methods 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 229940102223 injectable solution Drugs 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960003406 levorphanol Drugs 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 210000002751 lymph Anatomy 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 238000007726 management method Methods 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 229960002921 methylnaltrexone Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229960000805 nalbuphine Drugs 0.000 description 3
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 3
- OFYAYGJCPXRNBL-LBPRGKRZSA-N naphthalen-2-yl-3-alanine Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CC=CC2=C1 OFYAYGJCPXRNBL-LBPRGKRZSA-N 0.000 description 3
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 3
- 229960004300 nicomorphine Drugs 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 229960005118 oxymorphone Drugs 0.000 description 3
- 229960003294 papaveretum Drugs 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000006320 pegylation Effects 0.000 description 3
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 3
- 229960005301 pentazocine Drugs 0.000 description 3
- 229960003742 phenol Drugs 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 description 3
- 229950003779 propiram Drugs 0.000 description 3
- 229940043437 protein kinase A inhibitor Drugs 0.000 description 3
- 239000012656 protein kinase A inhibitor Substances 0.000 description 3
- 108010065251 protein kinase modulator Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 210000001187 pylorus Anatomy 0.000 description 3
- 229960003394 remifentanil Drugs 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000003229 sclerosing agent Substances 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 229940080313 sodium starch Drugs 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 3
- 229960004739 sufentanil Drugs 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 235000010215 titanium dioxide Nutrition 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-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
- 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 2
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- LORDFXWUHHSAQU-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LORDFXWUHHSAQU-UHFFFAOYSA-N 0.000 description 2
- JIMHYXZZCWVCMI-RIYZIHGNSA-N 4-[(e)-[4-oxo-2-sulfanylidene-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-5-ylidene]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1\C=C\1C(=O)N(C=2C=C(C=CC=2)C(F)(F)F)C(=S)S/1 JIMHYXZZCWVCMI-RIYZIHGNSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- SJQRQOKXQKVJGJ-UHFFFAOYSA-N 5-(2-aminoethylamino)naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(NCCN)=CC=CC2=C1S(O)(=O)=O SJQRQOKXQKVJGJ-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 101710095468 Cyclase Proteins 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 2
- 101001098806 Dictyostelium discoideum cGMP-specific 3',5'-cGMP phosphodiesterase 3 Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 102000000820 Enterotoxin Receptors Human genes 0.000 description 2
- 108010001687 Enterotoxin Receptors Proteins 0.000 description 2
- 229920003139 Eudragit® L 100 Polymers 0.000 description 2
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 229920001503 Glucan Polymers 0.000 description 2
- 102000005720 Glutathione transferase Human genes 0.000 description 2
- 108010070675 Glutathione transferase Proteins 0.000 description 2
- 235000005206 Hibiscus Nutrition 0.000 description 2
- 235000007185 Hibiscus lunariifolius Nutrition 0.000 description 2
- 244000284380 Hibiscus rosa sinensis Species 0.000 description 2
- 241000209219 Hordeum Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- QTYMDECKVKSGSM-YMUMJAELSA-N KT 5823 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CN(C)C(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@](OC)(C(=O)OC)[C@]4(C)O1 QTYMDECKVKSGSM-YMUMJAELSA-N 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 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
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 2
- OZYUPQUCAUTOBP-QXAKKESOSA-N Levallorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(CC=C)[C@@H]2CC2=CC=C(O)C=C21 OZYUPQUCAUTOBP-QXAKKESOSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000220225 Malus Species 0.000 description 2
- 241000219823 Medicago Species 0.000 description 2
- 235000009072 Mesembryanthemum Nutrition 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 241000209117 Panicum Species 0.000 description 2
- 235000006443 Panicum miliaceum subsp. miliaceum Nutrition 0.000 description 2
- 235000009037 Panicum miliaceum subsp. ruderale Nutrition 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 235000002634 Solanum Nutrition 0.000 description 2
- 241000207763 Solanum Species 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
- 241000219793 Trifolium Species 0.000 description 2
- 241001312519 Trigonella Species 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 241000209149 Zea Species 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229960002512 anileridine Drugs 0.000 description 2
- LKYQLAWMNBFNJT-UHFFFAOYSA-N anileridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 LKYQLAWMNBFNJT-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229950002202 asimadoline Drugs 0.000 description 2
- JHLHNYVMZCADTC-LOSJGSFVSA-N asimadoline Chemical compound C([C@@H](N(C)C(=O)C(C=1C=CC=CC=1)C=1C=CC=CC=1)C=1C=CC=CC=1)N1CC[C@H](O)C1 JHLHNYVMZCADTC-LOSJGSFVSA-N 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 229940093761 bile salts Drugs 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- LPPGGZUTTDVHJH-UHFFFAOYSA-N butan-1-amine piperazine Chemical compound N1CCNCC1.C(CCC)N LPPGGZUTTDVHJH-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-YPZZEJLDSA-N carbon-10 atom Chemical class [10C] OKTJSMMVPCPJKN-YPZZEJLDSA-N 0.000 description 2
- 150000001768 cations Chemical group 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 229940125400 channel inhibitor Drugs 0.000 description 2
- 210000000080 chela (arthropods) Anatomy 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 238000012321 colectomy Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 229960002069 diamorphine Drugs 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 2
- 229960004192 diphenoxylate Drugs 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 2
- 229950000484 exisulind Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 125000005313 fatty acid group Chemical group 0.000 description 2
- MVKIWCDXKCUDEH-QFIPXVFZSA-N fedotozine Chemical compound C([C@](CC)(N(C)C)C=1C=CC=CC=1)OCC1=CC(OC)=C(OC)C(OC)=C1 MVKIWCDXKCUDEH-QFIPXVFZSA-N 0.000 description 2
- 229950008449 fedotozine Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 206010016766 flatulence Diseases 0.000 description 2
- 229960002737 fructose Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 2
- 229960002743 glutamine Drugs 0.000 description 2
- 229940049654 glyceryl behenate Drugs 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 2
- 229960001410 hydromorphone Drugs 0.000 description 2
- 239000012051 hydrophobic carrier Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-AVRDEDQJSA-N 0.000 description 2
- 229960000263 levallorphan Drugs 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- 229940087121 levomethadyl Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 235000018977 lysine Nutrition 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000013379 molasses Nutrition 0.000 description 2
- 229960000938 nalorphine Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229960000292 pectin Drugs 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 238000006068 polycondensation reaction Methods 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 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 2
- 230000035945 sensitivity Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide 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
- 239000007787 solid Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 238000013223 sprague-dawley female rat Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- MVGSNCBCUWPVDA-MFOYZWKCSA-N sulindac sulfone Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)(=O)=O)C=C1 MVGSNCBCUWPVDA-MFOYZWKCSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940033663 thimerosal Drugs 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 150000003556 thioamides Chemical class 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 229960005345 trimebutine Drugs 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 229920003176 water-insoluble polymer Polymers 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- JFCBEFFZEOHJDG-MLWJPKLSSA-N (2s)-2,6-diamino-7-oxooctanoic acid Chemical compound CC(=O)C(N)CCC[C@H](N)C(O)=O JFCBEFFZEOHJDG-MLWJPKLSSA-N 0.000 description 1
- ULBLZIPFWGIOJF-QMMMGPOBSA-N (2s)-2-(bromoamino)-3-phenylpropanoic acid Chemical compound OC(=O)[C@@H](NBr)CC1=CC=CC=C1 ULBLZIPFWGIOJF-QMMMGPOBSA-N 0.000 description 1
- YYTDJPUFAVPHQA-VKHMYHEASA-N (2s)-2-amino-3-(2,3,4,5,6-pentafluorophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=C(F)C(F)=C(F)C(F)=C1F YYTDJPUFAVPHQA-VKHMYHEASA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- OPOTYPXOKUZEKY-QMMMGPOBSA-N (2s)-2-nitramido-3-phenylpropanoic acid Chemical compound [O-][N+](=O)N[C@H](C(=O)O)CC1=CC=CC=C1 OPOTYPXOKUZEKY-QMMMGPOBSA-N 0.000 description 1
- GIANIJCPTPUNBA-QMMMGPOBSA-N (2s)-3-(4-hydroxyphenyl)-2-nitramidopropanoic acid Chemical compound [O-][N+](=O)N[C@H](C(=O)O)CC1=CC=C(O)C=C1 GIANIJCPTPUNBA-QMMMGPOBSA-N 0.000 description 1
- DXAUAWUGCKCSFC-NSHDSACASA-N (2s)-3-phenyl-2-(prop-2-ynoxyamino)propanoic acid Chemical compound C#CCON[C@H](C(=O)O)CC1=CC=CC=C1 DXAUAWUGCKCSFC-NSHDSACASA-N 0.000 description 1
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- 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 1
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical group CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 description 1
- KXSKAZFMTGADIV-UHFFFAOYSA-N 2-[3-(2-hydroxyethoxy)propoxy]ethanol Chemical compound OCCOCCCOCCO KXSKAZFMTGADIV-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-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
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- WXLPKTIAUMCNDX-UHFFFAOYSA-N 2h-pyran-3-ol Chemical compound OC1=CC=COC1 WXLPKTIAUMCNDX-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- JPZXHKDZASGCLU-GFCCVEGCSA-N 3-(2-Naphthyl)-D-Alanine Chemical compound C1=CC=CC2=CC(C[C@@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-GFCCVEGCSA-N 0.000 description 1
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 1
- ZELFLGGRLLOERW-YECZQDJWSA-N 3-[(2r,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 ZELFLGGRLLOERW-YECZQDJWSA-N 0.000 description 1
- YPLZVJKSYBUKBU-UHFFFAOYSA-N 3-amino-4-methylchromen-2-one Chemical compound C1=CC=CC2=C1OC(=O)C(N)=C2C YPLZVJKSYBUKBU-UHFFFAOYSA-N 0.000 description 1
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 1
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- JZRBSTONIYRNRI-VIFPVBQESA-N 3-methylphenylalanine Chemical compound CC1=CC=CC(C[C@H](N)C(O)=O)=C1 JZRBSTONIYRNRI-VIFPVBQESA-N 0.000 description 1
