JP2019001800A - 片頭痛の治療または予防法 - Google Patents
片頭痛の治療または予防法 Download PDFInfo
- Publication number
- JP2019001800A JP2019001800A JP2018154482A JP2018154482A JP2019001800A JP 2019001800 A JP2019001800 A JP 2019001800A JP 2018154482 A JP2018154482 A JP 2018154482A JP 2018154482 A JP2018154482 A JP 2018154482A JP 2019001800 A JP2019001800 A JP 2019001800A
- Authority
- JP
- Japan
- Prior art keywords
- cgrp receptor
- binding fragment
- antigen
- migraine
- receptor antibody
- 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.)
- Granted
Links
- 206010027599 migraine Diseases 0.000 title claims abstract description 384
- 208000019695 Migraine disease Diseases 0.000 title claims abstract description 351
- 238000000034 method Methods 0.000 title claims abstract description 227
- 102000005962 receptors Human genes 0.000 claims abstract description 410
- 108020003175 receptors Proteins 0.000 claims abstract description 410
- 230000027455 binding Effects 0.000 claims abstract description 388
- 239000012634 fragment Substances 0.000 claims abstract description 377
- 239000000427 antigen Substances 0.000 claims abstract description 270
- 108091007433 antigens Proteins 0.000 claims abstract description 270
- 102000036639 antigens Human genes 0.000 claims abstract description 270
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 119
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 65
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 54
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 claims abstract description 17
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 claims abstract 2
- 229960004015 calcitonin Drugs 0.000 claims abstract 2
- 238000011282 treatment Methods 0.000 claims description 114
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 claims description 77
- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 claims description 75
- 239000003814 drug Substances 0.000 claims description 72
- 230000000694 effects Effects 0.000 claims description 72
- 150000001413 amino acids Chemical class 0.000 claims description 64
- 229920001184 polypeptide Polymers 0.000 claims description 56
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 56
- 229940079593 drug Drugs 0.000 claims description 52
- DNKYDHSONDSTNJ-XJVRLEFXSA-N chembl1910953 Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C1=CN=CN1 DNKYDHSONDSTNJ-XJVRLEFXSA-N 0.000 claims description 48
- 229930006000 Sucrose Natural products 0.000 claims description 46
- 239000005720 sucrose Substances 0.000 claims description 46
- 238000011321 prophylaxis Methods 0.000 claims description 41
- 230000000306 recurrent effect Effects 0.000 claims description 41
- 230000002411 adverse Effects 0.000 claims description 32
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 28
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 28
- 229940068968 polysorbate 80 Drugs 0.000 claims description 28
- 229920000053 polysorbate 80 Polymers 0.000 claims description 28
- 102100024654 Calcitonin gene-related peptide type 1 receptor Human genes 0.000 claims description 27
- 101000584583 Homo sapiens Receptor activity-modifying protein 1 Proteins 0.000 claims description 27
- 230000003449 preventive effect Effects 0.000 claims description 26
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 20
- 230000007423 decrease Effects 0.000 claims description 20
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 20
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 20
- 229940068977 polysorbate 20 Drugs 0.000 claims description 20
- 102000050292 human RAMP1 Human genes 0.000 claims description 19
- 239000004094 surface-active agent Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- 239000000935 antidepressant agent Substances 0.000 claims description 17
- 229940005513 antidepressants Drugs 0.000 claims description 17
- 229940090047 auto-injector Drugs 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 16
- 238000007920 subcutaneous administration Methods 0.000 claims description 16
- 239000003381 stabilizer Substances 0.000 claims description 14
- 239000000872 buffer Substances 0.000 claims description 13
- 239000008351 acetate buffer Substances 0.000 claims description 12
- 230000001430 anti-depressive effect Effects 0.000 claims description 11
- 239000002876 beta blocker Substances 0.000 claims description 11
- 229940097320 beta blocking agent Drugs 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 8
- 238000007911 parenteral administration Methods 0.000 claims description 6
- 101000760563 Homo sapiens Calcitonin gene-related peptide type 1 receptor Proteins 0.000 claims description 5
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 5
- 125000000185 sucrose group Chemical group 0.000 claims description 5
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 5
- 230000003252 repetitive effect Effects 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 description 73
- 210000004027 cell Anatomy 0.000 description 63
- 229940024606 amino acid Drugs 0.000 description 60
- 229940068196 placebo Drugs 0.000 description 58
- 239000000902 placebo Substances 0.000 description 58
- 230000037396 body weight Effects 0.000 description 45
- 206010019233 Headaches Diseases 0.000 description 42
- 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 41
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 40
- 231100000869 headache Toxicity 0.000 description 40
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 36
- 239000001632 sodium acetate Substances 0.000 description 36
- 235000017281 sodium acetate Nutrition 0.000 description 36
- 125000003275 alpha amino acid group Chemical group 0.000 description 34
- 230000005764 inhibitory process Effects 0.000 description 31
- 102000004169 proteins and genes Human genes 0.000 description 31
- 238000002347 injection Methods 0.000 description 30
- 239000007924 injection Substances 0.000 description 30
- 235000018102 proteins Nutrition 0.000 description 30
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 29
- 230000009467 reduction Effects 0.000 description 27
- 101710118454 Calcitonin gene-related peptide type 1 receptor Proteins 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 23
- 239000013598 vector Substances 0.000 description 23
- 235000017663 capsaicin Nutrition 0.000 description 20
- 229960002504 capsaicin Drugs 0.000 description 20
- 230000008859 change Effects 0.000 description 20
- 238000006467 substitution reaction Methods 0.000 description 20
- 108010076504 Protein Sorting Signals Proteins 0.000 description 18
- 229940071643 prefilled syringe Drugs 0.000 description 18
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 18
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 18
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 16
- 125000000539 amino acid group Chemical group 0.000 description 16
- 238000003556 assay Methods 0.000 description 16
- 230000014509 gene expression Effects 0.000 description 16
- 230000002354 daily effect Effects 0.000 description 15
- 230000006870 function Effects 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 14
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 14
- 210000004408 hybridoma Anatomy 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- 229960004394 topiramate Drugs 0.000 description 14
- 239000003446 ligand Substances 0.000 description 13
- 230000002265 prevention Effects 0.000 description 13
- 108060003951 Immunoglobulin Proteins 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 102000018358 immunoglobulin Human genes 0.000 description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 11
- 239000003623 enhancer Substances 0.000 description 11
- 230000001965 increasing effect Effects 0.000 description 11
- 229920000136 polysorbate Polymers 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000013604 expression vector Substances 0.000 description 10
- 229950008882 polysorbate Drugs 0.000 description 10
- 238000002203 pretreatment Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 241000894007 species Species 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 9
- 229960000836 amitriptyline Drugs 0.000 description 9
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 9
- 229960004943 ergotamine Drugs 0.000 description 9
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 9
- 229960003712 propranolol Drugs 0.000 description 9
- 238000012216 screening Methods 0.000 description 9
- 101500025150 Homo sapiens Adrenomedullin-2 Proteins 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 150000007523 nucleic acids Chemical class 0.000 description 8
- 238000010254 subcutaneous injection Methods 0.000 description 8
- 239000007929 subcutaneous injection Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 108020004707 nucleic acids Proteins 0.000 description 7