- FBTSQILOGYXGMD-LURJTMIESA-N 3-nitro-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C([N+]([O-])=O)=C1 FBTSQILOGYXGMD-LURJTMIESA-N 0.000 description 1
- IRZQDMYEJPNDEN-UHFFFAOYSA-N 3-phenyl-2-aminobutanoic acid Natural products OC(=O)C(N)C(C)C1=CC=CC=C1 IRZQDMYEJPNDEN-UHFFFAOYSA-N 0.000 description 1
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- VFTOHJFKIJLYKN-UHFFFAOYSA-N 7-nitro-9h-fluoren-2-ol Chemical group [O-][N+](=O)C1=CC=C2C3=CC=C(O)C=C3CC2=C1 VFTOHJFKIJLYKN-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 102000003678 AMPA Receptors Human genes 0.000 description 1
- 108090000078 AMPA Receptors Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WWXUGNUFCNYMFK-UHFFFAOYSA-N Acetyl citrate Chemical compound CC(=O)OC(=O)CC(O)(C(O)=O)CC(O)=O WWXUGNUFCNYMFK-UHFFFAOYSA-N 0.000 description 1
- 241000219068 Actinidia Species 0.000 description 1
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 241000349737 Afzelia africana Species 0.000 description 1
- 240000000972 Agathis dammara Species 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 244000080767 Areca catechu Species 0.000 description 1
- 235000006226 Areca catechu Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 235000012035 Boswellia serrata Nutrition 0.000 description 1
- 240000007551 Boswellia serrata Species 0.000 description 1
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 1
- 241000565319 Butea monosperma Species 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 244000281594 Cassia siamea Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 241000723343 Cichorium Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000016649 Copaifera officinalis Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 244000024469 Cucumis prophetarum Species 0.000 description 1
- 235000010071 Cucumis prophetarum Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 229920002871 Dammar gum Polymers 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 208000034423 Delivery Diseases 0.000 description 1
- 241000350046 Detarium Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000533845 Enterolobium cyclocarpum Species 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- RZSYLLSAWYUBPE-UHFFFAOYSA-L Fast green FCF Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC(O)=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 RZSYLLSAWYUBPE-UHFFFAOYSA-L 0.000 description 1
- 235000007162 Ferula assa foetida Nutrition 0.000 description 1
- 244000303564 Ferula assa foetida Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 241001412225 Firmiana simplex Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 108010061711 Gliadin Proteins 0.000 description 1
- 229920002581 Glucomannan Polymers 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 241000451105 Hakea gibbosa Species 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 101000693243 Homo sapiens Paternally-expressed gene 3 protein Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 244000162475 Juniperus rigida Species 0.000 description 1
- 235000009069 Juniperus rigida Nutrition 0.000 description 1
- 241000557752 Khaya Species 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 235000002262 Lycopersicon Nutrition 0.000 description 1
- 241000227653 Lycopersicon Species 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000057 Mannan Polymers 0.000 description 1
- 101710085938 Matrix protein Proteins 0.000 description 1
- 101710127721 Membrane protein Proteins 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241001057584 Myrrha Species 0.000 description 1
- OLYPWXRMOFUVGH-LURJTMIESA-N N(2)-methyl-L-lysine Chemical compound CN[C@H](C(O)=O)CCCCN OLYPWXRMOFUVGH-LURJTMIESA-N 0.000 description 1
- MXNRLFUSFKVQSK-QMMMGPOBSA-O N(6),N(6),N(6)-trimethyl-L-lysine Chemical compound C[N+](C)(C)CCCC[C@H]([NH3+])C([O-])=O MXNRLFUSFKVQSK-QMMMGPOBSA-O 0.000 description 1
- PQNASZJZHFPQLE-LURJTMIESA-N N(6)-methyl-L-lysine Chemical compound CNCCCC[C@H](N)C(O)=O PQNASZJZHFPQLE-LURJTMIESA-N 0.000 description 1
- RYFOQDQDVYIEHN-ZETCQYMHSA-N N,N-Dimethyllysine Chemical compound CN(C)[C@H](C(O)=O)CCCCN RYFOQDQDVYIEHN-ZETCQYMHSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-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
- NPKISZUVEBESJI-AWEZNQCLSA-N N-benzoyl-L-phenylalanine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 NPKISZUVEBESJI-AWEZNQCLSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 101100386053 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cys-3 gene Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- GEYBMYRBIABFTA-VIFPVBQESA-N O-methyl-L-tyrosine Chemical compound COC1=CC=C(C[C@H](N)C(O)=O)C=C1 GEYBMYRBIABFTA-VIFPVBQESA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 240000004371 Panax ginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 102100025757 Paternally-expressed gene 3 protein Human genes 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 241000745991 Phalaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- 241000746981 Phleum Species 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229920000175 Pistacia lentiscus Polymers 0.000 description 1
- 241001092090 Pittosporum Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241001085296 Primula x polyantha Species 0.000 description 1
- 241000052235 Prosopis africana Species 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 241000190932 Rhodopseudomonas Species 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 240000000203 Salix gracilistyla Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241001302210 Sida <water flea> Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 235000015125 Sterculia urens Nutrition 0.000 description 1
- 240000001058 Sterculia urens Species 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 102400000096 Substance P Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 0.000 description 1
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical compound CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 description 1
- 240000004584 Tamarindus indica Species 0.000 description 1
- 235000004298 Tamarindus indica Nutrition 0.000 description 1
- 241000736873 Tetraclinis articulata Species 0.000 description 1
- 241000218636 Thuja Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000013607 Treculia africana Nutrition 0.000 description 1
- 244000201269 Treculia africana Species 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 102400000230 Uroguanylin Human genes 0.000 description 1
- 101800000255 Uroguanylin Proteins 0.000 description 1
- 241000978782 Vachellia seyal Species 0.000 description 1
- 241001541238 Vachellia tortilis subsp. raddiana Species 0.000 description 1
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 1
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 1
- 240000001866 Vernicia fordii Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229920002310 Welan gum Polymers 0.000 description 1
- 241001532014 Xanthorrhoea Species 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- ZNOZWUKQPJXOIG-XSBHQQIPSA-L [(2r,3s,4r,5r,6s)-6-[[(1r,3s,4r,5r,8s)-3,4-dihydroxy-2,6-dioxabicyclo[3.2.1]octan-8-yl]oxy]-4-[[(1r,3r,4r,5r,8s)-8-[(2s,3r,4r,5r,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-sulfonatooxyoxan-2-yl]oxy-4-hydroxy-2,6-dioxabicyclo[3.2.1]octan-3-yl]oxy]-5-hydroxy-2-( Chemical compound O[C@@H]1[C@@H](O)[C@@H](OS([O-])(=O)=O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H]2OC[C@H]1O[C@H](O[C@H]1[C@H]([C@@H](CO)O[C@@H](O[C@@H]3[C@@H]4OC[C@H]3O[C@H](O)[C@@H]4O)[C@@H]1O)OS([O-])(=O)=O)[C@@H]2O ZNOZWUKQPJXOIG-XSBHQQIPSA-L 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 108091006088 activator proteins Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- SOGAXMICEFXMKE-UHFFFAOYSA-N alpha-Methyl-n-butyl acrylate Natural products CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 1
- HYOWVAAEQCNGLE-JTQLQIEISA-N alpha-methyl-L-phenylalanine Chemical compound OC(=O)[C@](N)(C)CC1=CC=CC=C1 HYOWVAAEQCNGLE-JTQLQIEISA-N 0.000 description 1
- UPNUIXSCZBYVBB-JVFUWBCBSA-N alvimopan Chemical compound C([C@@H](CN1C[C@@H]([C@](CC1)(C)C=1C=C(O)C=CC=1)C)C(=O)NCC(O)=O)C1=CC=CC=C1 UPNUIXSCZBYVBB-JVFUWBCBSA-N 0.000 description 1
- 229960004516 alvimopan Drugs 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 229920005601 base polymer Polymers 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229940092782 bentonite Drugs 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
- XSIFPSYPOVKYCO-UHFFFAOYSA-N benzoic acid butyl ester Natural products CCCCOC(=O)C1=CC=CC=C1 XSIFPSYPOVKYCO-UHFFFAOYSA-N 0.000 description 1
- 229960002130 benzoin Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 235000012745 brilliant blue FCF Nutrition 0.000 description 1
- 239000004161 brilliant blue FCF Substances 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000010238 camphora Substances 0.000 description 1
- 229940025250 camphora Drugs 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- IYRWEQXVUNLMAY-UHFFFAOYSA-N carbonyl fluoride Chemical compound FC(F)=O IYRWEQXVUNLMAY-UHFFFAOYSA-N 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- CEZCCHQBSQPRMU-UHFFFAOYSA-L chembl174821 Chemical compound [Na+].[Na+].COC1=CC(S([O-])(=O)=O)=C(C)C=C1N=NC1=C(O)C=CC2=CC(S([O-])(=O)=O)=CC=C12 CEZCCHQBSQPRMU-UHFFFAOYSA-L 0.000 description 1
- ATLYLVPZNWDJBW-KIHHCIJBSA-N chembl3137313 Chemical compound NC(=O)C1=CC=CC([C@H]2C[C@H]3CC[C@H](N3CCN(CC3CCCCC3)C(=O)[C@@H](O)CO)C2)=C1 ATLYLVPZNWDJBW-KIHHCIJBSA-N 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- ORQXBVXKBGUSBA-UHFFFAOYSA-N cyclohexyl D-alanine Natural products OC(=O)C(N)CC1CCCCC1 ORQXBVXKBGUSBA-UHFFFAOYSA-N 0.000 description 1
- 229940021746 d- serine Drugs 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229950006137 dexfosfoserine Drugs 0.000 description 1
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- 108700029474 dinitrophenyl-polylysine Proteins 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- LQJVOKWHGUAUHK-UHFFFAOYSA-L disodium 5-amino-4-hydroxy-3-phenyldiazenylnaphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].OC1=C2C(N)=CC(S([O-])(=O)=O)=CC2=CC(S([O-])(=O)=O)=C1N=NC1=CC=CC=C1 LQJVOKWHGUAUHK-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 210000000887 face Anatomy 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 235000019240 fast green FCF Nutrition 0.000 description 1
- 150000002187 fatty acyl carnitines Chemical class 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000004459 forage Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940046240 glucomannan Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 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 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000010985 glycerol esters of wood rosin Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 239000011019 hematite Substances 0.000 description 1
- 229910052595 hematite Inorganic materials 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 208000008384 ileus Diseases 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229940097275 indigo Drugs 0.000 description 1