- 102000039446 nucleic acids Human genes 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 229940043274 prophylactic drug Drugs 0.000 description 7
- 230000008326 skin blood flow Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 108091026890 Coding region Proteins 0.000 description 6
- 101100239636 Homo sapiens MYCBP gene Proteins 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 6
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 6
- 102100030697 Receptor activity-modifying protein 1 Human genes 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 6
- 238000012217 deletion Methods 0.000 description 6
- 230000037430 deletion Effects 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 238000003780 insertion Methods 0.000 description 6
- 230000037431 insertion Effects 0.000 description 6
- 238000002483 medication Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 239000002736 nonionic surfactant Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 108091033319 polynucleotide Proteins 0.000 description 6
- 102000040430 polynucleotide Human genes 0.000 description 6
- 239000002157 polynucleotide Substances 0.000 description 6
- 230000000069 prophylactic effect Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000009261 transgenic effect Effects 0.000 description 6
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 6
- 229960000604 valproic acid Drugs 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 206010028813 Nausea Diseases 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 5
- 102000025171 antigen binding proteins Human genes 0.000 description 5
- 108091000831 antigen binding proteins Proteins 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000010367 cloning Methods 0.000 description 5
- 235000018417 cysteine Nutrition 0.000 description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- 230000006735 deficit Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000008693 nausea Effects 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 4
- 108010001789 Calcitonin Receptors Proteins 0.000 description 4
- 102100038520 Calcitonin receptor Human genes 0.000 description 4
- 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 4
- 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 4
- 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 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 208000027109 Headache disease Diseases 0.000 description 4
- 101001081479 Homo sapiens Islet amyloid polypeptide Proteins 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 229940125684 antimigraine agent Drugs 0.000 description 4
- 239000002282 antimigraine agent Substances 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 238000013262 cAMP assay Methods 0.000 description 4
- 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 description 4
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 4
- 230000009610 hypersensitivity Effects 0.000 description 4
- 230000002163 immunogen 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
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 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 description 4
- 230000035772 mutation Effects 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 235000010356 sorbitol Nutrition 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229960004605 timolol Drugs 0.000 description 4
- 238000011830 transgenic mouse model Methods 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- 230000008673 vomiting Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101800001511 Adrenomedullin-2 Proteins 0.000 description 3
- 102100033770 Alpha-amylase 1C Human genes 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 101000779871 Homo sapiens Alpha-amylase 1A Proteins 0.000 description 3
- 101000779870 Homo sapiens Alpha-amylase 1B Proteins 0.000 description 3
- 101000779869 Homo sapiens Alpha-amylase 1C Proteins 0.000 description 3
- 101000584590 Homo sapiens Receptor activity-modifying protein 2 Proteins 0.000 description 3
- 101000584593 Homo sapiens Receptor activity-modifying protein 3 Proteins 0.000 description 3
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 3
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-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
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- 206010027603 Migraine headaches Diseases 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100032586 Protein ADM2 Human genes 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 108010022394 Threonine synthase Proteins 0.000 description 3
- 108010045627 Type I Pituitary Adenylate Cyclase-Activating Polypeptide Receptors Proteins 0.000 description 3
- 102000005737 Type I Pituitary Adenylate Cyclase-Activating Polypeptide Receptors Human genes 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960001948 caffeine Drugs 0.000 description 3
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 102000004419 dihydrofolate reductase Human genes 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000002173 dizziness Diseases 0.000 description 3
- 230000002996 emotional effect Effects 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 238000002825 functional assay Methods 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 229940090048 pen injector Drugs 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000012658 prophylactic medication Substances 0.000 description 3
- 235000019833 protease Nutrition 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- -1 sorbitan ester Chemical class 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 210000004989 spleen cell Anatomy 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- WKEMJKQOLOHJLZ-UHFFFAOYSA-N Almogran Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CS(=O)(=O)N1CCCC1 WKEMJKQOLOHJLZ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 102000014468 Calcitonin Gene-Related Peptide Receptors Human genes 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- 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 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- 241000206602 Eukaryota Species 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 101000732641 Homo sapiens Alpha-amylase 2B Proteins 0.000 description 2
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 2
- 101000693011 Homo sapiens Pancreatic alpha-amylase Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 2
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 2
- 102000000704 Interleukin-7 Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 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 description 2
- 102100026367 Pancreatic alpha-amylase Human genes 0.000 description 2
- 108010067372 Pancreatic elastase Proteins 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102100030711 Receptor activity-modifying protein 3 Human genes 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 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
- 108010057266 Type A Botulinum Toxins Proteins 0.000 description 2
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 2
- 241000711975 Vesicular stomatitis virus Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000001261 affinity purification Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960002133 almotriptan Drugs 0.000 description 2
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000008901 benefit Effects 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
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- 230000008512 biological response Effects 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 229940094657 botulinum toxin type a Drugs 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003093 cationic surfactant Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000012875 competitive assay Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 229940095074 cyclic amp Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
- HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 description 2
- 229960004704 dihydroergotamine Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 229960002472 eletriptan Drugs 0.000 description 2
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- 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 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229960002284 frovatriptan Drugs 0.000 description 2
- SIBNYOSJIXCDRI-SECBINFHSA-N frovatriptan Chemical compound C1=C(C(N)=O)[CH]C2=C(C[C@H](NC)CC3)C3=NC2=C1 SIBNYOSJIXCDRI-SECBINFHSA-N 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 108060003196 globin Proteins 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 229960000240 hydrocodone Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940100994 interleukin-7 Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000002563 ionic surfactant Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229960000318 kanamycin Drugs 0.000 description 2