- KHLVKKOJDHCJMG-QDBORUFSSA-L indigo carmine Chemical compound [Na+].[Na+].N/1C2=CC=C(S([O-])(=O)=O)C=C2C(=O)C\1=C1/NC2=CC=C(S(=O)(=O)[O-])C=C2C1=O KHLVKKOJDHCJMG-QDBORUFSSA-L 0.000 description 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- 239000004179 indigotine Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003871 intestinal function Effects 0.000 description 1
- 210000002011 intestinal secretion Anatomy 0.000 description 1
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 1
- 229920000554 ionomer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 229940025902 konjac mannan Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229950008325 levothyroxine Drugs 0.000 description 1
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000003750 lower gastrointestinal tract Anatomy 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 108010077127 lymphoguanylin Proteins 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 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
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000007498 myristoylation Effects 0.000 description 1
- SHDMMLFAFLZUEV-UHFFFAOYSA-N n-methyl-1,1-diphenylmethanamine Chemical compound C=1C=CC=CC=1C(NC)C1=CC=CC=C1 SHDMMLFAFLZUEV-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- XNKCCCKFOQNXKV-ZRSCBOBOSA-N naloxegol Chemical compound C([C@@H](N(CC1)CC=C)[C@]2(O)CC[C@@H]3OCCOCCOCCOCCOCCOCCOCCOC)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 XNKCCCKFOQNXKV-ZRSCBOBOSA-N 0.000 description 1
- 229960005171 naloxegol 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
- 229960004127 naloxone Drugs 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 239000003887 narcotic antagonist Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- XHTJLMYQJHCUPE-UHFFFAOYSA-N phosphanylphosphonic acid Chemical compound OP(O)(P)=O XHTJLMYQJHCUPE-UHFFFAOYSA-N 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 238000007699 photoisomerization reaction Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 229920000867 polyelectrolyte Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920006267 polyester film Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 150000003355 serines Chemical class 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000036259 sexual stimuli Effects 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- MSXHSNHNTORCAW-GGLLEASOSA-M sodium;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].O[C@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O MSXHSNHNTORCAW-GGLLEASOSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940100515 sorbitan Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 210000004514 sphincter of oddi Anatomy 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- 230000035322 succinylation Effects 0.000 description 1
- 238000010613 succinylation reaction Methods 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960004143 tapentadol hydrochloride Drugs 0.000 description 1
- 235000010491 tara gum Nutrition 0.000 description 1
- 239000000213 tara gum Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 210000000779 thoracic wall Anatomy 0.000 description 1
- 229960001402 tilidine Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- SJMPVWVIVWEWJK-AXEIBBKLSA-N uroguanylin Chemical compound SC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(N)=O SJMPVWVIVWEWJK-AXEIBBKLSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229920001221 xylan Polymers 0.000 description 1
- 150000004823 xylans Chemical class 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 229940006486 zinc cation Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 244000089265 zong er cha Species 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/51—Lyases (4)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本公开内容提供预防、控制和/或治疗阿片样物质诱导的功能障碍的方法,所述方法包括将鸟苷酸环化酶受体激动剂(GCRA)肽给予有需要的患者。还公开了包含鸟苷酸环化酶受体激动剂(GCRA)肽的组合物、制备方法和治疗方法。进一步公开了在同一组合物中配制的鸟苷酸环化酶受体激动剂(GCRA)肽和阿片样物质。
Description
相关申请的交叉引用
本申请要求2013年10月10日提交的美国临时申请号61/889,308的权益,其通过引用以其整体结合到本文中用于所有目的。
发明领域
本发明涉及鸟苷酸环化酶C (GC-C)激动剂治疗阿片样物质诱导的功能障碍,例如阿片样物质诱导的肠功能障碍、阿片样物质诱导的食道功能障碍和阿片样物质诱导的呼吸抑制的治疗应用。该激动剂可以单独使用或与其它活性剂同时或序贯使用以预防、治疗或减轻一种或多种阿片样物质诱导的功能障碍。
发明背景
阿片样物质是用于癌症和非癌症患者的疼痛管理的有效的和广泛使用的药物。然而,阿片样物质的使用常常具有致人虚弱的不良作用,例如阿片样物质诱导的功能障碍,包括呼吸抑制、食道功能障碍、内分泌破坏和阿片样物质诱导的肠功能障碍(OIBD),这包括阿片样物质诱导的便秘、口干、恶心、呕吐、胃潴留、胃气胀和腹痛。
需要对治疗和防止阿片样物质的副作用的组合物和方法。
发明背景
本发明提供通过给予有需要的受试者治疗有效量的包括鸟苷酸环化酶受体激动剂(GCRA)肽的组合物来防止、治疗阿片样物质诱导的功能障碍的病况或减轻其症状的方法。组合物可进一步包含阿片样物质和/或依赖cGMP的磷酸二酯酶抑制剂。在一个实施方案中,组合物包含鸟苷酸环化酶受体激动剂(GCRA)肽和阿片样物质。在又一个实施方案中,鸟苷酸环化酶受体激动剂(GCRA)肽和阿片样物质被配制在同一胶囊剂或片剂中。在又一个实施方案中,阿片样物质选自吗啡、可待因、羟考酮、氢可酮、二氢可待因、丙氧芬、芬太尼、曲马多、洛哌丁胺、布托啡诺或其组合。
本发明的组合物可进一步包含药用载体、赋形剂或稀释剂。在一个实施方案中,组合物包含选自以下的一种或多种靶向物质:pH依赖性聚合物、可膨胀聚合物和可降解组合物。在又一个实施方案中,使组合物制剂优化以递送至十二指肠、空肠、回肠、回肠末端或升结肠。在又一个实施方案中,使组合物制剂优化以在整个结肠中释放。在另一个实施方案中,组合物包含在4.5-5.5的pH范围下、在5.5-6.5的pH范围下或在6.5-7.5的pH范围下降解的一种或多种pH依赖性聚合物。在再一个实施方案中,配制组合物以时间依赖性方式释放。
本文所述方法可进一步包括给予受试者有效剂量的依赖cGMP的磷酸二酯酶抑制剂的步骤。例如,依赖cGMP的磷酸二酯酶抑制剂是舒林砜(sulindac sulfone)、扎普司特、莫他匹酮、伐地那非或西地那非。依赖cGMP的磷酸二酯酶抑制剂可与GCRA肽或其药物组合物同时或序贯给予。
本发明还提供包括阿片样物质和GCRA肽的组合物。组合物可另包括药用载体、赋形剂或稀释剂。
可用于本发明的任何方法或任何组合物的GCRA肽具有表2-8的任一个的氨基酸序列。例如,GCRA肽为SEQ ID NO: 1 (SP-304)、SEQ ID NO: 9 (SP-333)、SP373 (SEQ ID NO:104)、SP364 (SEQ ID NO: 100)、SP366 (SEQ ID NO: 102)或SEQ ID NO: 250。
附图简述
图1是显示尿鸟苷肽(uroguanylin)和SP-333的一级结构的图示。描述了氨基酸的单字母缩略语。SP-333与UG类似,只是UG的N端3位的天冬氨酸(D)被谷氨酸(E)取代。此外,两端的氨基酸被其各自的D-立体异构体置换。尿鸟苷肽以及SP-333具有4个半胱氨酸(C)残基,使得能够形成2个分子内二硫键。SP-333中取代的氨基酸用黑体字表示。
图2是显示环状CMP和环状AMP缓解阿片样物质诱导的肠功能障碍(OBD)的作用机制的方案。
图3A-B是显示用SP-333的顶端处理刺激跨T-84细胞单层和大鼠空肠的Isc的系列图。在将T84细胞(A)和大鼠空肠组织(B)用SP-333治疗后检出氯离子电流的浓度依赖性增加(以Isc的增加测量)。诱导Cl-电流的半最大增加(EC50)的SP-333的浓度在细胞和组织间相当;分别为1.69 x 10-7 M和2.99 x 10-7 M。值表示为均值± S.E.M.,n=4。将在Ussing室中固定的T84细胞和幼稚大鼠空肠在顶室中进行不同SP-333浓度的处理,记录最大Isc刺激,并作图。
图4A-B是显示用SP-333的顶端处理通过激活PKG-II和CFTR刺激Isc的系列图。在响应用指定抑制剂处理时,T84细胞(A)和大鼠空肠(B)中SP-333 (1 µM)的调节刺激顶端Isc。按实施例1所述,将T84细胞和大鼠空肠固定在顶侧和底外侧用各自的缓冲液浸浴的Ussing室中。为了评价PKA和PKG-II所起的作用,并且为了鉴定CFTR和CIC-2对于激动剂介导的Cl-离子的释放的相对贡献,在激酶和Cl-通道抑制剂存在和不存在时进行了实验。所用抑制剂为CdCl2 (CIC-2抑制剂;Sigma-Aldrich;St Louis,MO)、CFTRinh172 (CFTR抑制剂;Santa Cruz Biotech;Dallas,Texas)、KT5823 (PKG抑制剂;R&D Systems,Minneapolis,MN)、mPKI (PKA抑制剂;EMD Millipore;Billerica,MA)。在加入1 μM SP-333之前,T84细胞(n=4个跨孔(transwell)/条件)和大鼠空肠组织(n=4-6个制备物/条件)的顶表面用规定浓度的各抑制剂预处理5分钟。记录在加入SP-333之后达到的Isc的峰值,以百分比相对活性± SEM为单位计算。
图5A-B是显示吗啡不会不利影响SP-333刺激的Isc的系列图。T84细胞(A)和大鼠空肠(B)用5 µM吗啡在顶侧预处理5分钟。随后,将1 µM SP-333加入顶室,记录Isc的刺激。将在阿片样物质不存在时记录的电流视为100%。对相对Isc作图。值表示为均值±S.E.M.,对于T84细胞n = 3,对于大鼠空肠n = 5-13。
图6A-B是显示美沙酮不会不利影响SP-333刺激的Isc的系列图。T84细胞(A)和大鼠空肠(B)用5µM美沙酮在顶侧预处理5分钟。随后,将1 µM SP-333加入顶室中,记录Isc的刺激。将在阿片样物质不存在时记录的电流视为100%。对相对Isc作图。对于各阿片样物质,值表示为均值± S.E.M.,对于T84细胞n = 3,对于大鼠空肠n = 5-13。
图7A-B是显示用SP-333的口服治疗提高大鼠的GI运送的系列图。左组图显示SP-333剂量方案。图A是显示在阿片样物质幼稚动物中0.05、0.5和5 mg/kg的SP-333分别提高GI运送达5.6%、13%和23%的柱状图。图B是显示每个个别动物的数据的分布图。
图8A-B是显示在吗啡治疗后用SP-333口服治疗改善GI运送的系列图。通过IP注射将规定剂量的吗啡给予雌性Sprague-Dawley大鼠,并按实施例1所述评价GI运送。吗啡显著降低大鼠的GI运送(A)。与溶媒对照相比,在0.25、1.0和2.5 mg/kg阿片样物质的单一吗啡剂量后GI运送分别减慢52%、56%和56%。通过IP注射给予2.5 mg/kg吗啡,接着通过经口管饲给予规定量的SP-333,并按实施例1所述评价了GI运送,检查了SP-333减少吗啡诱导的GI运行延迟的能力。吗啡显著降低GI运送(23%对比溶媒处理中的53%;p<0.0001)。(B)与仅给予吗啡组相比,除0.5 mg/kg以外的所有剂量下,观察到在SP-333治疗后GI运送的剂量依赖性增加:在0.5、2.5、5和50 mg/kg下分别为27%、37%、46%和48% (P ≤0.002)。A和B中描述了GI运送均值± SEM。
图9A-B是显示在美沙酮治疗后用SP-333口服治疗改善GI运送的系列图。在给予0.25、2.5和5 mg/kg美沙酮的大鼠中观察到GI运送的统计显著性降低(A)。在2.5 mg/kg美沙酮下观察到的GI运送延迟与用相同剂量的吗啡观察到的相当(对于美沙酮和吗啡,相对于相应的溶媒对照分别为49%和56%)。给予SP-333在美沙酮处理的大鼠产生肠运送的剂量依赖性改善:在0.5、2.5、5和50 mg/kg下分别为40%、39%、44%和52% (在所有剂量下P≤0.01)。A和B中描述了GI运送均值± SEM。
图10A-B是显示在美沙酮处理后用SP-333每日一次治疗使GI运送正常并恢复粪便排出的系列图。通过给予2.5、5和7.5 mg/kg美沙酮的日剂量7天在大鼠中引起便秘。记录在光周期期间在给药后4小时内的平均粪便排出。在美沙酮的所有剂量下观察到粪便排出的统计显著性降低。为了评价SP-333缓解美沙酮诱导的便秘的能力,每日一次给予大鼠5 mg/kg美沙酮持续7天。在美沙酮给药后10分钟给予SP-333,如上所述监测粪便排出。给予美沙酮处理的动物2.5 mg/kg的SP-333显著缓解美沙酮诱导的便秘(B)。每治疗组粪粒的平均数± SEM描述于A和B。
图11是显示每日口服给予SP-333缓解因重复给予美沙酮引起的GI运送延迟的图示。在每日一次给予大鼠5 mg/kg美沙酮持续7天,接着再给予2.5 mg/kg持续一周后,监测重复给予美沙酮对GI运送的作用。在测试当日,给予大鼠2.5 mg/kg美沙酮,接着通过经口管饲给予2.5和5 mg/kg的SP-333。按实施例1所述计算GI运送,并以GI运送均值± SEM作图。美沙酮处理导致GI运送显著降低。然而,在给予SP-333的动物中观察到GI运送延迟的统计显著性改善。
图12是表明SP-333介导的阿片样物质诱导的GI运送延迟的减轻的机制的示意图。吗啡和美沙酮在外周激活表达的阿片样物质受体以引发下游信号转导,导致因抑制影响神经递质释放的腺苷酸环化酶所致的cAMP水平下降。因此,GI推进、蠕动和流体分泌受损,连同自肠腔的流体和电解质吸收增加,导致OIBD的出现。通过停留在肠细胞的GC-C受体上,SP-333促进胞内cGMP的合成和蓄积,这进而通过抑制磷酸二酯酶3而直接或间接结合并激活PKG-II。PKG-II可使CFTR通道磷酸化并将其激活以促进Cl-离子的流出,接着Na+和水分被动流出进入肠腔,从而有利大便。虽然美沙酮可抑制CIC-2,但SP-333介导的Cl-从T84细胞和大鼠空肠组织中的分泌却是通过PKG-II和CFTR。
发明详述
应了解,出于方便整个本申请中使用单数形式例如“a”、“an”和“the”,然而,除非文中或明确陈述另有说明,否则单数形式欲包括复数。另外,应了解本文提及的每份杂志文章、专利、专利申请、出版物等通过引用以其整体结合到本文中并用于所有目的。所有数值范围应理解为包括该数值范围内每一个数值点,并应解释为分别记载每一个数值点。涉及相同组分或性质的所有范围的终点也包括在内,并且旨在是可独立组合的。
“约”包括具有基本相同的作用或提供基本相同的结果的所有值作为提及值。因此,术语“约”所包括的范围将随其中使用该术语的上下文而变化,例如提及值与之有关的参数。因此,根据上下文,“约”可意指例如±15%、±10%、±5%、±4%、±3%、±2%、±1%或±小于1%。重要的是,术语“约”之后的提及值的所有记载还欲为仅对该提及值的记载。
本发明基于鸟苷酸环化酶-C (GC-C)的激动剂的开发。激动剂为尿鸟苷肽、鸟苷肽、淋巴鸟苷肽(lymphoguanylin)和大肠杆菌(E .coli) ST肽的类似物。
阿片样物质广泛用于治疗慢性疼痛,但其消耗常与各种副作用有关。阿片样物质诱导的功能障碍包括呼吸抑制、内分泌破坏、食道功能障碍和阿片样物质诱导的肠功能障碍。阿片样物质诱导的功能障碍影响胃肠道,其中在对标准轻泻药不是非常有效的人中常观察到的严重便秘。这种副作用是由流体分泌减少所致,影响胃肠(GI)蠕动和大便(BM)。表1列出阿片样物质的有害作用及其临床作用的几个非限制性实例。本发明部分基于使用GC-C激动剂治疗阿片样物质诱导的功能障碍的发现。尿鸟苷肽的类似物激活鸟苷酸环化酶-C/cGMP (GC-C/cGMP)信号转导以提高肠腔的流体分泌以使GI蠕动和BM正常,并可用于治疗阿片样物质诱导的便秘(OIC)。该治疗使由吗啡或美沙酮引起的GI运送延迟完全恢复。
表1:阿片样物质对胃肠道的作用
因此,本发明还提供通过给予有需要的受试者治疗有效量的GC-C激动剂预防、治疗或减轻阿片样物质诱导的功能障碍的症状的方法。
本发明的GC-C激动剂包括式I-XX所示氨基酸序列以及下表2-8中概括的那些氨基酸序列。本发明的GC-C激动剂在本文统称为“GCRA肽”。在一些实施方案中,GC-C激动剂具有SEQ ID NO: 1 (SP-304)、SEQ ID NO: 9 (SP-333)、SP373 (SEQ ID NO: 104)、SP364 (SEQID NO: 100)、SP366 (SEQ ID NO: 102)或SEQ ID NO: 250的序列。
所谓“阿片样物质”意指包括但不限于阿芬太尼、阿尼利定、阿西马多林、布马佐辛、丁丙诺啡、布托啡诺、可待因、地佐辛、二乙酰吗啡(海洛因)、二氢可待因、地芬诺酯、乙基吗啡、非多托秦、芬太尼、氟曲沙胺、氢可酮、氢吗啡酮、左洛啡烷、左醋美沙朵、左啡诺、洛哌丁胺、麦啶(哌替啶)、美沙酮、吗啡、吗啡-6-葡萄糖醛酸酐、纳布啡、烯丙吗啡、尼可吗啡、阿片、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、丙吡兰、丙氧芬、瑞芬太尼(remifentanyl)、舒芬太尼、替利定、曲美布汀和曲马多。
本文所用“阿片样物质诱导的功能障碍”和“阿片样物质使用的副作用”在本文互换使用,包括例如胃肠功能障碍(例肠蠕动的抑制、便秘、GI括约肌收缩、恶心、呕(呕吐))、胆痉挛、阿片样物质肠功能障碍、绞痛、病理性心境恶劣、瘙痒、尿潴留、呼吸抑制、瞳孔收缩(papillary constriction)、心血管作用、胸壁僵硬和咳嗽抑制、应激反应衰退和与使用麻醉性镇痛药有关的免疫抑制或其组合。因此,从经历使用阿片样物质的受试者的生命质量的观点来看,本发明的方法可能是有益的,以及有益于减轻产生于慢性便秘的例如痔、食欲抑制、粘膜破坏、脓毒症、结肠癌风险和心肌梗死等并发症。
在一些实施方案中,所提供的GC-C激动剂可用于给予经历急性阿片样物质使用的受试者。在一些实施方案中,所提供的制剂可用于给予患有术后胃肠功能障碍、肠功能障碍或呼吸抑制的患者。
在某些实施方案中,所提供的制剂还可用于给予经历慢性阿片样物质使用的受试者(例如接受阿片样物质疗法的临终疾病患者,例如AIDS患者、癌症患者、心血管患者;接受慢性阿片样物质疗法用于疼痛管理的受试者;经历阿片样物质疗法用于维持阿片样物质戒断的受试者)。在一些实施方案中,受试者是使用阿片样物质疗法用于慢性疼痛管理的受试者。在某些实施方案中,疼痛是非恶性疼痛(例如背痛、神经性疼痛、与纤维肌痛有关的疼痛、骨关节炎)。在一些实施方案中,受试者是临终疾病患者。在其它实施方案中,受试者是经历阿片样物质戒断维持疗法的人。
在某些实施方案中,将本文提供的制剂给予经选择用美沙酮或甲基纳曲酮治疗的受试者。在具体的实施方案中,受试者根据有发生上述一种或多种病况的风险增加的受试者来选择。在另一个实施方案中,受试者根据用于疼痛管理的阿片样物质疗法的使用或根据具有上述一种或多种病况来选择。在某些实施方案中,受试者患便秘或有因阿片样物质疗法引起的便秘史。在一个实施方案中,患便秘的受试者在前三天没有大便。在一个实施方案中,患便秘的受试者在前一周内有不到3次大便。在某些实施方案中,患便秘的受试者在最近的连续4周内平均每周有不到3次无拯救(rescue-free)大便和有以下的一种或多种:(a)大便硬结或呈块状,(b)大便时过度用力,和/或(c)大便后感到未完全排空。受试者可能间断性或习惯性地使用阿片样物质。
在一个实施方案中,经选择的受试者曾按需服食阿片样物质。在一个实施方案中,经选择的受试者曾服食阿片样物质少于一周。在一个实施方案中,经选择的受试者在至少一周的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少两周的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少三周的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少四周的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少3个月的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少6个月的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少12个月的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在超过一年的进程内曾服食阿片样物质。在另一个实施方案中,经选择的受试者在至少两周的进程内至少每隔一天服食阿片样物质。在一个实施方案中,经选择的受试者在至少14天内接受至少7剂>25 mg的口服吗啡等同物。在一个实施方案中,经选择的受试者在至少14天内接受>50 mg口服吗啡等同物的日剂量。在一个实施方案中,经选择的受试者因阿片样物质疗法所致患有便秘并接受>50 mg口服吗啡等同物的日剂量至少14天。在某些实施方案中,受试者接受>50 mg口服吗啡等同物的日剂量至少14天;在至少连续4周内平均每周有与以下一种或多种有关的少于3次无拯救大便:(a)对于至少25%的无拯救大便,Bristol大便形状标度(Bristol Stool Form Scale) 1或2型,(b)在至少25%的无拯救大便期间大便用力过度;和/或(c)在至少25%的无拯救大便后感到未完全排空。无拯救大便是指与在大便前24小时内未使用轻泻药有关的大便和/或(c)大便后感到未完全排空。