- 229930027917 kanamycin Natural products 0.000 description 2
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[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@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 2
- 229930182823 kanamycin A Natural products 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 229960005254 naratriptan Drugs 0.000 description 2
- AMKVXSZCKVJAGH-UHFFFAOYSA-N naratriptan Chemical compound C12=CC(CCS(=O)(=O)NC)=CC=C2NC=C1C1CCN(C)CC1 AMKVXSZCKVJAGH-UHFFFAOYSA-N 0.000 description 2
- 230000010807 negative regulation of binding Effects 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000001668 nucleic acid synthesis Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 229960002085 oxycodone Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000008447 perception Effects 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- 238000009522 phase III clinical trial Methods 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 230000037081 physical activity Effects 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 230000008569 process Effects 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
- 235000019419 proteases Nutrition 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000000541 pulsatile effect Effects 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 229960000425 rizatriptan Drugs 0.000 description 2
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000001953 sensory effect 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
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 229960003708 sumatriptan Drugs 0.000 description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 229960001360 zolmitriptan Drugs 0.000 description 2
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 2
- 239000002888 zwitterionic surfactant Substances 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
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical group COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 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 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- QKCKCXFWENOGER-UHFFFAOYSA-N 2-phenyloxazol-5(4H)-one Chemical compound O1C(=O)CN=C1C1=CC=CC=C1 QKCKCXFWENOGER-UHFFFAOYSA-N 0.000 description 1
- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 description 1
- 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 description 1
- 101710138639 5-hydroxytryptamine receptor 1B Proteins 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 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 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 241000713842 Avian sarcoma virus Species 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- 108091062157 Cis-regulatory element Proteins 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 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
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 208000010541 Familial or sporadic hemiplegic migraine Diseases 0.000 description 1
- 241000724791 Filamentous phage Species 0.000 description 1
- 241000700662 Fowlpox virus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 206010019476 Hemiplegic migraine Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000741445 Homo sapiens Calcitonin Proteins 0.000 description 1
- 101000741435 Homo sapiens Calcitonin receptor Proteins 0.000 description 1
- 101000690940 Homo sapiens Pro-adrenomedullin Proteins 0.000 description 1
- 208000033830 Hot Flashes Diseases 0.000 description 1
- 206010060800 Hot flush Diseases 0.000 description 1
- 241000701109 Human adenovirus 2 Species 0.000 description 1
- 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 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000010787 Interleukin-4 Receptors Human genes 0.000 description 1
- 108010038486 Interleukin-4 Receptors Proteins 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 241000110847 Kochia Species 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-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
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 240000004516 Madia sativa Species 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000019430 Motor disease Diseases 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 101710107068 Myelin basic protein Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 206010036086 Polymenorrhoea Diseases 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 229920002651 Polysorbate 85 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101710176177 Protein A56 Proteins 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
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 102100030696 Receptor activity-modifying protein 2 Human genes 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010052784 Retinal migraine Diseases 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 208000020764 Sensation disease Diseases 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 206010066901 Treatment failure Diseases 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
- 206010044565 Tremor Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 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
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- ULCUCJFASIJEOE-NPECTJMMSA-N adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 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
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-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
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- BTBJBAZGXNKLQC-UHFFFAOYSA-N ammonium lauryl sulfate Chemical compound [NH4+].CCCCCCCCCCCCOS([O-])(=O)=O BTBJBAZGXNKLQC-UHFFFAOYSA-N 0.000 description 1
- 229940063953 ammonium lauryl sulfate Drugs 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 101150062861 amy3 gene Proteins 0.000 description 1
- 108091005466 amylin receptors Proteins 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940124433 antimigraine drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 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 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000009141 biological interaction Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 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
- 239000002738 chelating agent Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- MRUAUOIMASANKQ-UHFFFAOYSA-N cocamidopropyl betaine Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O MRUAUOIMASANKQ-UHFFFAOYSA-N 0.000 description 1
- 229940073507 cocamidopropyl betaine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- WOQQAWHSKSSAGF-WXFJLFHKSA-N decyl beta-D-maltopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 WOQQAWHSKSSAGF-WXFJLFHKSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 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 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- SYELZBGXAIXKHU-UHFFFAOYSA-N dodecyldimethylamine N-oxide Chemical compound CCCCCCCCCCCC[N+](C)(C)[O-] SYELZBGXAIXKHU-UHFFFAOYSA-N 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 102000018146 globin Human genes 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 102000046663 human ADM Human genes 0.000 description 1
- 102000050254 human CALCRL Human genes 0.000 description 1
- 229940045644 human calcitonin Drugs 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229960002163 hydrogen peroxide Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000008449 language Effects 0.000 description 1
- 208000011977 language disease Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000011159 matrix material Substances 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
- 238000010197 meta-analysis Methods 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 108010065781 myosin light chain 2 Proteins 0.000 description 1
- DVEKCXOJTLDBFE-UHFFFAOYSA-N n-dodecyl-n,n-dimethylglycinate Chemical compound CCCCCCCCCCCC[N+](C)(C)CC([O-])=O DVEKCXOJTLDBFE-UHFFFAOYSA-N 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000022082 negative regulation of vasoconstriction Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000036565 night sweats Effects 0.000 description 1
- 206010029410 night sweats Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 230000027086 plasmid maintenance Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 210000004896 polypeptide structure Anatomy 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940113171 polysorbate 85 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 238000013105 post hoc analysis Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000001498 protein fragment complementation assay Methods 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 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