在某些实施方案中,所提供的制剂可用于预防、抑制、减轻、延缓、减少或治疗胃肠功能障碍的方法,包括但不限于肠易激综合征;阿片样物质诱导的肠功能障碍;结肠炎;术后或产后肠梗阻;恶心和/或呕吐;胃蠕动减慢和排空;胃和小和/或大肠推进的抑制;非推进性节段性收缩幅度增加;Oddi括约肌收缩;肛门括约肌伸缩性增加;反射松弛受损伴直肠膨胀;胃、胆汁、胰腺或肠分泌减少;来自肠内容物的水分吸收增加;胃-食道反流;胃轻瘫;绞痛;胃气胀;腹痛或上腹痛和不适;便秘;特发性便秘;在腹部手术(例如结肠切除术(例如右半结肠切除术;左半结肠切除术;横半结肠切除术;结肠切除术拆卸(takedown);低前位切除术);子宫切除术)之后的术后胃肠功能障碍和口服给予药物或营养物质的吸收延迟。
GCRA肽
本发明的GCRA肽是尿鸟苷肽、鸟苷肽、淋巴鸟苷肽和ST肽的类似物。术语“肽”未指明具体长度。在一些实施方案中,GCRA肽为长度小于25个氨基酸,例如长度小于或等于20、15、14、13、12、11、10或5个氨基酸。
GCRA肽可以是L-氨基酸、D-氨基酸或两者的组合的聚合物。例如,在不同的实施方案中,肽为D逆-倒位肽。术语“逆-倒位异构体”是指其中序列的方向逆转且各氨基酸残基的手性倒转的线性肽的异构体。参见例如Jameson等, Nature, 368, 744-746 (1994);Brady等, Nature, 368, 692-693 (1994)。综合D-对映异构体和逆向合成的净结果是各酰胺键中羰基和氨基的位置交换,同时保持各个α碳上侧链基团的位置。除非另有明确说明,否则假定可通过合成相应的天然L-氨基酸序列的逆转序列,将本发明的任何指定的L-氨基酸序列制备成D逆-倒位肽。例如GCRA肽包括式I-XX界定的序列和表2-8所列序列。
所谓诱导cGMP产生意指GCRA肽诱导胞内cGMP的产生。胞内cGMP通过本领域已知方法测量。例如,与天然存在的GC-C激动剂相比,本发明的GCRA肽刺激5%、10%、20%、30%、40%、50%、75%、90%或更高的胞内cGMP。在进一步的实施方案中,GCRA肽刺激细胞凋亡,例如,程序性细胞死亡或激活囊性纤维化跨膜传导调节因子(CFTR)。
本文所用PEG3、3 PEG,旨在表示聚乙二醇例如包括氨基乙基氧基-乙基氧基-乙酸(AeeA)。
本文所用术语“酰胺”旨在表示末端羧酸被酰胺基置换,即末端COOH被CONH2置换。
本文所用术语“pyGlu”是指焦谷氨酸。
如本文所用,(例如在式I-XX中) Xaa为任何天然、非天然的氨基酸或氨基酸类似物;Maa为半胱氨酸(Cys)、青霉胺(Pen)高半胱氨酸或3-巯基脯氨酸。Xaan1旨在表示长度为1、2或3个残基的任何天然、非天然的氨基酸或氨基酸类似物的氨基酸序列;Xaan2旨在表示长度为零或一个残基的任何天然、非天然氨基酸或氨基酸类似物的氨基酸序列;Xaan3旨在表示长度为0、1、2、3、4、5或6个残基的任何天然、非天然氨基酸或氨基酸类似物的氨基酸序列。此外,Xaa所示任何氨基酸可以是L-氨基酸、D-氨基酸、甲基化氨基酸、氟化氨基酸或其任何组合。优选N端、C端或两端的氨基酸为D-氨基酸。任选式I-XX所示任何GCRA肽可在N端、C端或两端含有一个或多个聚乙二醇残基。示例性聚乙二醇包括氨基乙基氧基-乙基氧基-乙酸及其聚合物。
可用于本发明的方法和制剂的GCC激动剂肽的具体实例包括选自表2-8的肽。
在一些实施方案中,GCC激动剂肽包括具有式I的氨基酸序列的肽,其中式I的至少一个氨基酸是D-氨基酸或甲基化氨基酸和/或16位的氨基酸为丝氨酸。优选,式I的16位的氨基酸为D-氨基酸或甲基化氨基酸。例如,式I的16位的氨基酸为d-亮氨酸或d-丝氨酸。任选式I的1-3位的氨基酸的一个或多个为D-氨基酸或甲基化氨基酸或D-氨基酸或甲基化氨基酸的组合。例如,式I的Asn1、Asp2或Glu3 (或其组合)为D-氨基酸或甲基化氨基酸。优选式I的Xaa6位的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在备选的实施方案中,GCC激动剂肽包括具有式II的氨基酸序列的肽,其中式II的至少一个氨基酸为D-氨基酸或甲基化氨基酸。优选式II的Xaan2所示氨基酸为D-氨基酸或甲基化氨基酸。在一些实施方案中,式II的Xaan2所示氨基酸为亮氨酸、d-亮氨酸、丝氨酸或d-丝氨酸。优选式II的Xaan1所示的一个或多个氨基酸为D-氨基酸或甲基化氨基酸。优选式II的Xaa6位的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在一些实施方案中,GCC激动剂肽包括具有式III的氨基酸序列的肽,其中式III的至少一个氨基酸为D-氨基酸或甲基化氨基酸和/或Maa不是半胱氨酸。优选式III的Xaan2所示氨基酸为D-氨基酸或甲基化氨基酸。在一些实施方案中,式III的Xaan2所示氨基酸为亮氨酸、d-亮氨酸、丝氨酸或d-丝氨酸。优选式III的Xaan1所示的一个或多个氨基酸为D-氨基酸或甲基化氨基酸。优选式III的Xaa6位的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在其它实施方案中,GCC激动剂肽包括具有式IV的氨基酸序列的肽,其中式IV的至少一个氨基酸为D-氨基酸或甲基化氨基酸,和/或Maa不是半胱氨酸。优选式IV的Xaan2为D-氨基酸或甲基化氨基酸。在一些实施方案中,式IV的Xaan2所示氨基酸为亮氨酸、d-亮氨酸、丝氨酸或d-丝氨酸。优选式IV的Xaan1所示氨基酸的一个或多个为D-氨基酸或甲基化氨基酸。优选式IV的Xaa6所示氨基酸为亮氨酸、丝氨酸或酪氨酸。
在进一步的实施方案中,GCC激动剂肽包括具有式V的氨基酸序列的肽,其中式V的至少一个氨基酸为D-氨基酸或甲基化氨基酸。优选式V的16位的氨基酸为D-氨基酸或甲基化氨基酸。例如,式V的16 (即Xaa16)位的氨基酸为d-亮氨酸或d-丝氨酸。任选式V的1-3位的氨基酸的一个或多个为D-氨基酸或甲基化氨基酸或D-氨基酸或甲基化氨基酸的组合。例如,式V的Asn1、Asp2或Glu3 (或其组合)为D-氨基酸或甲基化氨基酸。优选式V的Xaa6所示氨基酸为亮氨酸、丝氨酸或酪氨酸。
在其它实施方案中,GCRA肽包括具有式VI、VII-a、VII-b、VIII或IX的氨基酸序列的肽。优选式VI、VII-a、VII-b、VIII或IX的6位的氨基酸为亮氨酸、丝氨酸或酪氨酸。在一些方面,式VI、VII-a、VII-b、VIII或IX的16位的氨基酸为亮氨酸或丝氨酸。优选式VI、VII-a、VII-b、VIII或IX的16位的氨基酸为D-氨基酸或甲基化氨基酸。
在其它实施方案中,GCRA肽包括具有式X、XI、XII、XIII、XIV、XV、XVI或XVII的氨基酸序列的肽。任选式X、XI、XII、XIII、XIV、XV、XVI或XVII的一个或多个氨基酸为D-氨基酸或甲基化氨基酸。优选式X、XI、XII、XIII、XIV、XV、XVI或XVII的肽的羧基端氨基酸为D-氨基酸或甲基化氨基酸。例如式X、XI、XII、XIII、XIV、XV、XVI或XVII的肽的羧基端氨基酸为D-酪氨酸。
优选式XIV的Xaa6所示氨基酸为酪氨酸、苯丙氨酸或丝氨酸。最优选式XIV的Xaa6所示氨基酸为苯丙氨酸或丝氨酸。优选式XV、XVI或XVII的Xaa4所示氨基酸为酪氨酸、苯丙氨酸或丝氨酸。最优选式XV、XVI或XVII的Xaa4位的氨基酸为苯丙氨酸或丝氨酸。
在一些实施方案中,GCRA肽包括含有式XVIII的氨基酸序列的肽。优选式XVIII的1位的氨基酸为谷氨酸、天冬氨酸、谷氨酰胺或赖氨酸。优选式XVIII的2和3位的氨基酸为谷氨酸或天冬氨酸。优选5位的氨基酸为谷氨酸。优选式XVIII的6位的氨基酸为异亮氨酸、缬氨酸、丝氨酸、苏氨酸或酪氨酸。优选式XVIII的8位的氨基酸为缬氨酸或异亮氨酸。优选式XVIII的9位的氨基酸为天冬酰胺。优选式XVIII的10位的氨基酸为缬氨酸或甲硫氨酸。优选式XVIII的11位的氨基酸为丙氨酸。优选式XVIII的13位的氨基酸为苏氨酸。优选式XVIII的14位的氨基酸为甘氨酸。优选式XVIII的16位的氨基酸为亮氨酸、丝氨酸或苏氨酸。
在备选的实施方案中,GCRA肽包括含有式XIX的氨基酸序列的肽。优选式XIX的1位的氨基酸为丝氨酸或天冬酰胺。优选式XIX的2位的氨基酸为组氨酸或天冬氨酸。优选式XIX的3位的氨基酸为苏氨酸或谷氨酸。优选式XIX的5位的氨基酸为谷氨酸。优选式XIX的6位的氨基酸为异亮氨酸、亮氨酸、缬氨酸或酪氨酸。优选式XIX的8、10、11或13位的氨基酸为丙氨酸。优选式XIX的9位的氨基酸为天冬酰胺或苯丙氨酸。优选式XIX的14位的氨基酸为甘氨酸。
在进一步的实施方案中,GCRA肽包括含有式XX的氨基酸序列的肽。优选式XX的1位的氨基酸为谷氨酰胺。优选式XX的2或3位的氨基酸为谷氨酸或天冬氨酸。优选式XX的5位的氨基酸为谷氨酸。优选式XX的6位的氨基酸为苏氨酸、谷氨酰胺、酪氨酸、异亮氨酸或亮氨酸。优选式XX的8位的氨基酸为异亮氨酸或缬氨酸。优选式XX的9位的氨基酸为天冬酰胺。优选式XX的10位的氨基酸为甲硫氨酸或缬氨酸。优选式XX的11位的氨基酸为丙氨酸。优选式XX的13位的氨基酸为苏氨酸。优选式XX的1位的氨基酸为甘氨酸。优选式XX的15位的氨基酸为酪氨酸。任选式XX的15位的氨基酸的长度为2个氨基酸,且为半胱氨酸(Cys)、青霉胺(Pen)高半胱氨酸或3-巯基脯氨酸和丝氨酸、亮氨酸或苏氨酸。
在某些实施方案中,GCRA肽的一个或多个氨基酸可被非天然存在的氨基酸或天然或非天然存在的氨基酸类似物置换。在标准的20种(Ala、Arg、Asn、Asp、Cys、Gln、Glu、Gly、His、Ile、Leu、Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr和Val)以外还有许多氨基酸。一些是天然存在的,其它则不是。(参见例如Hunt, The Non-Protein Amino Acids: In Chemistryand Biochemistry of the Amino Acids, Barrett, Chapman and Hall, 1985)。例如,芳族氨基酸可被3,4-二羟基-L-苯丙氨酸、3-碘-L-酪氨酸、三碘甲腺原氨酸、L-甲状腺素、苯基甘氨酸(Phg)或正酪氨酸(nor-tyrosine, norTyr)置换。Phg和norTyr和包括Phe和Tyr在内的其它氨基酸可被例如卤素、-CH3、-OH、-CH2NH3、-C(O)H、-CH2CH3、-CN、-CH2CH2CH3、-SH或另一基团取代。任何氨基酸可被该氨基酸的D型取代。
至于非天然存在的氨基酸或天然和非天然存在的氨基酸类似物,本文所述多肽和激动剂中的多个取代可能是单独的或组合的。
例如,谷氨酰胺残基可被γ-羟基-Glu或γ-羧基-Glu取代。酪氨酸残基可被α取代的氨基酸例如L-α-甲基苯丙氨酸或例如以下类似物取代:3-氨基-Tyr、Tyr(CH3)、Tyr(PO3(CH3)2)、Tyr(SO3H)、β-环己基-Ala、β-(1-环戊烯基)-Ala、β-环戊基-Ala、β-环丙基-Ala、β-喹啉基-Ala、β-(2-噻唑基)-Ala、β-(三唑-1-基)-Ala、β-(2-吡啶基)-Ala、β-(3-吡啶基)-Ala、氨基-Phe、氟-Phe、环己基-Gly、tBu-Gly、β-(3-苯并噻吩基)-Ala、β-(2-噻吩基)-Ala、5-甲基-Trp和A-甲基-Trp。脯氨酸残基可被高脯氨酸(L-哌啶酸)、羟基-Pro、3,4-脱氢-Pro、4-氟-Pro或α-甲基-Pro或具有结构:n = 0、1、2、3的N(α)-C(α)环化氨基酸类似物取代。丙氨酸残基可被α-取代的或N-甲基化氨基酸(例如α-氨基异丁酸(aib))、L/D-α-乙基丙氨酸(L/D-异缬氨酸)、L/D-甲基缬氨酸或L/D-α-甲基亮氨酸或非天然氨基酸(例如β-氟-Ala)取代。丙氨酸还可被取代:n = 0、1、2、3。甘氨酸残基可被α-氨基异丁酸(aib)或L/D-α-乙基丙氨酸(L/D-异缬氨酸)取代。
非天然氨基酸的更多实例包括:丙氨酸的非天然类似物(例如L-1-Nal或L-2-Nal);酪氨酸的非天然类似物;谷氨酰胺的非天然类似物;苯丙氨酸的非天然类似物;丝氨酸的非天然类似物;苏氨酸的非天然类似物;烷基、芳基、酰基、叠氮基、氰基、卤素、肼、酰肼、羟基、烯基、炔基、醚、硫醇基、磺酰基、硒基、酯、硫代酸、硼酸酯基(borate)、硼酸酯基(boronate)、磷酸基、膦酰基、膦、杂环基、烯酮、亚胺、醛、羟胺、酮或氨基取代的氨基酸或其任何组合;含光可活化交联剂的氨基酸;自旋标记的氨基酸;荧光氨基酸;含新官能团的氨基酸;与另一分子共价或非共价相互作用的氨基酸;金属结合氨基酸;在不被天然酰胺化的位点上被酰胺化的氨基酸,含金属的氨基酸;放射性氨基酸;光束缚的(photocaged)和/或可光异构化的氨基酸;含有生物素或生物素-类似物的氨基酸;糖基化或糖修饰的氨基酸;含酮的氨基酸;包含聚乙二醇或聚醚的氨基酸;重原子取代的氨基酸(例如含氘、氚、13C、15N或18O的氨基酸);化学可切割的或光可切割的氨基酸;具有长侧链的氨基酸;含毒素基团的氨基酸;糖取代的氨基酸,例如糖取代的丝氨酸等;含有碳连接的糖的氨基酸;有氧化还原活性的氨基酸;含有α-羟基的酸;含有氨基硫代酸的氨基酸;α,α二取代的氨基酸;β-氨基酸;脯氨酸以外的环状氨基酸;O-甲基-L-酪氨酸;L-3-(2-萘基)丙氨酸;3-甲基-苯丙氨酸;ρ-乙酰基-L-苯丙氨酸;O-4-烯丙基-L-酪氨酸;4-丙基-L-酪氨酸;三-O-乙酰基-GlcNAc β-丝氨酸;左旋多巴;氟化苯丙氨酸;异丙基-L-苯丙氨酸;对叠氮基-L-苯丙氨酸;对酰基-L-苯丙氨酸;对苯甲酰基-L-苯丙氨酸;L-磷酸丝氨酸;膦酸丝氨酸;膦酸酪氨酸;对碘-苯丙氨酸;4-氟苯基甘氨酸;对溴苯丙氨酸;对氨基-L-苯丙氨酸;异丙基-L-苯丙氨酸;L-3-(2-萘基)丙氨酸;D-3-(2-萘基)丙氨酸(dNal);含有氨基-、异丙基-或O-烯丙基的苯丙氨酸类似物;多巴,0-甲基-L-酪氨酸;糖基化氨基酸;对(炔丙基氧基)苯丙氨酸;二甲基-赖氨酸;羟基-脯氨酸;巯基丙酸;甲基-赖氨酸;3-硝基-酪氨酸;正亮氨酸;焦谷氨酸;Z (苄氧羰基(Carbobenzoxyl));ε-乙酰基-赖氨酸;β-丙氨酸;β-天冬氨酸;β-环己基丙氨酸;氨基苯甲酰基衍生物;氨基丁酸(Abu);瓜氨酸;氨基己酸(Ahx);氨基异丁酸(AIB);环己基丙氨酸;d-环己基丙氨酸;环己基甘氨酸;羟基脯氨酸;硝基-精氨酸;硝基-苯丙氨酸;硝基-酪氨酸;正缬氨酸;八氢吲哚羧酸酯;鸟氨酸(Orn);青霉胺(PEN);四氢异喹啉;二氨基丁酸;二氨基庚二酸;焦谷氨酸;高半胱氨酸;高丝氨酸;N-ε-二硝基苯基-赖氨酸;N-ε-甲基-赖氨酸;N-ε-二甲基-赖氨酸;N,N,N-ε-三甲基-赖氨酸;乙酰氨基甲基保护的氨基酸和聚乙二醇化氨基酸。非天然氨基酸和氨基酸类似物的更多实例可参见U.S. 20030108885、U.S.20030082575、US20060019347 (第410-418段)及其中引用的参考文献。本发明的多肽可包括更多的修饰,包括描述于US20060019347,第589段的修饰。
本文所用“Nal”是指L-1-萘基丙氨酸(L-1-Nal)和L-2-萘基丙氨酸(L-2-Nal)两者。
在一些实施方案中,氨基酸可被天然存在的非必需氨基酸(例如牛磺酸)置换。
或者,GCRA肽是环肽。GCRA环肽通过本领域已知方法制备。例如,常常通过在肽N端和C端之间、在侧链和N端或C端之间[例如用pH 8.5下的K3Fe(CN)6] (Samson等,Endocrinology, 137: 5182-5185(1996))或在两个氨基酸侧链(例如半胱氨酸)之间形成酰胺键来实现大环化。参见例如DeGrado,Adv Protein Chem,39:51-124(1988)。在一些实施方案中,本发明的GCRA肽是二环肽。在不同的方面,GCRA肽是[4,12;7,15]二环。
在一些GCRA肽中,正常形成二硫键的一对或两对Cys残基的一个或两个成员可被高半胱氨酸、青霉胺、3-巯基脯氨酸(Kolodziej等, 1996 Int J Pept Protein Res 48:274);β,β二甲基半胱氨酸(Hunt等, 1993 Int JPept Protein Res 42:249)或二氨基丙酸(Smith等, 1978 J Med Chem 21:117)置换,在正常的二硫键位置上形成备选的内部交联键。
另外,一个或多个二硫键可被例如以下的备选的共价交联键置换:酰胺键(-CH2CH(O)NHCH2-或-CH2NHCH(O)CH2-)、酯键、硫酯键、内酰胺桥、氨甲酰基键、脲键、硫脲键、磷酸酯键、烷基键(-CH2CH2CH2CH2-)、烯基键(-CH2CH=CHCH2-)、醚键(-CH2CH2OCH2-或-CH2OCH2CH2-)、硫醚键(-CH2CH2SCH2-或-CH2SCH2CH2-)、胺键(-CH2CH2NHCH2-或-CH2NHCH2CH2-)或硫代酰胺键(-CH2CH(S)HNHCH2-或-CH2NHCH(S)CH2-)。例如,Ledu等(ProcNat'l Acad. Sci. 100:11263-78, 2003)描述了制备内酰胺和酰胺交联键的方法。示例性的包括内酰胺桥的GCRA肽包括例如SP-370。
GCRA肽可具有被备选键置换的一个或多个常规多肽键。这类置换可提高多肽的稳定性。例如,残基氨基端与芳族残基(例如Tyr、Phe、Trp)间多肽键被备选键的置换可降低被羧基肽酶切割,并可延长在消化道中的半寿期。可置换多肽键的键包括:逆-倒位键(C(O)-NH而非NH-C(O);还原的酰胺键(NH-CH2);硫代亚甲基键(S-CH2或CH2-S);氧代亚甲基键(O-CH2或CH2-O);亚乙基键(CH2-CH2);硫代酰胺键(C(S)-NH);交叉结构烯烃键(CH=CH);氟取代的交叉结构烯烃键(CF=CH);酮亚甲基键(C(O)-CHR或CHR-C(O),其中R为H或CH3;和氟-酮亚甲基键(C(O)-CFR或CFR-C(O),其中R为H或F或CH3。
GCRA肽可采用标准修饰法修饰。修饰可发生在氨基(N-)、羧基(C-)端、内部或任何前述的组合。在本文描述的一个方面,在多肽上可能有一个类型以上的修饰。修饰包括但不限于:乙酰化、酰胺化、生物素化、肉桂酰化、法尼基化、甲酰化、肉豆蔻酰化、棕榈酰化、磷酸化(Ser、Tyr或Thr)、硬脂酰化、琥珀酰化、磺酰化和环化(通过二硫桥或酰胺环化)和通过Cys3或Cys5的修饰。本文所述GCRA肽还可被2,4-二硝基苯基(DNP)、DNP-赖氨酸修饰、被7-氨基-4-甲基-香豆素(AMC)、荧光素、NBD (7-硝基苯并-2-氧杂-1,3-二唑)、对硝基-酰苯胺、罗丹明B、EDANS (5-((2-氨基乙基)氨基)萘-1-磺酸)、dabcyl、dabsyl、丹酰基、德克萨斯红、FMOC和Tamra (四甲基罗丹明)修饰。本文所述GCRA肽还可与例如以下缀合:聚乙二醇(PEG);烷基(例如C1-C20直链或支链烷基);脂肪酸基团;PEG、烷基和脂肪酸基团的组合(参见美国专利6,309,633;Soltero等, 2001 Innovations in Pharmaceutical Technology106-110);BSA and KLH (Keyhole Limpet Hemocyanin)。可用于修饰本发明多肽的PEG和其它聚合物的添加描述于US2006019347第IX节。
一方面,本发明按例如WO20140151206 (其通过引用以其整体结合到本文中用于所有目的)的教导,提供Aad-GCRA肽。WO20140151206的表1公开了GCRA肽的不同α-氨基己二酸衍生物的实例。Aad-GCRA肽是类似物尿鸟苷肽、鸟苷肽、淋巴鸟苷肽和ST肽。具体地讲,这些类似物含有α-氨基己二酸(Ad),优选在自各肽N端起的第3位或紧接第1个半胱氨酸(“Cys)残基N端侧的位置。例如Aad-GCRA肽包括可包含α-氨基己二酸的式I、II、III、IV、V、VI、VII、VII、VIII、IX、XVIII或XXI限定的序列。
在一些实施方案中,Aad-GCRA肽为Asn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16 (SEQ ID NO: 251;SP-304-Aad);dAsn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-dLeu16(SEQ ID NO: 253;SP-333-Aad);Pyglu1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-dLeu-AMIDE16 (SEQ ID NO: 254;SP-373-Aad);dAsn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-dSer16 (SEQID NO: 255;SP-364-Aad);dAsn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-dTyr16 (SEQ ID NO: 256;SP-366-Aad)或Xaan1-Cys4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Cys12-Xaa13-Xaa14-Xaa15-Xaan2 16 (SEQ ID NO: 257)。
本发明还包括生物学上或功能上等同于本文所述肽的肽。术语“生物学上等同的”或“功能上等同的”旨在意指本发明的组合物能够证实cGMP产生调节作用的一些或全部。
GCRA肽还可包括GCRA肽的衍生物,其旨在包括其中某些氨基酸已缺失或置换的GCRA肽的杂交形式和修饰形式和例如其中一个或多个氨基酸变成修饰的氨基酸或不常见氨基酸的修饰和例如糖基化的修饰,只要修饰形式保留GCRA肽的生物活性。所谓保留生物活性,意味着GCRA肽诱导cGMP和/或细胞凋亡,虽然不必在与已鉴定的天然存在的GCRA肽的效能水平相同的效能水平下。
优选的变体是具有在一个或多个预测的非必需氨基酸残基上进行的保守氨基酸取代的变体。“保守氨基酸取代”是其中氨基酸残基被具有相似侧链的氨基酸残基置换的取代。本领域已定义了具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-支链侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,GCRA多肽中的预测的非必需氨基酸残基被来自同一侧链家族的另一个氨基酸残基置换。或者,在另一个实施方案中,可通过例如饱和诱变,沿GCRA编码序列的全部或部分随机引入突变,可筛选所得突变体以鉴定保留活性的突变体。
术语“基本由……组成”包括与引述的序列(表2-8的任一个)相同的肽和就结构或功能而言无明显不同的其它序列。对于本申请的目的,如果它的结构与表2-8的任一个的肽相比相差大于3个氨基酸或如果它的细胞cGMP产生的活化降低或提高超过50%,则肽明显不同。优选基本相似的肽应相差不超过2个氨基酸之,且对于激活cGMP产生不相差超过约25%。
基本上同源的含义内还包括通过与GCRA肽的抗体交叉反应性可分离的任何GCRA肽。
GCRA肽的制备
GCRA肽可采用现代克隆技术容易地制备,或可通过固态方法或位点定向诱变合成。GCRA肽可包括多肽的显性阴性形式。
化学合成通常可采用标准溶液相或固相肽合成技术进行,其中肽键通过一个氨基酸的氨基与另一个氨基酸的羧基直接缩合除去一个水分子而产生。通过如上简述直接缩合所致的肽键合成,需要抑制第一氨基酸的氨基和第二氨基酸的羧基的反应性质。掩蔽取代基必须允许其易于除去,而不引起不稳定肽分子分解。
在溶液相合成中,可使用各种偶联方法和保护基(参见,Gross和Meienhofer, 编辑, "The Peptides: Analysis, Synthesis, Biology," 第1-4卷(Academic Press,1979);Bodansky和Bodansky, "The Practice of Peptide Synthesis," 第2版(Springer Verlag, 1994))。另外,中间体纯化和线性按比例增加是可能的。本领域普通技术人员应认识到,溶液合成要求考虑主链和侧链保护基和活化方法。另外,需要仔细的区段选择以使区段缩合期间的消旋化降到最低。溶解度考量也是一个因素。固相肽合成在有机合成期间使用不溶聚合物作为支持体。聚合物支持的肽链允许使用简单的洗涤和过滤步骤,而不是中间步骤的费力纯化。一般可按照Merrifield等, J. Am. Chem. Soc., 1963,85:2149的方法进行固相肽合成,该方法包括使用被保护的氨基酸,在树脂支持体上组装线性肽链。固相肽合成通常应用本领域众所周知的Boc或Fmoc策略。
本领域普通技术人员应认识到,在固相合成中,脱保护和偶联反应必须进行完成,且单链封端基团在整个合成中必须是稳定的。另外,当肽以小规模制备时,固相合成一般是最合适的。
可在从树脂上切割之前,通过使最终的肽与乙酸酐反应来完成N端的乙酰化。采用Boc技术,使用合适的树脂例如甲基二苯甲基胺树脂,实现C-酰胺化。
或者,GCRA肽通过现代克隆技术产生。例如,在细菌(包括而不限于大肠杆菌)中或在用于多肽或蛋白质产生的其它现有系统(例如枯草芽孢杆菌(Bacillus subtilis)、使用果蝇Sf9细胞的杆状病毒表达系统、酵母或丝状真菌表达系统、哺乳动物细胞表达系统)中产生GCRA肽,或它们可化学合成。如果GCRA肽或变体肽在细菌(例如大肠杆菌)中产生,编码该多肽的核酸分子也可编码允许成熟多肽从细胞中分泌的前导序列。因此,编码该多肽的序列可包括例如天然存在的细菌ST多肽的前序列和序列原。可从培养基中纯化分泌的成熟多肽。
可将编码本文所述GCRA肽的序列插入能够递送核酸分子至细菌细胞中并将核酸分子保持在细菌细胞中的载体中。可将DNA分子插入自主复制载体中(合适的载体包括例如pGEM3Z和pcDNA3及其衍生物)。载体核酸可以是细菌或噬菌体DNA,例如噬菌体λ或M13及其衍生物。含有本文所述核酸的载体的构建之后可接着宿主细胞(例如细菌)的转化。合适的细菌宿主包括但不限于大肠杆菌、枯草芽孢杆菌、假单胞菌属(Pseudomonas)、沙门氏菌属(Salmonella)。除编码核酸分子以外,遗传构建体还包括允许表达的元件,例如启动子和调节序列。表达载体可含有控制转录起始的转录控制序列,例如启动子、增强子、操纵基因和阻抑蛋白序列。
各种转录控制序列为本领域技术人员熟知。表达载体还可包括翻译调节序列(例如非翻译5'序列、非翻译3'序列或内部核糖体进入位点)。载体能够自主复制或它可整合至宿主DNA中以确保多肽产生期间的稳定性。
包括本文所述GCRA肽的蛋白质编码序列还可与编码多肽亲和标签的核酸融合以利于纯化,所述标签例如谷胱甘肽S-转移酶(GST)、麦芽糖E结合蛋白、蛋白A、FLAG标签、六组氨酸、myc标签或流感HA标签。亲和标签或报道基因融合物使目标多肽的读框与编码亲和标签的基因的读框连接,使得产生翻译融合物。融合基因的表达导致包括目标多肽和亲和标签两者的单一多肽的翻译。在使用亲和标签的某些情况下,编码蛋白酶识别位点的DNA序列可在亲和标签和目标多肽的读框之间融合。
还可使用适于在细菌以外且本领域技术人员众所周知的蛋白质表达系统中产生本文所述GCRA肽和变体的不成熟和成熟形式的遗传构建体和方法以在生物系统中产生多肽。
可通过连接赋予肽所需性质(例如延长体内的半寿期)的第二分子,来修饰(例如聚乙二醇化)本文公开的肽。所述修饰也落入本文所用术语“变体”的范围内。
所谓“抑制”或“阻止”或“降低”意指相对于在没有GCRA肽时蛋白质的活性和/或产生,GCRA肽降低蛋白质的活性和/或产生达至少5%、至少10%、至少15%、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%、至少80%、至少85%、至少90%、至少95%或至少100%或更高。
所谓“诱导”,意指相对于没有GCRA肽时的蛋白质的活性和/或产生,GCRA肽提高蛋白质的活性和/或产生达至少5%、至少10%、至少15%、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%、至少80%、至少85%、至少90%、至少95%或至少100%或更高。
术语“治疗”或“医治”是指减轻或缓解受试者的症状、防止症状恶化或发展和/或预防不受此影响的受试者的疾病。对于指定受试者,可通过任何客观或主观量度,确定症状的改善、恶化、消退或进展。治疗功效可以发病率或死亡率的改善(例如选定群体的存活曲线延长)来测量。因此,有效治疗可包括现有疾病的治疗、通过减慢或停止其发展控制疾病、预防疾病发生、减少症状的数目或严重性或其组合。可在受控研究中利用一个或多个统计显著性标准来显示效果。
与指定疾病或病症有关的术语“预防”意指:如果无疾病发生,则防止疾病发生的开始,防止可能易患病症或疾病但尚未诊断为患有病症或疾病的受试者发生疾病或病症,和/或如果已存在则防止疾病/病症进一步发展。
通过暴露,例如使组织(例如胃肠组织、肺组织、食道组织)或细胞与GCRA激动剂接触,产生胞内cGMP。所谓诱导意指与未与GCRA肽或变体接触的组织或细胞相比,cGMP产生增加。使组织或细胞与GCRA肽或变体直接接触。或者,全身性给予GCRA肽或变体。以足以提高胞内cGMP浓度的量给予GCRA肽或变体。通过本领域已知的基于细胞的测定法测量cGMP产生(25)。
通过将治疗有效剂量的GCRA肽给予有需要的受试者(例如哺乳动物,例如人),来治疗、预防或减缓病症。GCRA肽可连同一种或多种药学上可接受的赋形剂呈单位剂型的药物组合物。术语“单位剂型”是指单一药物递送实体,例如片剂、胶囊剂、溶液剂或吸入制剂。当给予患者时,存在的肽的量应足以具有积极的治疗作用(通常介于10 μg和3 g之间)。构成“积极的治疗作用”的方面将取决于待治疗的具体病况,并可包括易被本领域技术人员识别的任何显著改善。
GCRA肽可单独给予或与阿片样物质组合给予。可用于止痛的阿片样物质是本领域已知的。例如,阿片样物质化合物包括但不限于阿芬太尼、阿尼利定、阿西马多林、布马佐辛、丁丙诺啡、布托啡诺、可待因、地佐辛、二乙酰吗啡(海洛因)、二氢可待因、地芬诺酯、乙基吗啡、非多托秦、芬太尼、氟曲沙胺、氢可酮、氢吗啡酮、左洛啡烷、左醋美沙朵、左啡诺、洛哌丁胺、麦啶(哌替啶)、美沙酮、吗啡、吗啡-6-葡萄糖醛酸酐、纳布啡、烯丙吗啡、尼可吗啡、阿片、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、丙吡兰、丙氧芬、瑞芬太尼、舒芬太尼、替利定、曲美布汀和曲马多。在一些实施方案中,阿片样物质是选自以下的至少一种阿片样物质:阿芬太尼、丁丙诺啡、布托啡诺、可待因、地佐辛、二氢可待因、芬太尼、氢可酮、氢吗啡酮、左啡诺、麦啶(哌替啶)、美沙酮、吗啡、纳布啡、尼可吗啡、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、丙吡兰、丙氧芬、舒芬太尼和/或曲马多。在本发明的某些实施方案中,阿片样物质选自吗啡、可待因、羟考酮、氢可酮、二氢可待因、丙氧芬、芬太尼、曲马多及其混合物。在一个具体实施方案中,阿片样物质是洛哌丁胺。在其它实施方案中,阿片样物质是混合型激动剂,例如布托啡诺。在一些实施方案中,给予受试者一种以上的阿片样物质,例如吗啡和海洛因或美沙酮和海洛因。
GCRA肽可单独给予或与另一种治疗剂(例如治疗、预防或改善阿片样物质诱导的功能障碍的症状的治疗剂)组合给予。示例性治疗剂包括但不限于口服轻泻药(例如软化剂或蠕动诱导剂)、栓剂、灌肠剂、阿片样物质拮抗剂(例如纳洛酮、纳美芬、甲基纳曲酮)、聚乙二醇、选择性靶向外周μ-阿片样物质受体的药物(例如甲基纳曲酮、阿维莫泮)、2型氯离子通道激活剂(例如卢比前列酮)、多巴胺受体拮抗剂(例如甲氧氯普胺)、非阿片样物质、5-羟色胺(Serotonin、5HT)受体配体、安帕金、N-甲基-D-天冬氨酸受体抑制剂、AMPA受体调节剂、他喷他多、NKTR-118、TD-1211和/或小神经胶质抑制剂(例如米诺环素)。
术语“组合疗法”意指同时或序贯给予两种或更多种活性剂。同时给药可以其中将两种或更多种活性剂混合的制剂来实现,或以同时给予独立配制的两种或更多种活性剂来实现。两种或更多种活性剂的序贯给药可使用独立配制的两种或更多种活性剂,以依次先给予一种药剂,接着在给予第一药剂后几秒钟、几分钟、几小时或几天给予第二药剂来实现。
可通过给予其每一种单独配制和给予的两种或更多种药剂(例如本文所述GCRA肽或本文所述组合物和另一种化合物),或通过给予单一制剂中的两种或更多种药剂,来实现组合疗法。组合疗法还包括其它组合。例如,两种药剂可配制在一起,并连同含有第三药剂的独立制剂给予。虽然两种或更多种药剂在组合疗法中可同时给予,但它们不必如此。例如,第一药剂(或药剂的组合)的给予可先于第二药剂(或药剂的组合)的给予几分钟、几小时、几天或几周。因此,两种或更多种药剂可在彼此的几分钟内或在彼此的1、2、3、6、9、12、15、18或24小时内或在彼此的1、2、3、4、5、6、7、8、9、10、12、14天内或在彼此的2、3、4、5、6、7、8、9或10周内给予。在某些情况下,甚至更长的间隔是可能的。虽然在许多情况下,需要用于组合疗法的两种或更多种药剂同时存在于患者体内,但不必如此。
本文所述GCRA肽可与例如sulindae sulfone、扎普司特、西地那非、伐地那非或他达拉非等磷酸二酯酶抑制剂组合以进一步提高靶组织或器官中cGMP的水平。
组合疗法还可包括两次或多次给予用于所述组合的药剂的一种或多种。例如,如果药剂X和药剂Y组合使用,则以任何组合一次或多次序贯给予它们,例如以X-Y-X、X-X-Y、Y-X-Y、Y-Y-X、X-X-Y-Y等的顺序给予。
组合疗法还可包括通过不同的途径或位置给予两种或更多种药剂。例如,(a)一种药剂口服给予,另一种药剂静脉内给予,或(b)一种药剂口服给予,另一种局部给予。在各种情况下,药剂可同时或序贯给予。本文所述的一些组合疗法药剂的大致剂量参见WO01/76632第11-17页表中的“BNF推荐剂量”栏(表中的数据出自2000年3月英国国家处方集),还可参见其它标准处方集和其它药物处方指南。对于某些药物,适应症的习惯处方剂量在国家与国家间可略有不同。
单独或组合的GCRA肽可与任何药学上可接受的载体或介质组合。因此,它们可与当给予患者时不产生不利的、变应性的或另外其它不良反应的物质组合。所用的载体或介质可包括溶剂、分散剂、包衣材料、吸收促进剂、控制释放剂和一种或多种惰性赋形剂(这包括淀粉、多元醇、成粒剂、微晶纤维素(例如celphere、Celphere beads®)、稀释剂、润滑剂、粘合剂、崩解剂等)等。如有需要,所公开的组合物的片剂剂量可用标准水法或非水法技术包衣。
配制本发明的药物组合物以与其预定的给药途径相容。给药途径的实例包括胃肠外,例如静脉内、皮内、皮下、口服(例如吸入)、经皮(局部)、跨粘膜和直肠给药。用于胃肠外、皮内或皮下施用的溶液剂或混悬剂可包括下列组分:无菌稀释剂,例如注射用水、盐水溶液、固定油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲液,例如乙酸盐、柠檬酸盐或磷酸盐;和张度调节剂,例如氯化钠或葡萄糖。可用酸或碱(例如盐酸或氢氧化钠)调节pH。可将胃肠外制剂包封在由玻璃或塑料制成的安瓿,一次性注射器或多剂量小瓶中。
适于注射用的药物组合物包括:无菌水性溶液剂(其中水可溶解的)或分散剂和用于无菌注射溶液剂或分散剂即时制备的无菌粉剂。对于静脉内给药,合适的载体包括生理盐水、抑菌水、Cremophor ELTM (BASF,Parsippany,N.J.)或磷酸缓冲盐水(PBS)。在所有情况下,组合物必须是无菌的,且就存在易于注射性而言应是流体。在制造和存贮条件下必须是稳定的,且必须防止微生物(例如细菌和真菌)的污染作用。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)及其合适的混合物的溶剂或分散介质。可例如通过使用包衣材料(例如卵磷脂)、在分散剂的情况下通过保持所需粒径和通过使用表面活性剂,来保持合适的流动性。可通过各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、抗坏血酸、硫柳汞等,实现微生物作用的防止。在许多情况下,优选在组合物中包括等渗剂,例如糖、多元醇例如甘露糖醇、山梨糖醇、氯化钠。可通过在组合物中包括延迟吸收的作用剂(例如单硬脂酸铝和明胶),引起可注射组合物的吸收延长。
可通过在合适的溶剂中以所需的量掺入活性化合物(例如GCRA激动剂)与上列成分的一种或组合(按需要),接着过滤除菌,来制备无菌注射溶液剂。通常通过将活性化合物掺入含有碱性分散介质和所需的来自上列那些的其它成分的无菌溶媒中来制备分散剂。在用于制备无菌注射溶液剂的无菌粉剂的情况下,制备方法为真空干燥和冷冻干燥,这得到来自其之前除菌过滤的溶液中的活性成分加上任何其它所需成分的粉末。
口服组合物一般包括惰性稀释剂或可食用载体。例如甘露糖醇、果寡糖、聚乙二醇和其它赋形剂。可将它们包封在明胶胶囊中或压制成片剂。出于口服治疗性给予的目的,活性化合物可与赋形剂一起掺入,并用于片剂、锭剂或胶囊剂的形式。还可使用流体载体制备口服组合物以用作漱口剂,其中流体载体中的化合物经口施用和漱口和吐出或吞下。可包括药学上相容的粘合剂和/或辅料作为组合物的部分。片剂、丸剂、胶囊剂、锭剂等可含有下列成分的任一种或类似性质的化合物:粘合剂,例如微晶纤维素、西黄蓍胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如藻酸、Primogel或玉米淀粉;润滑剂,例如硬脂酸镁或Sterotes;助流剂,例如胶态二氧化硅;甜味剂,例如蔗糖或糖精;或矫味剂,例如薄荷、水杨酸甲酯或橙味调味料。
对于通过吸入的给药,从含有合适推进剂(例如二氧化碳等气体)的加压容器或分配器或喷雾器中,以气溶胶喷雾的形式递送化合物。
全身性给药也可通过跨粘膜或经皮手段。对于跨粘膜或经皮给药,在制剂中使用适于待渗透的屏障的渗透剂。这类渗透剂通常是本领域已知的,例如对于跨粘膜给药包括去污剂、胆汁盐和梭链孢酸衍生物。跨粘膜给药可通过使用鼻喷雾剂或栓剂实现。对于经皮给药,将活性化合物配制成如本领域一般已知的软膏剂、油膏剂、凝胶剂或乳膏剂。
化合物还可以栓剂(例如用常规栓剂基质,例如可可脂和其它甘油酯)或滞留型灌肠剂的形式制备用于直肠递送。
在一个实施方案中,将活性化合物与可防止化合物从机体快速清除的载体一起制备,例如控释制剂,包括植入剂和微囊化递送系统。可使用生物可降解的生物相容性聚合物,例如乙烯乙酸乙酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。用于制备这类制剂的方法对于本领域技术人员将是显而易见的。材料也可市购获自Alza Corporation和NovaPharmaceuticals,Inc。脂质体混悬剂(包括以病毒抗原的单克隆抗体靶向受感染细胞的脂质体)也可用作药学上可接受的载体。这些可按本领域技术人员已知方法,例如如美国专利号4,522,811 (通过引用全部结合到本文中)所述来制备。
特别有优势的是以剂量单位形式配制口服或胃肠外组合物以易于剂量的给予和一致性。本文所用剂量单位形式是指适宜作为待治疗的受试者的单位剂量的物理离散单位;各单位含有经计算产生所需治疗作用的预定量的活性化合物以及所需的药用载体。本发明的剂量单位形式的规格受制于并直接取决于活性化合物的独特性质和要实现的具体治疗作用。
药物组合物可与给药说明书一起包括在容器、药包或分配器中。
本发明的组合物还可任选包括其它治疗成分、防结块剂、防腐剂、甜味剂、着色剂、香料剂、干燥剂、增塑剂、染料、助流剂、抗粘剂、抗静电剂、表面活性剂(润湿剂)、抗氧化剂、薄膜包衣剂等。任何这类任选的成分必须与本文所述化合物相容以确保制剂的稳定性。
组合物可按需含有其它添加剂,包括例如乳糖、葡萄糖、果糖、半乳糖、海藻糖、蔗糖、麦芽糖、棉子糖、麦芽糖醇、松三糖、水苏糖、乳糖醇、直辉中基性岩(palatinite)、淀粉、木糖醇、甘露糖醇、肌醇等及其水合物和氨基酸,例如丙氨酸、甘氨酸和甜菜碱及多肽和蛋白质,例如白蛋白。
用作药学上可接受的载体和药学上可接受的惰性载体和前述其它成分的赋形剂的实例包括但不限于粘合剂、填充剂、崩解剂、润滑剂、抗微生物剂和包衣剂,例如:粘合剂:玉米淀粉、马铃薯淀粉、其它淀粉、明胶、天然和合成树胶例如阿拉伯树胶、黄原胶、藻酸钠、藻酸、其它藻酸盐、西黄蓍胶粉、瓜尔胶、纤维素及其衍生物(例如乙基纤维素、醋酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯吡咯烷酮(例如聚维酮、交联聚维酮、共聚维酮(copovidone)等)、甲基纤维素、Methocel、预胶化淀粉(例如Colorcon,Ltd.销售的STARCH1500®和STARCH 1500 LM®)、羟丙基甲基纤维素、微晶纤维素(FMC Corporation, MarcusHook, PA, USA)或其混合物;填充剂:滑石粉、碳酸钙(例如粒料或粉末)、磷酸氢钙、磷酸三钙、硫酸钙(例如粒料或粉末)、微晶纤维素、纤维素粉、葡萄糖结合剂、高岭土、甘露糖醇、硅酸、山梨糖醇、淀粉、预胶化淀粉、葡萄糖、果糖、蜂蜜、无水乳糖、乳糖一水合物、乳糖和阿司帕坦、乳糖和纤维素、乳糖和微晶纤维素、麦芽糖糊精、麦芽糖、甘露糖醇、微晶纤维素&;瓜尔胶、糖蜜、蔗糖或其混合物;崩解剂:琼脂、藻酸、碳酸钙、微晶纤维素、交联羧甲基纤维素纳、交联聚维酮、聚克立林钾、羟基乙酸淀粉钠、马铃薯或木薯淀粉、其它淀粉、预胶化淀粉、粘土、其它藻胶、其它纤维素、树胶(像吉兰糖)、低取代的羟丙基纤维素或其混合物;润滑剂:硬脂酸钙、硬脂酸镁、矿物油、轻质矿物油、甘油、山梨糖醇、甘露糖醇、聚乙二醇、其它二醇、硬脂酸、十二烷基硫酸钠、硬脂酰醇富马酸钠、植物型脂肪酸润滑剂、滑石粉、氢化植物油(例如花生油、棉籽油、向日葵油、芝麻油、橄榄油、玉米油和大豆油)、硬脂酸锌、油酸乙酯、月桂酸乙酯、琼脂、syloid硅胶(AEROSIL 200, W.R. Grace Co., Baltimore, MDUSA)、合成二氧化硅的凝聚型气溶胶(Deaussa Co., Piano, TX USA),发热二氧化硅(CAB-O-SIL, Cabot Co., Boston, MA USA)或其混合物;防结块剂:硅酸钙、硅酸镁、二氧化硅、胶态二氧化硅、滑石粉或其混合物;抗微生物剂:苯扎氯铵、苄索氯铵、苯甲酸、苄醇、对羟基苯甲酸丁酯、西吡氯铵、甲酚、三氯叔丁醇、脱氢醋酸、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、苯酚、苯乙醇、苯氧乙醇、醋酸苯汞、硝酸苯汞、山梨酸钾、对羟基苯甲酸丙酯、苯甲酸钠、脱氢醋酸钠、丙酸钠、山梨酸、硫柳汞、thymo或其混合物;和包衣剂:羧甲基纤维素钠、醋酸邻苯二甲酸纤维素、乙基纤维素、明胶、药用釉料、羟丙基纤维素、羟丙基甲基纤维素(羟丙甲纤维素)、羟丙基甲基纤维素邻苯二甲酸酯、甲基纤维素、聚乙二醇、聚醋酸乙烯邻苯二甲酸酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、吉兰糖胶、麦芽糖糊精、甲基丙烯酸酯、微晶纤维素和角叉菜胶或其混合物。
制剂还可包括其它赋形剂及其类别,包括但不限于L-组氨酸、Pluronic®、泊洛沙姆(例如Lutrol®和Poloxamer 188)、抗坏血酸、谷胱甘肽、渗透促进剂(例如脂质、胆酸钠、酰基肉碱、水杨酸酯、混合胆汁盐、脂肪酸胶束、螯合剂、脂肪酸、表面活性剂、中链甘油酯)、蛋白酶抑制剂(例如大豆胰蛋白酶抑制剂、有机酸)、有效提高生物利用度的pH降低剂和吸收增强剂(包括但不限于描述于US6086918和US5912014中的那些)、乳膏和洗剂(像麦芽糖糊精和角叉菜胶);用于咀嚼片的材料(像葡萄糖、果糖、乳糖一水合物、乳糖和阿司帕坦、乳糖和纤维素、麦芽糖糊精、麦芽糖、甘露糖醇、微晶纤维素和瓜尔胶、山梨糖醇晶体);parenterals (像甘露糖醇和聚维酮);增塑剂(像癸二酸二丁酯、用于包衣的增塑剂、聚醋酸乙烯邻苯二甲酸酯);粉末润滑剂(像山嵛酸甘油酯);软明胶胶囊剂(像山梨糖醇特种溶液);用于包衣的球体(像糖球体);滚圆剂(像山嵛酸甘油酯和微晶纤维素);助悬/胶凝剂(像角叉菜胶、吉兰糖胶、甘露糖醇、微晶纤维素、聚维酮、羟基乙酸淀粉钠、黄原胶);甜味剂(像阿司帕坦、阿司帕坦和乳糖、葡萄糖、果糖、蜂蜜、麦芽糖糊精、麦芽糖、甘露糖醇、糖蜜、山梨糖醇晶体、山梨糖醇特种溶液、蔗糖);湿法制粒剂(像碳酸钙、无水乳糖、乳糖一水合物、麦芽糖糊精、甘露糖醇、微晶纤维素、聚维酮、淀粉)、焦糖、羧甲基纤维素钠、樱桃奶油香料和樱桃香料、无水柠檬酸、柠檬酸、糖粉、D&C Red No. 33、D&C Yellow #10铝色淀、依地酸二钠、乙醇15%、FD&C Yellow No. 6铝色淀、FD&C Blue # 1铝色淀、FD&C Blue No. 1、FD&C Blue No. 2铝色淀、FD&C Green No.3、FD&C Red No. 40、FD&C Yellow No. 6铝色淀、FD&C Yellow No. 6、FD&C Yellow No.10、棕榈酰硬脂酸甘油酯、单硬脂酸甘油酯、靛胭脂、卵磷脂、甘露糖醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、甘草酸一铵、天然和人工橙味香料、药用釉料、泊洛沙姆188、聚葡萄糖、聚山梨醇酯20、聚山梨醇酯80、聚维酮、预胶化玉米淀粉、预胶化淀粉、氧化铁红、糖精钠、羧甲基醚钠、氯化钠、柠檬酸钠、磷酸钠、草莓香料、合成氧化铁黑、合成氧化铁红、二氧化钛和白蜡。
固体口服剂型可任选用包衣系统处理(例如Opadry® fx薄膜包衣系统,例如Opadry®蓝(OY-LS-20921)、Opadry®白(YS-2-7063)、Opadry®白(YS-1-7040)和黑油墨(S-1-8 106)。
呈其游离形式或作为盐的作用剂可与以下聚合物混合以产生缓释制剂:例如聚乳酸-乙醇酸(PLGA)、聚(I)-乳酸-乙醇酸-酒石酸(P(I)LGT) (WO 01/12233)、聚乙醇酸(U.S.3,773,919)、聚乳酸(U.S. 4,767,628)、聚(ε-己内酯)和聚(环氧烷) (U.S.20030068384)。这类制剂可用于在几天、几周或几个月的时间内释放多肽或另一种药剂的植入剂,所述时间取决于聚合物、聚合物的粒径和植入剂的大小(参见例如U.S. 6,620,422)。使用的其它缓释制剂和聚合物描述于EP 0 467 389 A2、WO 93/24150、U.S. 5,612,052、WO 97/40085、WO 03/075887、WO 01/01964A2、U.S. 5,922,356、WO 94/155587、WO 02/074247A2、WO 98/25642、U.S. 5,968,895、U.S. 6,180,608、U.S. 20030171296、U.S.20020176841、U.S. 5,672,659、U.S. 5,893,985、U.S. 5,134,122、U.S.5,192,741、U.S.5,192,741、U.S. 4,668,506、U.S. 4,713,244、U.S. 5,445,832、U.S. 4,931,279、U.S. 5,980,945、WO 02/058672、WO 97/26015、WO 97/04744和US20020019446。在这类缓释制剂中,将多肽的微粒(Delie和Blanco-Prieto 2005 Molecule 10:65-80)与聚合物的微粒混合。可将一种或多种缓释植入剂置于大肠、小肠或两者中。U.S. 6,011,011和WO 94/06452描述了提供聚乙二醇(即PEG 300和PEG 400)或三醋精的缓释制剂。WO 03/053401描述了即可提高生物利用度又可提供药剂在GI道内控释的制剂。其它控释制剂描述于WO 02/38129、EP326151、U.S. 5,236,704、WO 02/30398、WO 98/13029;U.S. 20030064105、U.S.20030138488A1、U.S. 20030216307A1、U.S. 6,667,060、WO 01/49249、WO 01/49311、WO01/49249、WO 01/49311和U.S. 5,877,224。材料可包括描述于WO04041195的材料(包括其中描述的密封包衣和肠包衣),实现在结肠中递送的pH敏感性包衣材料包括描述于US4,910,021和WO9001329的那些。US4910021描述了使用pH敏感性材料以包覆胶囊剂。WO9001329描述了在含酸珠粒上使用pH敏感性包衣材料,其中珠粒芯上的酸延长pH敏感性包衣材料的溶解。美国专利号5,175,003公开了用于递药系统的由pH敏感性肠衣材料和能够赋予肠衣材料渗透性的薄膜形成增塑剂组成的双重机制聚合物混合物;由充满药物和有时覆盖药物中性核(pharmaceutically neutral nucleus)的双重机制聚合物混合物组成的基质小丸(matrix pellet);膜包覆的小丸,其包含用相同或不同组成的双重机制聚合物混合物包封包覆的基质小丸;和含基质小丸的药物剂型。通过在酸性pH中扩散和通过在标称约5.0或更高的pH水平下崩解,基质小丸释放出酸溶性药物。
在一些实施方案中,以pH依赖性释放形式配制本文所述组合物。或者,以在胃肠(GI)道的特定区域(例如十二指肠、空肠、回肠、回肠末端或升结肠)释放肽的形式配制这类组合物。制剂可含有用组合物包覆的惰性载体和在特定pH (例如pH5或pH7)下释放肽的肠溶包衣材料。十二指肠或空肠释放的优选pH为pH 4.5-5.5或pH 5.5-6.5。回肠、回肠末端或升结肠释放的优选pH为pH 5.5-6.5或pH 6.5-7.5。优选惰性载体选自甘露糖醇、乳糖、微晶纤维素或淀粉。
可在描述于WO04052339的pH引发的靶向控释系统中配制本文所述的GCRA肽。可按照以下任一个描述的方法配制本文所述药剂:WO03105812 (挤出的能水合的聚合物);WO0243767 (酶可切割膜易位蛋白);WO03007913和WO03086297 (粘膜粘附系统);WO02072075 (包含pH降低剂和吸收增强剂的双层分层制剂);WO04064769 (酰胺化多肽);WO05063156 (熔融时具有假变和/或触变性质的固体脂质混悬剂);WO03035029和WO03035041 (易蚀的胃滞留剂型);US5007790和US5972389 (缓释剂型);WO041 1271 1(口服延时释放组合物);WO05027878、WO02072033和WO02072034 (含天然或合成树胶的延缓释放组合物);WO05030182 (释放速率递增的控释制剂);WO05048998 (微囊化系统);美国专利5,952,314 (生物聚合物);US5,108,758 (玻璃化直链淀粉基质递送);US 5,840,860 (基于改性淀粉的递送);JP10324642 (包含脱乙酰壳多糖和例如麦醇溶蛋白或玉米醇溶蛋白等耐胃腐蚀材料的递送系统);US 5,866,619和US 6,368,629 (含有聚合物的糖);US 6,531,152 (描述了含有水溶性芯的药物递送系统(果胶酸钙或其它水不溶聚合物)和爆裂的外层(例如疏水聚合物-Eudragrit));US 6,234,464;US 6,403,130 (具有含酪蛋白和高甲氧基果胶的聚合物的包衣材料;WO0174 175 (Maillard反应产物);WO05063206 (溶解度提高制剂);WO040 19872 (转移融合蛋白)。