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000037439 somatic mutation Effects 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
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000008362 succinate buffer Substances 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 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
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Treatment And Processing Of Natural Fur Or Leather (AREA)
Abstract
Description
本出願は、2015年4月24日出願の米国仮出願第62/152,708号の利益を請求し、米国仮出願第62/152,708号は、本明細書中参照としてそのまま全体が援用される。
本出願は、ASCIIフォーマットで電子出願された配列表を含み、この配列表は、参照としてそのまま全体が援用される。コンピューターで読み取り可能なフォーマットの配列表コピーは、2015年8月3日付で作成されており、ファイル名はA−1945−WO−PCT_ST25.txtであり、ファイルサイズは134キロバイトである。
本発明は、神経学及び生物製剤の分野に関する。詳細には、本発明は、ヒトカルシトニン遺伝子関連ペプチド(CGRP)受容体を選択的に阻害する抗体を用いた、片頭痛の予防的治療に関する。
(a)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号14、23、及び34の配列を有する;
(b)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号15、24、及び35の配列を有する;
(c)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号16、25、及び36の配列を有する;
(d)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号17、26、及び37の配列を有する;
(e)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号18、27、及び38の配列を有する;
(f)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号15、29、及び35の配列を有する;
(g)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号20、30、及び40の配列を有する;
(h)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号15、31、及び35の配列を有する;
(i)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号14、23、及び41の配列を有する;
(j)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号21、32、及び42の配列を有する;
(k)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号22、33、及び43の配列を有する;または
(l)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号19、28、及び39の配列を有する。
(a)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号44、55、及び65の配列を有する;
(b)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号45、56、及び66の配列を有する;
(c)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号46、57、及び67の配列を有する;
(d)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号47、58、及び68の配列を有する;
(e)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号48、59、及び69の配列を有する;
(f)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号49、60、及び70の配列を有する;
(g)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号50、59、及び69の配列を有する;
(h)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号45、61、及び66の配列を有する;
(i)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号51、62、及び71の配列を有する;
(j)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号52、59、及び69の配列を有する;
(k)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号53、63、及び72の配列を有する;
(l)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号54、64、及び73の配列を有する;または
(m)CDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号54、64、及び74の配列を有する。
(a)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号14、23、及び34の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号44、55、及び65の配列を有する;
(b)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号14、23、及び41の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号44、55、及び65の配列を有する;
(c)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号15、24、及び35の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号45、56、及び66の配列を有する;
(d)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号15、29、及び35の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号45、61、及び66の配列を有する;
(e)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号15、31、及び35の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号45、61、及び66の配列を有する;
(f)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号16、25、及び36の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号46、57、及び67の配列を有する;
(g)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号17、26、及び37の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号47、58、及び68の配列を有する;
(h)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号18、27、及び38の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号48、59、及び69の配列を有する;
(i)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号18、27、及び38の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号50、59、及び69の配列を有する;
(j)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号19、28、及び39の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号49、60、及び70の配列を有する;
(k)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号20、30、及び40の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号51、62、及び71の配列を有する;
(l)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号21、32、及び42の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号53、63、及び72の配列を有する;