控释制剂
在一个实施方案中,GCC激动剂制剂包含提供控制(时间依赖性)释放的GCC激动剂的靶向物质。在这种情况下控释包括延缓的持续释放、延缓的控释、延缓的缓慢释放、延缓的延时释放、延缓的延长释放和突然释放或“爆发(burst)”。
优选控释制剂含有包含被靶向物质包覆的GCC激动剂的缓慢崩解的芯。靶向物质优选包含至少一种可溶胀聚合物。用于本发明的控释制剂的可溶胀聚合物的非限制性实例包括丙烯酸共聚物,例如EUDRAGIT RL、EUDRAGIT RS或EUDRAGIT NE;聚乙烯乙酸酯,例如KOLLICOAT SR 30D;和纤维素衍生物,例如乙基纤维素或醋酸纤维素,例如SURELEASE和AQUACOAT ECD。在一个优选的实施方案中,靶向物质包含EUDRAGIT RL、EUDRAGIT RS或EUDRAGIT NE的一种或多种以通过不依赖于pH的溶胀提供GCC激动剂的控时释放。在一个具体实施方案中,靶向物质包含EUDRAGIT RL:RS (2:8)和包含EUDRAGIT FS的外层包衣材料。
可用于本发明的缓释制剂的可溶胀聚合物的其它非限制性实例包括分子量为30,000-5,000.000的聚羟基烷基甲基丙烯酸酯;κ-角叉菜胶;分子量为10,000-360,000的聚乙烯吡咯烷酮;阴离子和阳离子水凝胶;聚电解质复合物;具有少量乙酸酯、与乙二醛、甲醛或戊二醛交联且聚合度为200-30,000的聚乙烯醇;包含甲基纤维素、交联的琼脂和羧甲基纤维素的混合物;通过细碎的马来酐与苯乙烯、乙烯、丙烯、丁烯或异丁烯形成分散体而产生的水不溶的水可溶胀共聚物;N-乙烯基内酰胺的水可溶胀聚合物;多糖、水可溶胀树胶、高粘度羟丙基甲基纤维素和/或其混合物。在某些实施方案中,可溶胀聚合物选自果胶酸钙、交联多糖、水不溶性淀粉、微晶纤维素、水不溶性交联肽、水不溶性交联蛋白质、水不溶性交联明胶、水不溶性交联水解明胶、水不溶性交联胶原、改性纤维素和交联聚丙烯酸。交联多糖的非限制性实例包括藻酸盐的不溶性金属盐或交联衍生物、果胶、黄原胶、瓜尔胶、西黄蓍胶和刺槐豆胶、角叉菜胶、其金属盐及其共价交联衍生物。改性纤维素的非限制性实例包括羟丙基甲基纤维素、羟乙基纤维素、甲基纤维素、羧甲基纤维素、羧甲基纤维素的金属盐和羟丙基纤维素的交联衍生物。
在某些实施方案中,可溶胀芯还包含芯吸剂(wicking agent),例如二氧化硅。芯吸剂还可选自崩解剂(例如微晶纤维素)以提高吸水速度。其它合适的芯吸剂包括但不限于高岭土、二氧化钛、气相二氧化硅、氧化铝、烟酰胺、十二烷基硫酸钠、低分子量聚乙烯吡咯烷酮、m-pyrol、膨润土、硅酸镁铝、聚酯、聚乙烯及其混合物。
在某些实施方案中,可包含部分芯和/或形成包覆芯的一层或多层的靶向物质任选另包含以下的至少一种:润滑剂、促流动剂、增塑剂、抗粘剂、表面活性剂、润湿剂、助悬剂和分散剂。
在某些实施方案中,靶向物质包含水不溶性聚合物和成孔剂。成孔剂的非限制性实例包括蔗糖、氯化钠、氯化钾、聚乙烯吡咯烷酮和/或聚乙二醇、水溶性有机酸、糖和糖醇。在某些实施方案中,成孔剂形成外层或包衣的部分。在其它实施方案中,成孔剂均匀分布在全部水不溶性聚合物中。
在一个实施方案中,靶向物质包含压制包衣材料。可用作压制包衣材料的材料的非限制性实例包括选自以下的树胶:黄原胶、刺槐豆胶、半乳聚糖、甘露聚糖、藻酸盐、刺梧桐树胶、果胶、琼脂、西黄蓍胶、阿拉伯树胶、角叉菜胶、西黄蓍胶、脱乙酰壳多糖、琼脂、藻酸、水胶体儿茶、salai guggal、indian bodellum、苦配巴香脂胶、阿魏胶、cambi树胶、象耳豆(Enterolobium cyclocarpum)、黄连木树胶、安息香胶、山达脂胶、黑儿茶胶、buteafrondosa (Flame of Forest Gum)、没药、魔芋甘露聚糖、瓜尔胶、welan树胶、吉兰糖胶、他拉胶(tara gum)、刺槐豆胶、角叉菜胶、葡甘露聚糖、半乳聚糖树胶、藻酸钠、西黄蓍胶、脱乙酰壳多糖、黄原胶、脱乙酰基黄原胶、果胶、聚果胶酸钠、谷蛋白、刺梧桐树胶、罗望子胶、印度树胶、Accaroid/Yacca/Red树胶、达玛树胶、杜松树胶、酯树胶、银合欢种籽胶、gum talha(acacia seyal)和栽培植物细胞胶,包括以下属的植物的细胞胶:金合欢属(acacia)、猕猴桃属(actinidia)、露草属(aptenia)、剑叶花属(carbobrotus)、菊苣属(chickorium)、黄瓜属(cucumis)、大豆属(glycine)、木槿属(hibiscus)、大麦属(hordeum)、letuca、番茄属(lycopersicon)、苹果属(malus)、苜蓿属(medicago)、松叶菊属(mesembryanthemum)、稻属(oryza)、黍属(panicum)、虉草属(phalaris)、梯牧草属(phleum)、polyanthus、polycarbophil、sida、茄属(solanum)、三叶草属(trifolium)、胡卢巴属(trigonella);非洲缅茄木(Afzelia africana)种籽胶、Treculia africana树胶、detarium树胶、cassia树胶、角豆树胶、Prosopis africana树胶、Colocassia esulenta树胶、Hakea gibbosa树胶、卡欧属树胶、小核菌聚糖和玉蜀黍属(zea)以及任何前述的混合物。
在一些实施方案中,靶向物质另包含增塑剂、硬化剂、润湿剂、助悬剂或分散剂或其组合。增塑剂的非限制性实例包括癸二酸二丁酯、聚乙二醇和聚丙二醇、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、柠檬酸三乙酯、柠檬酸三丁酯、乙酰化甘油单酯、乙酰基柠檬酸三丁酯、三醋精、邻苯二甲酸二甲酯、苯甲酸苄酯、脂肪酸的丁基酯和/或二醇酯、精练矿物油、油酸、蓖麻油、玉米油、樟脑、甘油和山梨糖醇或其组合。在一个实施方案中,硬化剂包含鲸蜡醇。润湿剂的非限制性实例包括泊洛沙姆、聚氧乙烯醚、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧亚甲基硬脂酸酯、十二烷基硫酸钠、山梨糖醇酐脂肪酸酯、苯扎氯铵、聚乙氧基化蓖麻油和多库酯钠。助悬剂的非限制性实例包括藻酸、膨润土、卡波姆、羧甲基纤维素、羧甲基纤维素钙、羟乙基纤维素、羟丙基纤维素、微晶纤维素、胶态二氧化硅、糊精、明胶、瓜尔胶、黄原胶、高岭土、硅酸镁铝、麦芽糖醇、中链甘油三酯、甲基纤维素、聚氧乙烯山梨糖醇酐脂肪酸酯、聚乙烯吡咯烷酮、丙二醇藻酸盐、藻酸钠、山梨糖醇酐脂肪酸酯和西黄蓍胶。分散剂的非限制性实例包括泊洛沙姆、聚氧乙烯山梨糖醇酐脂肪酸酯和山梨糖醇酐脂肪酸酯。
在某些实施方案中,靶向释放制剂在靶向释放材料上另包含外层肠溶包衣材料。优选肠溶包衣材料选自醋酸邻苯二甲酸纤维素、醋酸羟基丙基甲基纤维素琥珀酸酯、EUDRAGIT L100和EUDRAGIT L30D-55。
爆发制剂
在一个实施方案中,GCC激动剂制剂是经设计在结肠或小肠中以快速爆发释放GCC激动剂的延时制剂(“爆发制剂(burst formulation)”)。制剂包含芯和外层。芯包含至少一种GCC激动剂和至少一种爆发控制剂。在某些实施方案中,芯另包含选自以下的至少一种崩解剂:交联羧甲基纤维素纳、交联聚维酮(交联PVP)、羧甲基淀粉钠(羟基乙酸淀粉钠)、交联羧甲基纤维素钠(交联羧甲纤维素)、预胶化淀粉(STARCH 1500)、微晶淀粉、水不溶性淀粉、羧甲基纤维素钙和硅酸镁铝或其组合。在其它实施方案中,芯另包含以下的至少一种:吸收增强剂、粘合剂、硬度增强剂、缓冲剂、填充剂、流动调节剂、润滑剂、增效剂、螯合剂、抗氧化剂、稳定剂和防腐剂。任选芯还包含一种或多种其它赋形剂。
芯中的爆发控制剂优选包含用于控制水渗入芯的速率和提高芯内的内部压力(渗透压力)的水不溶性聚合物。这类爆发控制剂优选能够在与液体接触时溶胀。合适的水不溶性聚合物的非限制性实例包括交联多糖、水不溶性淀粉、微晶纤维素、水不溶性交联肽、水不溶性交联蛋白质、水不溶性交联明胶、水不溶性交联水解明胶、水不溶性交联胶原、改性纤维素和交联聚丙烯酸。在一个实施方案中,水不溶性聚合物为选自以下的交联多糖:藻酸盐的不溶金属盐或交联衍生物、果胶、黄原胶、瓜尔胶、西黄蓍胶和刺槐豆胶、角叉菜胶、其金属盐及其共价交联衍生物。在一个实施方案中,水不溶性聚合物为选自以下的改性纤维素:羟丙基甲基纤维素、羟乙基纤维素、甲基纤维素、羧甲基纤维素、羧甲基纤维素的金属盐和羟丙基纤维素的交联衍生物。在另一个实施方案中,水不溶性聚合物选自果胶酸钙、微晶纤维素或其组合。
外层包含水不溶性疏水载体和由水不溶性亲水微粒物质组成的成孔剂。成孔剂为允许液体进入芯的透水剂。任选外层另包含润湿剂、助悬剂、分散剂、硬化剂和增塑剂的至少一种。
在某些实施方案中,水不溶性疏水载体选自丙烯酸二甲氨基乙酯/甲基丙烯酸乙酯共聚物,该共聚物基于具有低含量的季铵基团的丙烯酸酯和甲基丙烯酸酯,其中铵基与其余的中性(甲基)丙烯酸酯的摩尔比率约为1:20,该聚合物相当于USP/NF “铵基甲基丙烯酸酯共聚物A型”;甲基丙烯酸乙酯/氯三甲基铵乙基甲基丙烯酸酯共聚物,该共聚物基于具有低含量的季铵基团的丙烯酸酯和甲基丙烯酸酯,其中铵基与其余的中性(甲基)丙烯酸酯的摩尔比率为1:40,该聚合物相当于USP/NF “铵基甲基丙烯酸酯共聚物B型”;甲基丙烯酸二甲氨基乙酯/甲基丙烯酸甲酯和甲基丙烯酸丁酯共聚物,该共聚物基于中性甲基丙烯酸酯和甲基丙烯酸二甲氨基乙酯,其中聚合物在酸存在下为阳离子;丙烯酸乙酯和丙烯酸甲酯/甲基丙烯酸乙酯和甲基丙烯酸甲酯共聚物,该共聚物是基于中性甲基丙烯酸和丙烯酸酯的中性共聚物;乙基纤维素;虫胶;玉米醇溶蛋白和蜡。
在某些实施方案中,水不溶性微粒物质是亲水却是水不溶性的聚合物,优选选自水不溶性交联多糖、水不溶性交联蛋白质、水不溶性交联肽、水不溶性交联明胶、水不溶性交联水解明胶、水不溶性交联胶原、水不溶性交联聚丙烯酸、水不溶性交联纤维素衍生物、水不溶性交联聚乙烯吡咯烷酮、微晶纤维素、不溶性淀粉、微晶淀粉和其组合。最优选水不溶性微粒物质是微晶纤维素。
在某些实施方案中,爆发制剂在外层另包含肠溶包衣材料。肠溶包衣材料优选选自醋酸邻苯二甲酸纤维素、醋酸羟基丙基甲基纤维素琥珀酸酯和EUDRAGIT聚合物,例如EUDRAGIT L100或EUDRAGIT L30D-55。
生物可降解制剂
在一个实施方案中,GCC激动剂制剂包含易被至少一种结肠细菌酶降解的天然或合成聚合物。优选GCC激动剂嵌入聚合物基质中。这类聚合物的非限制性实例包括多糖的聚合物,例如直链淀粉、脱乙酰壳多糖、硫酸软骨素、环糊精、葡聚糖、瓜尔胶、果胶和木聚糖。优选天然或合成聚合物被胶凝或与阳离子(例如来自硫酸锌、氯化锌或乙酸锌的锌阳离子)交联。制剂优选为离子交联珠粒的形式,所述珠粒随后用肠溶包衣材料进行包衣。肠溶包衣材料可包含任何合适的肠溶包衣材料,例如羟丙基甲基纤维素邻苯二甲酸酯、聚醋酸乙烯邻苯二甲酸酯、醋酸邻苯二甲酸纤维素、醋酸羟基丙基甲基纤维素琥珀酸酯、藻酸和藻酸钠或EUDRAGIT聚合物。
在另一个实施方案中,GCC激动剂制剂包含与载体分子共价缀合的GCC激动剂,使得GCC激动剂和载体间的共价键在胃和小肠中是稳定的,但在下胃肠道(尤其在结肠)中是不稳定的。与载体分子共价连接的GCC激动剂称为“GCC前药”。在某些实施方案中,GCC前药包含通过偶氮键或糖苷键与载体分子共价缀合的GCC激动剂。在其它实施方案中,GCC前药包含葡糖苷酸、环糊精、葡聚糖酯或极性氨基酸。在某些实施方案中,GCC前药为聚合前药。在一个实施方案中,聚合前药包含含有偶氮基的聚酰胺。
剂量
本文所述GCRA肽可采用胃肠滞留型系统技术(GIRES;Merrion Pharmaceuticals)配制。GIRES包含可充气小袋内的控释剂型,所述袋被置于药物胶囊中用于口服给药。在胶囊溶解时,产气系统使小袋在胃中充气,在胃中保留16-24小时,一直释放本文所述药剂。
可在渗透装置(包括在公开于US4,503,030、US5,609,590和US5,358,502的渗透装置中)配制本文所述GCRA肽。US4,503,030公开了用于将药物分配到胃肠道的某些pH区的渗透装置。更具体地讲,该发明涉及包含由半渗透性pH敏感组合物形成的壁和穿过壁的通道的渗透装置,该壁包围含有药物的室,该通道连接装置外部与室。该装置在pH小于3.5的胃肠道的区域以受控速率递送药物,而在大于3.5的pH的胃肠道区域,该装置自毁并释放其所有药物,从而提供用于药物吸收的总可用性。美国专利号5,609,590和5,358,502公开了用于将有益作用剂分配到水性环境的渗透爆发装置。该装置包含至少部分被半渗透膜包围的有益作用剂和渗透剂(osmagent)。有益作用剂也可用作渗透剂。半渗透膜是可透水的,但基本透不过有益作用剂和渗透剂。使引发工具(trigger means)与半渗透膜连接(例如连接两个半胶囊节)。引发工具被pH 3-9激活,引发有益作用剂最终的但是突然的递送。这些装置通过渗透爆发,使得能够进行pH引发的有益作用剂芯作为快速注射释放。
药物组合物中活性成分的剂量水平也可改变,使得在受试者(尤其在炎症部位或疾病区中和附近)中达到化合物的瞬时或持续的浓度,并产生所需反应。尽在本领域技能中的是以低于达到所需作用所需要的水平开始化合物的剂量,逐渐增加剂量直到达到所需作用。应了解的是,用于任何特定受试者的具体剂量水平可取决于各种因素,包括体重、一般健康状况、饮食、疾病自然史、给药途径和给药方案、与一种或多种其它药物的组合和疾病的严重程度。
组合物的有效剂量通常可介于约1 μg和约10 mg/千克体重之间,优选介于约10 μg与5 mg化合物/千克体重之间。剂量调整可采用本领域常规的方法进行,并可基于正使用的特定组合物和临床考量。
可口服、全身或局部给予用于上述方法的鸟苷酸环化酶受体激动剂。剂型包括吸入或注射的制剂、溶液剂、混悬剂、乳剂、片剂、胶囊剂、局部油膏剂和洗剂、经皮组合物、其它已知的肽制剂和聚乙二醇化肽类似物。激动剂可作为唯一的活性剂或与其它药物(例如依赖cGMP的磷酸二酯酶的抑制剂和抗炎药)组合给予。在所有情况下,应采用现有技术作为指导以治疗有效的剂量给予其它药物。药物可以单一组合物给予或序贯给予。
用于本发明方法的GCR激动剂的剂量水平通常为每日约0.001 mg-约10,000 mg,优选每日约0.005 mg-约1,000 mg。例如,用于本发明方法的GCRA肽的有效剂量为每天约0.1、约0.2、约0.3、约 0.4、约 0.5、约0.6、约0.7、约0.8、约0.9、约1.0、约1.5、约2.0、约2.5、约3.0、约3.5、约4.0、约4.5、约5.0、约5.5、约6.0、约6.5、约7.0、约7.5、约8.0、约8.5、约9.0、约9.5、约10、约11、约12、约13、约14、约15、约16、约17、约18、约19或约20 mg,或任选一天两次。优选GCRA肽餐后给予(即30分钟)。在一些实施方案中,给予可用于治疗脂质代谢障碍、胆囊病症、心血管病、肥胖病或内分泌障碍的第二药剂。本文描述了合适的第二药剂。在一些方面,以小于用于治疗特定病症的标准剂量给予第二药剂,因为GCRA肽与第二药剂协同作用。例如,一天两次在餐后(即30分钟)给予约2.5、约5、约7.5或约10 mg Liptor。在或以单剂量或以分剂量给予的mg/kg每日剂量的基础上,剂量范围通常为约0.001/75 mg/kg-约10,000/75 mg/kg、优选约0.005/75 mg/kg-约1,000/75 mg/kg。
各抑制剂的总日剂量可以单剂量或以多个分剂量给予患者。通常,分剂量可每天给予2-6次,优选每天2-4次,甚至更优选每天2-3次。剂量可呈充分有效获得对医学病况的所需控制的即释形式或缓释形式。
根据各种因素,选择用本发明的组合和组合物预防、治疗、免除或改善医学病况或病症或以别的方式防止或治疗医学病况的剂量方案。这些因素包括但不限于受试者的类型、年龄、体重、性别、饮食和医学病况、疾病的严重程度、给药途径、例如所用特定抑制剂的活性、功效、药代动力学和毒理学特征等药理学考量、是否使用药物递送系统和抑制剂是否与其它活性成分一起给予。因此,实际采用的剂量方案可在很大程度上变化,因此偏离上文给出的优选的剂量方案。
实施例
实施例1:大鼠中用尿鸟苷肽的类似物SP-333口服治疗通过鸟苷酸环化酶-C和囊性纤维化跨膜传导调节因子的活化缓解吗啡和美沙酮诱导的便秘
阿片样物质广泛用于治疗慢性疼痛,但其消耗常常与标准轻泻药对其不是非常有效的人的严重便秘有关。这种副作用被认为是由于流体分泌减少,影响了胃肠(GI)蠕动和大便(BM)所致。发生阿片样物质诱导的肠功能障碍的机制见图2。因此,需要能够缓解多种阿片样物质诱导的便秘的安全的可口服给药的药理学作用剂。
SP-333,一种尿鸟苷肽的类似物,激活GC-C以刺激环状GMP的产生,其进而激活囊性纤维化跨膜传导调节因子(CFTR)这种负责氯离子从内衬胃肠(GI)道的肠细胞中流出的顶端氯离子通道,导致水分净流出进入肠腔以利于大便和GI蠕动(Shailubhai,2002;Forte,2004;Basu等,2010;Steinbrecher,2014)。
该研究表明SP-333作为用于治疗阿片样物质诱导的便秘(OIC)的口服药物疗法的可能性。甚至在吗啡或美沙酮的存在下,用SP-333治疗也引起短路电流(Isc)跨越T84细胞单层和大鼠空肠组织的浓度依赖性增加。Isc的这种增加似乎通过激活蛋白质激酶G-II和囊性纤维化跨膜传导调节因子的GC-C/cGMP机制而介导。在大鼠研究中,每日腹膜内给予美沙酮持续7天在GI运送中产生明显延迟,导致每日排便大大减少。口服给予的SP-333完全恢复由吗啡或美沙酮引起的GI运送延迟。用SP-333口服治疗(2.5和5 mg/kg/天)不仅仅使GI运送正常,而且还部分恢复排便。
材料与方法
细胞培养:T84,人癌细胞系,购自美国典型培养物保藏中心(American Type CultureCollection,ATCC) (Manassas,VA,USA)。按所述(Shailubhai等,2000),将细胞培养在含有10%胎牛血清(Atlanta Biologicals,Flowery Branch,GA)、1%青霉素/链霉素(Invitrogen,Carlsbad,CA)和1% glutamax (Invitrogen,Carlsbad,CA)的DMEM/F-12培养基(Fisher Scientific,Pittsburgh,PA)中。对于Ussing室实验,以~150,000个细胞/插入皿的接种密度使细胞在12 mm可渗透聚酯膜(孔径0.4 μm) Snapwell插入皿(CLS 3801,Sigma,Saint Louis,MO)上生长,并在5% CO2的潮湿环境于37℃温育。
动物:根据MB Research Labs (Spinnerstown,PA)或Lampire BiologicalLaboratories (Pipersville,PA)的公共机构动物管理与使用委员会(InstitutionalAnimal Care and Use Committee)批准的研究概要进行所有研究程序。7-8周龄雌性Sprague-Dawley大鼠[Crl:CD(SD)],体重为~180-210克,获自Charles RiverLaboratories,并允许适应一周。使动物保持在12小时光-暗周期下。对于肠组织收集和GI运送评价,在实验前使大鼠禁食至少18小时,但自由饮水。
大鼠组织收获:通过CO2吸入使大鼠安乐死。进行中线剖腹术。确定特赖茨氏韧带远端1-cm的空肠近端5-cm区,切下,并转移到冰冷的含有吲哚美辛(10 µM)的RPMI培养基中。10分钟后,将组织转移到无吲哚美辛的新鲜的冰冷RPMI培养基中。如下所述,将组织钉在解剖垫上,沿肠系膜边缘切割,顶面面朝上,固定在Ussing室滑板上。
短路电流测量: SC 测量在具有VCCMC8多通道电流电压(I-V)钳(PhysiologicInstruments,San Diego,CA)的EasyMount Ussing室系统(4室)中进行。使用EVOM上皮伏特欧姆计(EMD Millipore,MA),定期监测跨培养在透性膜上的细胞单层的跨上皮电阻(TER)。使用TER >1000 ohm. cm2的汇合的T84细胞。将细胞和组织固定在由PhysiologicInstruments提供的特定滑板(1.12 cm2狭缝面积用于细胞,0.5 cm2用于组织)上,并固定在Ussing室中。将各室连续用Krebs Ringer缓冲溶液冲洗。基底外浴液含有以mM计) 115NaCl、25 NaHCO3、3.3 KH2PO4、0.8 K2HPO4、1.12 MgCl2、1.2 CaCl2和10 Hepes (Cuppoletti等,2004)。为了检查SP-333或特定抑制剂对顶端膜上的氯离子通道的作用,通过用相等浓度的葡糖酸钠替换与顶端膜接触的缓冲液中的NaCl,强制施加基底外到顶端氯离子梯度。由于葡糖酸盐螯合Ca2+离子,因此CaCl2浓度提高到4mM。(Bijvelds等,2009)。将缓冲液溶液用碳合气(95% O2和5% CO2的混合物)连续充气,用加热器使温度在37℃下保持恒定。使钳与Acquire & Analyze软件(Physiologic Instruments)连接用于所有4个室的自动数据收集。使用Ag/AgCl参比电极用于测量跨上皮电压和通过电流。
为了评价跨越T84细胞单层(n=4个跨孔/浓度)和大鼠空肠组织(n=4个制备物/浓度)的SP-333 Isc,在基线稳定后将规定量的激动剂加入顶端缓冲溶液中,记录峰值活性,并以I SC (µA/cm2) ± SEM作图。通过用阿片样物质预处理顶侧的细胞(n=3个跨孔/阿片样物质浓度)和大鼠空肠(n=4-15个制备物/阿片样物质浓度) 5分钟,来测定吗啡或美沙酮对SP-333刺激的Isc的作用(Cuppoletti等,2013)。随后,将1µM SP-333加入顶侧的缓冲液中,测量经刺激的电流的峰值活性,表示为氯离子电流(Isc) (相对于溶媒对照) ± SEM。为了评价PKA和PKG-II所起的作用,并鉴定CFTR和CIC-2对激动剂介导的Cl-离子的释放的相对贡献,在激酶和Cl-通道抑制剂存在和不存在时进行了实验。所用抑制剂为CdCl2(CIC-2抑制剂;Sigma-Aldrich;St Louis,MO)、CFTRinh172 (CFTR抑制剂;Santa CruzBiotech;Dallas,Texas)、KT5823 (PKG抑制剂;R&D Systems,Minneapolis,MN)、mPKI (PKA抑制剂;EMD Millipore;Billerica,MA)。在加入1 mM SP-333之前,将T84细胞(n=4个跨孔/条件)和空肠组织(n=4-6个制备物/条件)用规定浓度的各抑制剂预处理5分钟。记录在加入SP-333后达到的峰值电流,以百分比相对活性± SEM为单位计算。
SP-333对大鼠中阿片样物质诱导的GI运送延迟的作用:通过经IP注射给予0 (溶媒)、0.25、1和2.5 mg/kg吗啡或0 (溶媒)、0.25、2.5和5 mg/kg美沙酮(1.5 ml/kg剂量体积),测试阿片样物质延迟大鼠的GI运送的能力。水用作溶媒对照。10分钟后,通过经口管饲给予2 mL由水中的10%活性炭(Sigma-Aldrich, St. Louis, MO)和10%阿拉伯树胶(Sigma-Aldrich, St. Louis, MO)组成的活性炭餐。在活性炭餐后10分钟通过IP注射150 mg/kgBeuthanasia-D溶液(戊巴比妥钠,390 mg/mL)使大鼠安乐死。取出小肠,记录从幽门括约肌到回盲连接的总长度,以及由活性碳的前沿移动的距离。通过计算幽门括约肌和活性碳前沿之间的距离与幽门括约肌和回盲连接间的距离的比率(表示为百分比)测定肠运送。
为了评价SP-333逆转吗啡诱导的延缓GI运送的能力,在0 (溶媒)、0.5、2.5、5和50mg/kg SP-333 (1.5 ml/kg剂量体积)的经口管饲之后,立即通过IP注射给予动物2.5 mg/kg吗啡。水用作溶媒对照。如上所述10分钟后给予活性碳餐,在活性碳餐后10分钟,使动物安乐死,并计算肠运送。
为了评价SP-333逆转美沙酮诱导的延缓GI运送的能力,通过IP注射给予动物2.5mg/kg美沙酮。10分钟后,在2 mL活性碳餐的经口管饲后,立即经口管饲给予0 (溶媒)、0.1、0.5、2.5、5和50 mg/kg SP-333 (1.5 ml/kg剂量体积)。在活性碳餐后10分钟,如上所述使动物安乐死,并计算肠运送。
还以类似方式,评价了SP-333减轻通过重复给予美沙酮诱导的GI运送延迟的能力。雌性Sprague-Dawley CD大鼠7-8周龄(n=7/组)接受通过IP注射的16剂的美沙酮(每日一次;5 mg/kg 7剂,2.5 mg/kg 9剂)。在各美沙酮剂量后10分钟,各组接受经口管饲的溶媒、2.5和5 mg/kg SP-333。在给药方案结束时,使动物禁食过夜,如上所述评价GI运送。
SP-333对大鼠的美沙酮诱导的便秘的作用:为了鉴定引起大鼠便秘的美沙酮剂量,通过IP注射一天一次给予7-8周龄雌性Sprague-Dawley CD大鼠(n=6/组) 0 (溶媒)、2.5、5和7.5 mg/kg美沙酮(1.5ml/kg剂量体积)持续5天。在研究进程期间,在美沙酮的每日剂量给予后,在光周期期间以4小时间隔收集粪粒,并记录各组粪粒的平均数。
为了评价SP-333缓解美沙酮诱导的便秘的能力,通过IP注射每天给予7-8周龄雌性Sprague-Dawley CD大鼠(n=7 /组) 5 mg/kg美沙酮(或溶媒)达7天以诱导便秘。在每天IP剂量后10分钟,经口管饲给予2.5和5 mg/kg SP-333或溶媒(缓冲液)。在研究进程中在每日给予溶媒、美沙酮或美沙酮和SP-333的组合后,在光周期期间以4小时间隔收集粪粒,并记录各组粪粒的平均数。
统计分析:应用GraphPad Prism (6.01版)计算汇总统计和推理检验。数据表示为均值± SEM和通过双尾斯氏t 检验评价对照组和治疗组间的差异的显著性。
结果
T84细胞和大鼠空肠中通过SP-333的Cl-电流的PKG-II和CFTR通道依赖性刺激:SP-333刺激T84细胞和大鼠空肠中的Cl-电流(表示为I sc 升高)。结果见图3。在与T84细胞(图3A)或大鼠空肠(图3B)的粘膜表面接触的缓冲溶液中加入SP-333 (0.01-10 µM)导致I sc的浓度依赖性提高,在两种情况下在10 µM下接近饱和。空肠组织的总体I sc比T84细胞所观察到的高得多。然而,诱导跨越T84细胞单层(EC50 = 1.69 x 10-7 M)或空肠组织(EC50 = 2.99 x10-7 M)的I sc的50%提高的SP-333浓度相当。
在T84细胞中,与仅1 µM SP-333所观察到的相比,在10 µM CFTRinh172存在下观察到SP-333刺激的I sc的80%抑制(图4A)。在PKG-II抑制剂(4 µM)存在时相对I sc也被抑制达约35% (图4A)。在CIC-2抑制剂、CdCl2 (300 µM)和3.2 µM 蛋白质激酶A (mPKI-)抑制剂存在时,未观察到刺激的I sc的可观降低(图4A)。用大鼠空肠观察到类似模式,虽然与在T84细胞中检测的相比,用等量的CFTRinh172的抑制幅度较小(图4B)。总之,结果表明在模型细胞系统以及在大鼠组织中,对于SP-333介导的I sc提高需要激活的PKG-II和CFTR通道。
吗啡和美沙酮对SP-333刺激的Cl-电流的作用:在T84细胞和大鼠空肠中,评价了吗啡和美沙酮的选定浓度对SP-333刺激的I sc的作用。结果见图5 (吗啡)和图6 (美沙酮)。
顶端膜用5 µM吗啡预处理对来自T84细胞和大鼠空肠组织的1 µM SP-333刺激的I sc的作用可忽略(图5)。同样用5 µM美沙酮预处理的T84细胞和大鼠空肠对SP-333介导的电流无作用(图6A和B)。
口服给予SP-333对吗啡诱导的大鼠GI运送延迟的作用:观察到与溶媒对照相比,在SP-333的单一经口管饲剂量后小肠运送剂量依赖性增强(在0.05 mg/kg、0.5 mg/kg和5mg/kg下分别为5.6%、13%、23%—参见图7),表明在阿片样物质幼稚动物中,仅SP-333治疗引起GI运送增强(Joshi等,2014)。腹膜内(IP)给予吗啡显著降低大鼠的GI运送(图8A)。与溶媒对照相比,在0.25、1.0和2.5 mg/kg的阿片样物质下,在单一吗啡剂量后GI运送分别减慢52%、56%和56%。
为了评价SP-333缓解吗啡诱导的延缓的GI运送的能力,通过IP注射给予动物2.5mg/kg吗啡,接着立即通过经口管饲给予0 (溶媒)、0.5、2.5、5和50 mg/kg SP-333。10分钟后使动物安乐死,按在材料与方法下所述计算GI运送。吗啡显著降低GI运送(23%与溶媒处理的53%;p<0.0001) (图8B)。在吗啡治疗的大鼠中,SP-333产生肠运送的剂量依赖性改善:在0.5、2.5、5和50 mg/kg下分别为27%、37%、46%和48% (与仅吗啡相比,在所有剂量下P ≤0.0001,0.5 mg/kg除外)。结果表明5 mg/kg的SP-333剂量足以缓解吗啡对GI运送的作用。GI运送均值± SEM见图8B。
口服给予SP-333对美沙酮诱导的大鼠GI运送延迟的作用:腹膜内给予美沙酮显著降低大鼠的GI运送。2.5 mg/kg的美沙酮剂量足以显著降低GI运送。此外,结果与用2.5 mg/kg吗啡观察到的相当(相对于相应的溶媒对照,美沙酮和吗啡分别为49%和56%)。GI运送均值± SEM见图9A。
为了评价SP-333缓解美沙酮诱导的GI运送延缓的能力,通过IP注射给予动物2.5mg/kg美沙酮。10分钟后,经口管饲给予0 (溶媒)、0.5、2.5、5和50 mg/kg SP-333。10分钟后使动物安乐死,按在材料与方法下所述计算GI运送。美沙酮显著降低GI运送(28%相对于溶媒处理中的55%;P<0.0001)。如图9B所示,在美沙酮处理的大鼠中给予SP-333产生肠运送的剂量依赖性改善:在0.5、2.5、5和50 mg/kg下分别为40%、39%、44%和52% (P<0.01,在所有剂量下)。这些数据表明5 mg/kg的SP-333剂量足以缓解美沙酮对GI运送的作用。GI运送均值±SEM见图9B。
口服给予SP-333对大鼠中因重复给予美沙酮诱导的便秘的作用:大鼠中通过IP每日一次给予2.5、5和7.5 mg/kg美沙酮达5天的时间诱导便秘。与溶媒组相比,在光周期期间在4小时时间内收集的粪粒的平均数在美沙酮给药动物组中显著较低;在2.5、5和7.5 mg/kg下分别低29%、77%和54%(P<0.01,在所有剂量下) (图10A)。在5 mg/kg剂量下观察到美沙酮对排便的最显著的作用。为了评价SP-333缓解美沙酮诱导的便秘的能力,通过IP注射每日一次给予动物5.0 mg/kg美沙酮达7天的时间。在给予阿片样物质后10分钟,每天经口管饲给予0 (溶媒)、2.5和5 mg/kg SP-333,在光周期期间在4小时期限内监测排便。如图10B所示,在仅用美沙酮给药的动物中观察到粪粒的平均数显著减少(相对于溶媒对照少82%)。与美沙酮给药组相比,在SP-333的所有剂量下粪粒的平均数均较高。与不接受任何SP-333的美沙酮给药组所观察到的相比,在2.5 mg/kg的SP-333下观察到粪粒计数的3倍增加,表明SP-333缓解在重复给予美沙酮后大鼠的便秘。另外,给予SP-333减轻因重复给予美沙酮引起的GI运送延迟(图11)。
讨论
用T84细胞和大鼠空肠进行的Ussing室实验表明SP-333介导的短路电流的刺激依赖于功能性PKG-II和CFTR通道。体内动物模型研究进一步证实,口服给予的SP-333能够减轻在大鼠中通过单次或重复给予阿片样物质诱导的GI运送延迟,以及缓解通过重复给予美沙酮诱导的便秘。
图12提供了GC-C激动剂籍以缓解阿片样物质诱导的GI运送延迟和便秘的机制。外周表达的阿片样物质受体被吗啡和美沙酮激活引发下游信号转导,这导致cAMP合成酶、腺苷酸环化酶的抑制和例如乙酰胆碱、物质P和血管活性肠肽的神经递质的释放(Sobczak等,2013)。因此,胃排空受抑制,GI运送和蠕动受损,分泌减少伴以肠腔流体和电解质的吸收同时增加,导致了OIBD的出现(Holzer,2009;Müller-Lissner,2010;Sobczak等,2013)。由SP-333引起的顶端表达的肠上皮细胞GC-C受体的参与促进胞内cGMP的合成和蓄积(Zhang等,2012)。这种第二信使具有影响细胞内的多个效应物的潜力;它可结合并激活PKG-II、直接或通过抑制磷酸二酯酶3间接激活蛋白质激酶A (PKA),这使cAMP水解成为AMP。PKG-II和PKA可使CFTR通道磷酸化,并激活CFTR通道以促进Cl-离子流出,接着Na+和水被动流出进入肠腔,因此有助于大便。电生理数据表明,跨越T84细胞单层和大鼠空肠组织的I sc的SP-333介导的提高是通过PKG-II和CFTR进行的。PKA抑制剂(mPKI)和CIC-2抑制剂(CdCl2)的存在对来自细胞和组织的SP-333刺激的I sc具有最小作用。
本领域技术人员应认识到或只是采用常规实验便能够确定本文所述具体实施方案的许多等同内容。所述等同内容欲包括在本文提供的权利要求书中。
通过引用的结合
本申请通过引用本文公开的所有出版物或参考文献以其整体予以结合用于所有目的。
参考文献
Barrett KE和Keely SJ (2000) Chloride secretion by the intestinalepithelium: molecular basis and regulatory aspects (肠上皮的氯离子分泌:分子基础和调节方面). Annu Rev Physiol 62:535-572。
Basu N, Arshad N和Visweswariah SS (2010) Receptor guanylyl cyclase C(GC-C): regulation and signal transduction (受体鸟苷酰环化酶C (GC-C):调节和信号转导). Mol Cell Biochem 334:67-80。
Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T和Williamson R(2009) The prevalence, severity, and impact of opioid-induced boweldysfunction: results of a US and European Patient Survey (PROBE 1) (阿片样物质诱导的肠功能障碍的流行性、严重程度和影响:美国和欧洲患者调查的结果(PROBE 1)).Pain medicine 10:35-42。
Bianchi G, Fiocchi R, Peracchia F, Petrillo P, Tavani A和Manara L(1984) The peripheral narcotic antagonist N-allyl levallorphan-bromide (CM32191) selectively prevents morphine antipropulsive action and buprenorphinein-vivo binding in the rat intestine (大鼠肠中外周麻醉药拮抗剂N-烯丙基左洛啡烷-溴化物(CM 32191)选择性地防止吗啡抗推进作用和丁丙诺啡体内结合). J PharmPharmacol 36:326-330。
Bijvelds MJC, Bot AGM, Escher JC和de Jonge HR (2009) Activation ofIntestinal Cl- Secretion by Lubiprostone Requires the Cystic FibrosisTransmembrane Conductance Regulator (由卢比前列酮引起的肠Cl-分泌的活化需要囊性纤维化跨膜传导调节因子). Gastroenterology 137:976-985。
Camilleri M (2011) Opioid-induced constipation: challenges andtherapeutic opportunities (阿片样物质诱导的便秘:挑战和治疗机会). Am JGastroenterol 106:835-842;quiz 843。
Clarke LL (2009) A guide to Ussing chamber studies of mouse intestine(小鼠肠Ussing室研究指南). Am J Physiol Gastrointest Liver Physiol 296:G1151-1166。
Cook SF, Lanza L, Zhou X, Sweeney CT, Goss D, Hollis K, Mangel AW和Fehnel SE (2008) Gastrointestinal side effects in chronic opioid users:results from a population-based survey (慢性阿片样物质使用者中的胃肠副作用:基于群体调查的结果). Aliment Pharmacol Ther 27:1224-1232。
Cryer BL, Katz S, Vallejo R, Scott CB, Joswick TR, Dolecek G和Ueno R(2010) 906 A Phase 3, Randomized, Double-Blind, Placebo-Controlled ClinicalTrial of Lubiprostone for the Treatment of Opioid-Induced Bowel Dysfunctionin Patients With Chronic, Non-Cancer Pain (患有慢性非癌症疼痛的患者中用于阿片样物质诱导的肠功能障碍治疗的卢比前列酮的3期随机双盲安慰剂对照的临床试验).Gastroenterology 138:S-129。
Cuppoletti J, Chakrabarti J, Tewari K和Malinowska DH (2013) Methadonebut not morphine inhibits lubiprostone-stimulated Cl- currents in T84intestinal cells and recombinant human ClC-2, but not CFTR Cl- currents (美沙酮但非吗啡抑制T84肠细胞和重组人ClC-2中的卢比前列酮刺激的Cl-电流而非CFTR Cl-电流). Cell Biochem Biophys 66:53-63。
Cuppoletti J, Chakrabarti J, Tewari KP和Malinowska DH (2014)Differentiation between Human ClC-2 and CFTR Cl- Channels withPharmacological Agents (用药理学作用剂的人ClC-2和CFTR Cl-通道间的差异). Am JPhysiol Cell Physiol。
Cuppoletti J, Malinowska DH, Tewari KP, Li QJ, Sherry AM, Patchen ML和Ueno R (2004) SPI-0211 activates T84 cell chloride transport andrecombinant human ClC-2 chloride currents (SPI-0211激活T84细胞氯离子转运和重组人ClC-2氯离子电流). Am J Physiol Cell Physiol 287:C1173-1183。
Fiocchi R, Bianchi G, Petrillo P, Tavani A和Manara L (1982) Morphineinhibits gastrointestinal transit in the rat primarily by impairingpropulsive activity of the small intestine (吗啡主要通过损害小肠的推进活性抑制大鼠的胃肠运送). Life Sci 31:2221-2223。
Forte LR, Jr. (2004) Uroguanylin and guanylin peptides: pharmacologyand experimental therapeutics (尿鸟苷肽和鸟苷肽肽:药理学和实验治疗学).Pharmacol Ther 104:137-162。
Furlan AD, Sandoval JA, Mailis-Gagnon A和Tunks E (2006) Opioids forchronic noncancer pain: a meta-analysis of effectiveness and side effects (用于慢性非癌性疼痛的阿片样物质:有效性和副作用的元分析). CMAJ 174:1589-1594。
Golin-Bisello F, Bradbury N和Ameen N (2005) STa and cGMP stimulateCFTR translocation to the surface of villus enterocytes in rat jejunum and isregulated by protein kinase G (STa和cGMP刺激CFTR易位至大鼠空肠绒毛肠细胞的表面并被蛋白质激酶G调节). Am J Physiol Cell Physiol 289:C708-716。
Holzer P (2009) Opioid receptors in the gastrointestinal tract (胃肠道中的阿片样物质受体). Regul Pept 155:11-17。
Joshi A, Patwa V, Thadi A, Vemalapally L, Foss J, Feng R, Comiskey S,Ricci A, Palejwala V, Brancale A和Shailubhai K (2014) Plecanatide and SP-333,Novel Homologs of Uroguanylin, Activate Guanylate Cyclase C to PromoteGastrointestinal Motility and Bowel Movement in Rats and Monkeys (Plecanatide和尿鸟苷肽的新的同系物SP-333激活鸟苷酸环化酶C以促进大鼠和猴的胃肠蠕动和大便).Dig Dis Sci:Communicated。
Ketwaroo GA, Cheng V和Lembo A (2013) Opioid-induced bowel dysfunction(阿片样物质诱导的肠功能障碍). Curr Gastroenterol Rep 15:344。
Kumar L, Barker C和Emmanuel A (2014) Opioid-induced constipation:pathophysiology, clinical consequences, and management (阿片样物质诱导的便秘:病理生理学、临床结果和管理). Gastroenterology research and practice 2014:141737。
Kurz A和Sessler DI (2003) Opioid-induced bowel dysfunction:pathophysiology and potential new therapies (阿片样物质诱导的肠功能障碍:病理生理学和可能的新疗法). Drugs 63:649-671。
Lipecka J, Bali M, Thomas A, Fanen P, Edelman A和Fritsch J (2002)Distribution of ClC-2 chloride channel in rat and human epithelial tissues(ClC-2氯离子通道在大鼠和人上皮组织中的分布). Am J Physiol Cell Physiol 282:C805-816。
Love BL, Johnson A和Smith LS (2014) Linaclotide: A novel agent forchronic constipation and irritable bowel syndrome(Linaclotide:用于慢性便秘和肠易激综合征的新药剂). Am J Health Syst Pharm 71:1081-1091。
Manara L, Bianchi G, Ferretti P和Tavani A (1986) Inhibition ofgastrointestinal transit by morphine in rats results primarily from directdrug action on gut opioid sites (大鼠中吗啡对胃肠运送的抑制主要产生于对肠阿片样物质部位的直接药物作用). J Pharmacol Exp Ther 237:945-949。
Manara L, Bianchi G, Fiocchi R, Notarnicola A, Peracchia F和Tavani A(1982) Inhibition of gastrointestinal transit by morphine and FK 33-824 inthe rat and comparative narcotic antagonist properties of naloxone and its N-methyl quaternary analog (大鼠中由吗啡和FK 33-824引起的胃肠运送的抑制和纳洛酮及其N-甲基季铵类似物的相当的麻醉性拮抗剂性质). Life Sci 31:1271-1274。
Miner PB, Surowitz R, Fogel R, Koltun W, Drossman DA, Camilleri M,Mangel A, Barrow L, Jacob G和Shailubhai K (2013) Plecanatide, a novelguanylate cyclase-C (GC-C) receptor agonist, is efficacious and safe inpatients with chronic idiopathic constipation (CIC): results from a 951patient, 12 week, multi-center trial (新的鸟苷酸环化酶-C (GC-C)受体激动剂Plecanatide在患有慢性特发性便秘(CIC)的患者中是安全和有效的:来自12周多中心试验的951名患者的结果). Gastroenterology 144:S-263 (文摘925g)。
Müller-Lissner S (2010) Opioid-induced Constipation–Mechanisms,Relevance and Management (阿片样物质诱导的便秘—机制、关联性和管理). EurGastroenterol Hepatol Rev 6:54-57。
Nighot PK, Moeser AJ, Ryan KA, Ghashghaei T和Blikslager AT (2009)ClC-2 is required for rapid restoration of epithelial tight junctions inischemic-injured murine jejunum (缺血性损伤的鼠空肠中上皮紧密连接处快速恢复需要ClC-2). Exp Cell Res 315:110-118。
Pappagallo M (2001) Incidence, prevalence, and management of opioidbowel dysfunction (阿片样物质肠功能障碍的发生率、流行性和管理). Am J Surg 182:11S-18S。
Pena-Munzenmayer G, Catalan M, Cornejo I, Figueroa CD, Melvin JE,Niemeyer MI, Cid LP和Sepulveda FV (2005) Basolateral localization of nativeClC-2 chloride channels in absorptive intestinal epithelial cells andbasolateral sorting encoded by a CBS-2 domain di-leucine motif (吸收性肠上皮细胞中的天然ClC-2氯离子通道的基底外定位和由CBS-2结构域二亮氨酸基序编码的基底外分选). J Cell Sci 118:4243-4252。
Penning-van Beest FJ, van den Haak P, Klok RM, Prevoo YF, van derPeet DL和Herings RM (2010) Quality of life in relation to constipation amongopioid users (阿片样物质使用者中与便秘有关的生命质量). Journal of medicaleconomics 13:129-135。
Quigley C (2005) The role of opioids in cancer pain (阿片样物质在癌症疼痛中的作用). BMJ 331:825-829。
Rauck RL (2013) Treatment of Opioid-Induced Constipation: Focus onthe Peripheral mu-Opioid Receptor Antagonist Methylnaltrexone (阿片样物质诱导的便秘的治疗:集中于外周μ-阿片样物质受体拮抗剂甲基纳曲酮). Drugs 73:1297-1306。
Shailubhai K (2002) Therapeutic applications of guanylate cyclase-Creceptor agonists (鸟苷酸环化酶-C受体激动剂的治疗应用). Curr Opin Drug DiscovDevel 5:261-268。
Shailubhai K, Comiskey S, Foss JA, Feng R, Barrow L, Comer GM和JacobGS (2013) Plecanatide, an oral guanylate cyclase C agonist acting locally inthe gastrointestinal tract, is safe and well-tolerated in single doses (单剂量的胃肠道中局部起作用的口服鸟苷酸环化酶C激动剂Plecanatide是安全和耐受性良好的). Dig Dis Sci 58:2580-2586。
Shailubhai K, Yu HH, Karunanandaa K, Wang JY, Eber SL, Wang Y, JooNS, Kim HD, Miedema BW, Abbas SZ, Boddupalli SS, Currie MG和Forte LR (2000)Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse andinduces apoptosis in human colon adenocarcinoma cells via cyclic GMP (尿鸟苷肽治疗抑制Apc(Min/+)小鼠中的息肉形成并通过环状GMP诱导人结肠腺癌细胞的凋亡).Cancer Res 60:5151-5157.
Sobczak M, Salaga M, Storr MA和Fichna J (2013) Physiology, signaling, andpharmacology of opioid receptors and their ligands in the gastrointestinaltract: current concepts and future perspectives (胃肠道中阿片样物质受体及其配体的生理学、信号转导和药理学:当前概念和未来远景). J Gastroenterol。
Steinbrecher KA (2014) The multiple roles of guanylate cyclase C, aheat stable enterotoxin receptor (热稳定性肠毒素受体鸟苷酸环化酶C的多重作用).Current opinion in gastroenterology 30:1-6。
Steinbrecher KA和Cohen MB (2011) Transmembrane guanylate cyclase inintestinal pathophysiology (肠病理生理学中的跨膜鸟苷酸环化酶). Currentopinion in gastroenterology 27:139-145。
Sun X, Wang X, Wang GD, Xia Y, Liu S, Qu M, Needleman BJ, Mikami DJ,Melvin WS, Bohn LM, Ueno R和Wood JD (2011) Lubiprostone reverses theinhibitory action of morphine on mucosal secretion in human small intestine(卢比前列酮逆转吗啡对人小肠中的粘膜分泌的抑制作用). Dig Dis Sci 56:330-338。
Sykes NP (1998) The relationship between opioid use and laxative usein terminally ill cancer patients (临终疾病癌症患者中阿片样物质使用和轻泻药使用之间的关系). Palliat Med 12:375-382。
Thiagarajah JR, Broadbent T, Hsieh E和Verkman AS (2004) Prevention oftoxin-induced intestinal ion and fluid secretion by a small-molecule CFTRinhibitor (通过小分子CFTR抑制剂防止毒素诱导的肠离子和流体分泌).Gastroenterology 126:511-519。
Wang G-D, Wang X, Qu M-H, Xia Y和Wood JD (2014) 414 Reversal ofOpioid-Induced Constipation by Lubiprostone (Amitiza®) in Guinea Pig Ileum(豚鼠回肠中通过卢比前列酮(Amitiza®)逆转阿片样物质诱导的便秘).Gastroenterology 146:S-89。
Wong BS和Camilleri M (2011) Lubiprostone for the treatment of opioid-induced bowel dysfunction (用于治疗阿片样物质诱导的肠功能障碍的卢比前列酮).Expert Opin Pharmacother 12:983-990。
Zhang G, Arjunan KP, Foss J, Comiskey S和Shailubhai K (2012) SP-333,a Proteolysis-resistant Agonist of Guanylate Cyclase-C, Inhibits Activationof NF-kappa B and Suppresses Production of Inflammatory Cytokines toAmeliorate DSS-induced Colitis in Mice (鸟苷酸环化酶-C的耐蛋白酶解的激动剂SP-333抑制NF-κB的活化并抑制炎性细胞因子的产生以改善小鼠的DSS诱导的结肠炎). Am JGastroenterol 107:S626-S626。
Claims (16)
1.一种预防、治疗阿片样物质诱导的功能障碍的病况或缓解阿片样物质诱导的功能障碍的症状的方法,所述方法包括给予有需要的受试者治疗有效量的包含基本上由表2-8的任一个的氨基酸序列组成的鸟苷酸环化酶受体激动剂(GCRA)肽的组合物。
2.权利要求1中任一项的方法,所述方法进一步包括给予有效剂量的依赖cGMP的磷酸二酯酶抑制剂。
3.权利要求2的方法,其中所述依赖cGMP的磷酸二酯酶抑制剂选自舒林砜、扎普司特、莫他匹酮、伐地那非和西地那非。
4.权利要求2的方法,其中所述依赖cGMP的磷酸二酯酶抑制剂与所述GCRA肽或其药物组合物同时或序贯给予。
5. 权利要求1的方法,其中所述GCRA肽为SEQ ID NO: 1 (SP-304)、SEQ ID NO: 9(SP-333)、SP373 (SEQ ID NO: 104)、SP364 (SEQ ID NO: 100)、SP366 (SEQ ID NO: 102)或SEQ ID NO: 250。
6.一种组合物,其包含基本上由表2-8的任一个的氨基酸序列组成的鸟苷酸环化酶受体激动剂(GCRA)肽。
7.权利要求6的组合物,其进一步包含有效剂量的依赖cGMP的磷酸二酯酶抑制剂。
8.一种组合物,其包含阿片样物质和基本上由表2-8的任一个的序列组成的鸟苷酸环化酶受体激动剂(GCRA)肽。
9.权利要求8的组合物,其中所述阿片样物质和鸟苷酸环化酶受体激动剂(GCRA)肽以一个片剂或胶囊剂给予。
10.权利要求6-8中任一项的组合物,其进一步包含选自以下的一种或多种靶向物质:pH依赖性聚合物、可膨胀聚合物和可降解组合物。
11.权利要求6-8中任一项的组合物,其进一步包含药用载体、赋形剂或稀释剂。
12.权利要求10的组合物,其中使所述制剂优化以递送至十二指肠、空肠、回肠、回肠末端或升结肠。
13.权利要求10的组合物,其中使所述制剂优化以在整个结肠中释放。
14.权利要求10的组合物,其中所述制剂包含一种或多种在4.5-5.5的pH范围下、在5.5-6.5的pH范围下或在6.5-7.5的pH范围下降解的pH依赖性聚合物。
15.权利要求10的组合物,其中所述组合物的释放是时间依赖性的。
16.权利要求8的组合物,其中所述阿片样物质选吗啡、可待因、羟考酮、氢可酮、二氢可待因、丙氧芬、芬太尼、曲马多、洛哌丁胺、布托啡诺或其组合。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361889308P | 2013-10-10 | 2013-10-10 | |
US61/889308 | 2013-10-10 | ||
PCT/US2014/060157 WO2015054649A2 (en) | 2013-10-10 | 2014-10-10 | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions |
Publications (1)
Publication Number | Publication Date |
---|---|
CN106061494A true CN106061494A (zh) | 2016-10-26 |
Family
ID=52813754
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480067381.3A Pending CN106061494A (zh) | 2013-10-10 | 2014-10-10 | 可用于治疗阿片样物质诱导的功能障碍的鸟苷酸环化酶的激动剂 |
Country Status (10)
Country | Link |
---|---|
US (2) | US20160220630A1 (zh) |
EP (1) | EP3054969B1 (zh) |
JP (2) | JP6661531B2 (zh) |
CN (1) | CN106061494A (zh) |
AU (2) | AU2014331704A1 (zh) |
CA (1) | CA2926691A1 (zh) |
EA (1) | EA201690732A1 (zh) |
IL (1) | IL244970B (zh) |
MY (1) | MY176976A (zh) |
WO (1) | WO2015054649A2 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3054969B1 (en) * | 2013-10-10 | 2021-03-10 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions |
CA3001727A1 (en) * | 2015-11-18 | 2017-05-26 | Synergy Pharmaceuticals, Inc. | Compositions and method for the treatment and detection of colon cancer |
CN108884130B (zh) * | 2016-01-11 | 2022-09-13 | 博士医疗爱尔兰有限公司 | 用于治疗溃疡性结肠炎的制剂和方法 |
CN106653954B (zh) * | 2017-02-27 | 2018-06-29 | 常州亿晶光电科技有限公司 | 一种多晶硅太阳能电池用二氧化硅钝化层的制备工艺 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100120694A1 (en) * | 2008-06-04 | 2010-05-13 | Synergy Pharmaceuticals, Inc. | Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders |
CN101772513A (zh) * | 2007-06-04 | 2010-07-07 | 协同医药品公司 | 有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂 |
WO2012037380A2 (en) * | 2010-09-15 | 2012-03-22 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
CN102858361A (zh) * | 2009-12-03 | 2013-01-02 | 药物协和股份有限公司 | 用于治疗高胆固醇血症、动脉粥样硬化、冠心病、胆结石、肥胖症和其它心血管疾病的鸟苷酸环化酶的激动剂 |
Family Cites Families (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4503030A (en) | 1983-06-06 | 1985-03-05 | Alza Corporation | Device for delivering drug to certain pH environments |
US4931279A (en) | 1985-08-16 | 1990-06-05 | Bausch & Lomb Incorporated | Sustained release formulation containing an ion-exchange resin |
US4713244A (en) | 1985-08-16 | 1987-12-15 | Bausch & Lomb Incorporated | Sustained-release formulation containing an amino acid polymer with a lower alkyl (C1 -C4) polar solvent |
US4668506A (en) | 1985-08-16 | 1987-05-26 | Bausch & Lomb Incorporated | Sustained-release formulation containing and amino acid polymer |
IL77186A0 (en) | 1985-11-29 | 1986-04-29 | Touitou Elka | Pharmaceutical insulin composition |
GB2209937B (en) | 1987-09-21 | 1991-07-03 | Depiopharm S A | Water insoluble polypeptides |
US5236704A (en) | 1988-01-28 | 1993-08-17 | Sumitomo Pharmaceuticals Co., Ltd. | Controlled release formulation |
GB8812490D0 (en) | 1988-05-26 | 1988-06-29 | Agricultural & Food Res | Delayed release formulations |
JP2792862B2 (ja) | 1988-07-30 | 1998-09-03 | 寛治 高田 | 経口腸溶製剤 |
US5007790A (en) | 1989-04-11 | 1991-04-16 | Depomed Systems, Inc. | Sustained-release oral drug dosage form |
CH679207A5 (zh) | 1989-07-28 | 1992-01-15 | Debiopharm Sa | |
US5175003A (en) | 1990-04-06 | 1992-12-29 | Biosytes Usa, Inc. | Dual mechanism controlled release system for drug dosage forms |
IL98087A (en) | 1990-05-04 | 1996-11-14 | Perio Prod Ltd | Preparation for dispensing drugs in the colon |
CA2046830C (en) | 1990-07-19 | 1999-12-14 | Patrick P. Deluca | Drug delivery system involving inter-action between protein or polypeptide and hydrophobic biodegradable polymer |
CH683149A5 (fr) | 1991-07-22 | 1994-01-31 | Debio Rech Pharma Sa | Procédé pour la préparation de microsphères en matériau polymère biodégradable. |
GB9211268D0 (en) | 1992-05-28 | 1992-07-15 | Ici Plc | Salts of basic peptides with carboxyterminated polyesters |
DE69312947T2 (de) | 1992-09-21 | 1998-01-08 | Pharmacia & Upjohn Company Kal | Proteinhaftige arzneimittel mit verzögerter wirkstoffabgabe |
ATE236655T1 (de) | 1993-01-06 | 2003-04-15 | Kinerton Ltd | Ionische molekularkonjugate von bioabbaubaren polyestern und bioaktiven polypeptiden |
US5672659A (en) | 1993-01-06 | 1997-09-30 | Kinerton Limited | Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides |
US5358502A (en) | 1993-02-25 | 1994-10-25 | Pfizer Inc | PH-triggered osmotic bursting delivery devices |
DE69429927T2 (de) | 1993-11-17 | 2002-11-07 | Commw Scient Ind Res Org | Fettsäure-abgabesystem |
US5952314A (en) | 1994-04-01 | 1999-09-14 | Demichele; Stephen Joseph | Nutritional product for a person having ulcerative colitis |
ES2188657T3 (es) | 1994-04-22 | 2003-07-01 | Yamanouchi Pharma Co Ltd | Sistema para la liberacion especifica en el colon de un farmaco. |
US5612052A (en) | 1995-04-13 | 1997-03-18 | Poly-Med, Inc. | Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof |
US5877224A (en) | 1995-07-28 | 1999-03-02 | Rutgers, The State University Of New Jersey | Polymeric drug formulations |
US5980945A (en) | 1996-01-16 | 1999-11-09 | Societe De Conseils De Recherches Et D'applications Scientifique S.A. | Sustained release drug formulations |
US5912014A (en) | 1996-03-15 | 1999-06-15 | Unigene Laboratories, Inc. | Oral salmon calcitonin pharmaceutical products |
EP1479708A3 (en) | 1996-04-23 | 2005-05-25 | Ipsen Manufacturing Ireland Limited | Biodegradable polyesters and method for their preparation |
US6403130B2 (en) | 1996-09-09 | 2002-06-11 | Kiwitech Limited | High-methoxyl pectin-acid casein polymer and process of making |
US5972389A (en) | 1996-09-19 | 1999-10-26 | Depomed, Inc. | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter |
HRP970493A2 (en) | 1996-09-23 | 1998-08-31 | Wienman E. Phlips | Oral delayed immediate release medical formulation and method for preparing the same |
CA2217134A1 (en) | 1996-10-09 | 1998-04-09 | Sumitomo Pharmaceuticals Co., Ltd. | Sustained release formulation |
US5968895A (en) | 1996-12-11 | 1999-10-19 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
US5893985A (en) | 1997-03-14 | 1999-04-13 | The Lincoln Electric Company | Plasma arc torch |
JPH10324642A (ja) | 1997-03-26 | 1998-12-08 | Meiji Seika Kaisha Ltd | 大腸送達性構造体 |
DE19830375A1 (de) | 1998-07-08 | 2000-01-13 | K D Pharma Bexbach Gmbh | Mikroverkapselte ungesättigte Fettsäure oder Fettsäureverbindung oder Mischung aus Fettsäuren und/oder Fettsäureverbindungen |
US6531152B1 (en) | 1998-09-30 | 2003-03-11 | Dexcel Pharma Technologies Ltd. | Immediate release gastrointestinal drug delivery system |
IT1304152B1 (it) | 1998-12-10 | 2001-03-08 | Mediolanum Farmaceutici Srl | Composizioni comprendenti un peptide ed acido polilattico-glicolicoatte alla preparazione di impianti sottocutanei aventi un prolungato |
SK288541B6 (sk) | 1999-03-31 | 2018-03-05 | Janssen Pharmaceutica N. V. | Predželatínovaný škrob v hydrofilnej formulácii s riadeným uvoľňovaním |
US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
EP1194128A2 (en) | 1999-06-23 | 2002-04-10 | Sedum Laboratories | Ionically formulated biomolecule microcarriers |
JP4303438B2 (ja) | 1999-08-18 | 2009-07-29 | ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス | ペプチドの持続放出製剤 |
US7521061B2 (en) | 1999-12-31 | 2009-04-21 | Rutgers, The State University Of New Jersey | Pharmaceutical formulation for regulating the timed release of biologically active compounds based on a polymer matrix |
JP2003519164A (ja) | 1999-12-31 | 2003-06-17 | ルトガーズ、ザ ステイト ユニバーシティ | ポリマーマトリクスに基づく生理活性化合物徐放調節用医薬製剤 |
US7326425B2 (en) | 1999-12-31 | 2008-02-05 | Rutgers, The State University | Pharmaceutical formulation composed of a polymer blend and an active compound for time-controlled release |
US20030064105A1 (en) | 2000-08-25 | 2003-04-03 | Myung-Jin Kim | Lipophilic-coated microparticle containing a protein drug and formulation comprising same |
PH12001000675B1 (en) | 2000-04-04 | 2009-09-22 | Australian Food Ind Sci Ct | Encapsulation of food ingredients |
GB0025208D0 (en) | 2000-10-13 | 2000-11-29 | Euro Celtique Sa | Delayed release pharmaceutical formulations |
DE10055857A1 (de) | 2000-11-10 | 2002-08-22 | Creative Peptides Sweden Ab Dj | Neue pharmazeutische Depotformulierung |
US6673574B2 (en) | 2000-11-30 | 2004-01-06 | Unigene Laboratories Inc. | Oral delivery of peptides using enzyme-cleavable membrane translocators |
CA2435415A1 (en) | 2001-01-26 | 2002-08-01 | Debio Recherche Pharmaceutique S.A. | Microparticles of biodegradable polymer encapsulating a biologically active substance |
US7316819B2 (en) | 2001-03-08 | 2008-01-08 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
HUP0501071A3 (en) | 2001-03-13 | 2007-06-28 | Penwest Pharmaceutical Co | Chronotherapeutic dosage forms |
WO2002074247A2 (en) | 2001-03-19 | 2002-09-26 | Praecis Pharmaceuticals Incorporated | Pharmaceutical formulations for sustained release |
DK2322631T3 (en) | 2001-04-19 | 2015-01-12 | Scripps Research Inst | Methods and compositions for the production of orthogonal tRNA-aminoacyl-tRNA syntetasepar |
AU2002319653A1 (en) | 2001-07-20 | 2003-03-03 | Samir Mitragotri | Method for oral drug delivery |
US20030091630A1 (en) | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
CA2409552A1 (en) | 2001-10-25 | 2003-04-25 | Depomed, Inc. | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
CN1606432A (zh) | 2001-12-19 | 2005-04-13 | 阿尔扎公司 | 用于增加亲水性大分子的口服生物利用度的制剂和剂型 |
EP1480618B1 (en) | 2002-03-04 | 2009-06-03 | Ipsen Pharma | Sustained release drug formulations containing a carrier peptide |
WO2003086297A2 (en) | 2002-04-08 | 2003-10-23 | Lavipharm Laboratories, Inc. | Multi-layer mucoadhesive drug delivery device with bursting release layer |
GB0214013D0 (en) | 2002-06-18 | 2002-07-31 | Euro Celtique Sa | Pharmaceutical product |
AU2003270009A1 (en) | 2002-08-30 | 2004-03-19 | Biorexis Pharmaceutical Corporation | Oral delivery of modified transferrin fusion proteins |
CA2503150A1 (en) | 2002-10-31 | 2004-05-21 | Supergen, Inc. | Pharmaceutical formulations targeting specific regions of the gastrointestinal tract |
US7670627B2 (en) | 2002-12-09 | 2010-03-02 | Salvona Ip Llc | pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients |
WO2004064769A2 (en) | 2003-01-21 | 2004-08-05 | Hector Herrera | Methods for making and using topical delivery agents |
EP1597349A4 (en) | 2003-02-21 | 2007-02-14 | Queens Medical Ct | METHODS OF SCREENING TRPM5 MODULATORS |
CA2529307C (en) * | 2003-06-13 | 2013-12-24 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
WO2004112711A2 (en) | 2003-06-16 | 2004-12-29 | Andrx Pharmaceuticals, Llc | Oral extended-release composition |
MXPA06003100A (es) | 2003-09-19 | 2006-06-20 | Penwest Pharmaceuticals Co | Formas de dosis de liberacion retardada. |
CA2540059C (en) | 2003-09-26 | 2013-08-06 | Alza Corporation | Controlled release formulations exhibiting an ascending rate of release |
WO2005048998A1 (en) | 2003-11-21 | 2005-06-02 | Commonwealth Scientific & Industrial Research Organisation | G i tract delivery systems |
US20050136121A1 (en) | 2003-12-22 | 2005-06-23 | Shear/Kershman Laboratories, Inc. | Oral peptide delivery system with improved bioavailability |
CA2550866A1 (en) | 2003-12-23 | 2005-07-14 | Alza Corporation | Methods and dosage forms for increasing solubility of drug compositions for controlled delivery |
BRPI0512396A (pt) | 2004-07-21 | 2008-03-11 | Ambrx Inc | polipeptìdeos biossintéticos utilizando aminoácidos codificados não naturalmente |
WO2009149278A1 (en) * | 2008-06-04 | 2009-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
CA2994066A1 (en) * | 2008-12-03 | 2010-06-10 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase c agonists and methods of use |
US9616097B2 (en) * | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
EP3054969B1 (en) * | 2013-10-10 | 2021-03-10 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions |
-
2014
- 2014-10-10 EP EP14851594.3A patent/EP3054969B1/en active Active
- 2014-10-10 CA CA2926691A patent/CA2926691A1/en not_active Abandoned
- 2014-10-10 CN CN201480067381.3A patent/CN106061494A/zh active Pending
- 2014-10-10 US US15/026,563 patent/US20160220630A1/en not_active Abandoned
- 2014-10-10 JP JP2016521789A patent/JP6661531B2/ja active Active
- 2014-10-10 MY MYPI2016000617A patent/MY176976A/en unknown
- 2014-10-10 AU AU2014331704A patent/AU2014331704A1/en not_active Abandoned
- 2014-10-10 EA EA201690732A patent/EA201690732A1/ru unknown
- 2014-10-10 WO PCT/US2014/060157 patent/WO2015054649A2/en active Application Filing
-
2016
- 2016-04-06 IL IL244970A patent/IL244970B/en active IP Right Grant
-
2019
- 2019-11-07 JP JP2019202043A patent/JP2020037570A/ja active Pending
- 2019-12-20 AU AU2019284019A patent/AU2019284019A1/en not_active Abandoned
-
2020
- 2020-05-14 US US16/874,218 patent/US20200330548A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101772513A (zh) * | 2007-06-04 | 2010-07-07 | 协同医药品公司 | 有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂 |
US20100120694A1 (en) * | 2008-06-04 | 2010-05-13 | Synergy Pharmaceuticals, Inc. | Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders |
CN102858361A (zh) * | 2009-12-03 | 2013-01-02 | 药物协和股份有限公司 | 用于治疗高胆固醇血症、动脉粥样硬化、冠心病、胆结石、肥胖症和其它心血管疾病的鸟苷酸环化酶的激动剂 |
WO2012037380A2 (en) * | 2010-09-15 | 2012-03-22 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
Also Published As
Publication number | Publication date |
---|---|
EA201690732A1 (ru) | 2016-12-30 |
EP3054969B1 (en) | 2021-03-10 |
AU2019284019A1 (en) | 2020-01-23 |
CA2926691A1 (en) | 2015-04-16 |
JP6661531B2 (ja) | 2020-03-11 |
WO2015054649A2 (en) | 2015-04-16 |
AU2014331704A1 (en) | 2016-04-28 |
IL244970B (en) | 2020-08-31 |
US20160220630A1 (en) | 2016-08-04 |
US20200330548A1 (en) | 2020-10-22 |
WO2015054649A3 (en) | 2015-08-06 |
MY176976A (en) | 2020-08-28 |
IL244970A0 (en) | 2016-05-31 |
JP2020037570A (ja) | 2020-03-12 |
JP2016538249A (ja) | 2016-12-08 |
EP3054969A2 (en) | 2016-08-17 |
EP3054969A4 (en) | 2017-03-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2014218599B2 (en) | Guanylate cyclase receptor agonists for use in colonic cleansing | |
ES2627848T3 (es) | Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos | |
US8748575B2 (en) | Therapeutic peptides | |
CN102822194B (zh) | 用于胃肠病症的治疗 | |
JP2007501866A (ja) | 胃腸疾患の治療のための方法および組成物 | |
CN108348574A (zh) | 具有对抗革兰氏阴性菌的活性的溶素多肽 | |
US20200330548A1 (en) | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions | |
ES2638589T3 (es) | Tratamientos para trastornos intestinales | |
TW201116291A (en) | Treatments for gastrointestinal disorders | |
JP2024015335A (ja) | 結腸洗浄及び胃腸障害の治療のための組成物 | |
US9650417B2 (en) | Treatments for gastrointestinal disorders | |
US20140348942A1 (en) | Treatments for Gastrointestinal Disorders | |
US9527887B2 (en) | Treatments for gastrointestinal disorders | |
US20200009215A1 (en) | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions | |
CN108884130A (zh) | 用于治疗溃疡性结肠炎的制剂和方法 | |
EA040600B1 (ru) | Агонисты гуанилатциклазы, используемые для лечения индуцированных опиоидами дисфункций | |
JPH07285879A (ja) | 合成ペプチドの経口投与用製剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20200420 Address after: Ai Erlandubailin Applicant after: Doctor medical Ireland Limited Address before: New York, USA Applicant before: SYNERGY PHARMACEUTICALS, Inc. |
|
TA01 | Transfer of patent application right | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20161026 |
|
WD01 | Invention patent application deemed withdrawn after publication |