(m)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号22、33、及び43の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号54、64、及び73の配列を有する;または
(n)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号22、33、及び43の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号54、64、及び74の配列を有する;または
(o)CDRH1、CDRH2、及びCDRH3は、それぞれ、配列番号18、27、及び38の配列を有し、かつCDRL1、CDRL2、及びCDRL3は、それぞれ、配列番号52、59、及び69の配列を有する。
(a)VLは配列番号75の配列を含み、かつVHは配列番号92の配列を含む;
(b)VLは配列番号76の配列を含み、かつVHは配列番号93の配列を含む;
(c)VLは配列番号77の配列を含み、かつVHは配列番号94の配列を含む;
(d)VLは配列番号78の配列を含み、かつVHは配列番号95の配列を含む;
(e)VLは配列番号79の配列を含み、かつVHは配列番号96の配列を含む;
(f)VLは配列番号80の配列を含み、かつVHは配列番号92の配列を含む;
(g)VLは配列番号81の配列を含み、かつVHは配列番号97の配列を含む;
(h)VLは配列番号82の配列を含み、かつVHは配列番号96の配列を含む;
(i)VLは配列番号83の配列を含み、かつVHは配列番号92の配列を含む;
(j)VLは配列番号84の配列を含み、かつVHは配列番号98の配列を含む;
(k)VLは配列番号85の配列を含み、かつVHは配列番号99の配列を含む;
(l)VLは配列番号86の配列を含み、かつVHは配列番号100の配列を含む;
(m)VLは配列番号86の配列を含み、かつVHは配列番号101の配列を含む;
(n)VLは配列番号87の配列を含み、かつVHは配列番号96の配列を含む;
(o)VLは配列番号88の配列を含み、かつVHは配列番号102の配列を含む;
(p)VLは配列番号89の配列を含み、かつVHは配列番号103の配列を含む;
(q)VLは配列番号90の配列を含み、かつVHは配列番号104の配列を含む;または
(r)VLは配列番号91の配列を含み、かつVHは配列番号104の配列を含む。
(a)配列番号105の配列を含む重鎖及び配列番号118の配列を含む軽鎖;
(b)配列番号106の配列を含む重鎖及び配列番号119の配列を含む軽鎖;
(c)配列番号107の配列を含む重鎖及び配列番号120の配列を含む軽鎖;
(d)配列番号108の配列を含む重鎖及び配列番号121の配列を含む軽鎖;
(e)配列番号109の配列を含む重鎖及び配列番号122の配列を含む軽鎖;
(f)配列番号105の配列を含む重鎖及び配列番号123の配列を含む軽鎖;
(g)配列番号110の配列を含む重鎖及び配列番号124の配列を含む軽鎖;
(h)配列番号109の配列を含む重鎖及び配列番号125の配列を含む軽鎖;
(i)配列番号105の配列を含む重鎖及び配列番号126の配列を含む軽鎖;
(j)配列番号111の配列を含む重鎖及び配列番号127の配列を含む軽鎖;
(k)配列番号112の配列を含む重鎖及び配列番号128の配列を含む軽鎖;
(l)配列番号113の配列を含む重鎖及び配列番号129の配列を含む軽鎖;
(m)配列番号114の配列を含む重鎖及び配列番号129の配列を含む軽鎖;
(n)配列番号109の配列を含む重鎖及び配列番号130の配列を含む軽鎖;
(o)配列番号115の配列を含む重鎖及び配列番号131の配列を含む軽鎖;
(p)配列番号116の配列を含む重鎖及び配列番号132の配列を含む軽鎖;
(q)配列番号117の配列を含む重鎖及び配列番号133の配列を含む軽鎖;または
(r)配列番号117の配列を含む重鎖及び配列番号134の配列を含む軽鎖。
AMG334(本明細書中、抗体4E4とも称する)は、高いin vitro力価でヒトCGRP受容体と結合する完全ヒトIgG2モノクローナル抗体である。皮膚血流(DBF)のカプサイシン(CAP)誘導型増加の阻害は、CGRP受容体アンタゴニストの薬物動態学的効果を特性決定するための翻訳モデルとして広く使用されてきた。この確証されたモデルを使用して、AMG334の単回及び複数回投与後の、AMG334の薬物動態学的効果の特性決定、ならびに健康な対象者(HS)及び片頭痛患者(MP)におけるDBFのCAP誘導型増加に対するAMG334の阻害効果の定量を行った。
片頭痛は、日常生活に支障をきたす頭痛であり、この頭痛にはカルシトニン遺伝子関連ペプチド(CGRP)が関与すると思われる。AMG334(4E4抗体)は、CGRP受容体に対する完全ヒトモノクローナル抗体である。これらの第I相、無作為化、プラセボ対照、単回投与(SD)及び複数回投与(MD)試験では、健康な対象者及び片頭痛患者におけるAMG334の薬物動態学(PK)、薬力学(PD)、及び安全性を評価した。
この第II相、二重盲検、プラセボ対照臨床では、反復性片頭痛の予防におけるAMG334(すなわち4E4抗体)の効果を評価した。
この第II相臨床試験では、慢性片頭痛の予防におけるAMG334(すなわち4E4抗体)の効果をプラセボと比較して評価した。
・ベースライン相中、頭痛日数が≧15日であり、頭痛日数のうち≧8日は片頭痛基準を満たす;
・ベースライン相中、≧4回の明らかな頭痛エピソードがあり、エピソードはそれぞれ、4時間以上継続するか、または、それより短い場合は、カレンダー上の同一日にトリプタンまたは麦角誘導体の使用を伴うものであった;及び
・eダイアリーの少なくとも80%順守を示した(例えば、ベースライン相中、28日のうち少なくとも23日はeダイアリーの項目を全部記入しなければならない)。
・慢性片頭痛のある患者で、月々の片頭痛日数のベースラインからの変化;
・月々の片頭痛日数にベースラインから少なくとも50%の減少がある対象者の割合;
・慢性片頭痛のある患者で、月々の片頭痛発作のベースラインからの減少;
・片頭痛身体機能インパクトダイアリー(MPFID)により測定した場合の経時的な身体的支障の変化;及び
・MPFIDにより測定した場合の経時的な日々の活動に対する影響の変化。
この臨床試験の第一目的は、反復性片頭痛のある対象者における、月々の片頭痛の平均日数のベースラインからの変化について、プラセボと比較したAMG334(すなわち4E4抗体)の効果を評価することである。臨床試験の第二目的には、月々の片頭痛の平均日数のベースラインから少なくとも50%の減少を示す対象者の割合、月々の急性片頭痛専用薬治療の平均日数のベースラインからの変化、片頭痛身体機能インパクトダイアリー(MPFID)により測定した場合の身体的支障のベースラインからの変化、及びMPFIDにより測定した場合の日々の活動に対する影響のベースラインからの変化が含まれる。
Claims (122)
- 片頭痛の発生を予防または減少させる必要がある患者における片頭痛の発生の予防または減少方法であって、前記患者に、抗カルシトニン遺伝子関連ペプチド(CGRP)受容体抗体またはその抗原結合断片を含む医薬組成物を、1ヶ月あたり約35mg〜約210mgの用量で、投与することを含む、前記方法。
- 前記用量は、1ヶ月あたり約70mg〜約140mgである、請求項1に記載の方法。
- 前記用量は、1ヶ月あたり約70mgである、請求項1に記載の方法。
- 前記用量は、1ヶ月あたり約140mgである、請求項1に記載の方法。
- 前記医薬組成物は、1ヶ月に1回投与される、請求項1から4のいずれか1項に記載の方法。
- 前記医薬組成物は、非経口で投与される、請求項1から5のいずれか1項に記載の方法。
- 前記非経口投与は、皮下投与である、請求項6に記載の方法。
- 前記医薬組成物は、前記医薬組成物を充填済であるシリンジを用いて、前記患者に投与される、請求項1から7のいずれか1項に記載の方法。
- 前記医薬組成物は、自己注射器を用いて、前記患者に投与される、請求項1から7のいずれか1項に記載の方法。
- 前記患者が経験する月々の片頭痛日数は、前記医薬組成物を投与されない患者が経験する月々の片頭痛日数と比較して、前記医薬組成物の投与後に減少する、請求項1から9のいずれか1項に記載の方法。
- 前記患者が経験する月々の片頭痛時間数は、前記医薬組成物を投与されない患者が経験する月々の片頭痛時間数と比較して、前記医薬組成物の投与後に減少する、請求項1から9のいずれか1項に記載の方法。
- 前記患者が経験する月々の片頭痛専用薬物使用日数は、前記医薬組成物を投与されない患者が経験する月々の片頭痛専用薬物使用日数と比較して、前記医薬組成物の投与後に減少する、請求項1から9のいずれか1項に記載の方法。
- 前記医薬組成物の投与は、前記患者に有害副作用を実質的に引き起こさない、請求項1から12のいずれか1項に記載の方法。
- 前記患者は、反復性片頭痛を有しているか、反復性片頭痛と診断されている、請求項1から13のいずれか1項に記載の方法。
- 前記患者は、慢性片頭痛を有しているか、慢性片頭痛と診断されている、請求項1から13のいずれか1項に記載の方法。
- 前記患者は、以前に片頭痛の予防的治療を受けたことがない、請求項1から15のいずれか1項に記載の方法。
- 前記患者は、少なくとも1つの他の片頭痛予防的治療に失敗したことがあるか、それに対して不耐性である、請求項1から15のいずれか1項に記載の方法。
- 前記他の片頭痛予防的治療は、抗癲癇薬、三環系抗鬱薬、またはベータ遮断薬である、請求項17に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、ヒトCGRP受容体のヒトCRLRポリペプチド構成要素及びヒトRAMP1ポリペプチド構成要素の両方のアミノ酸から形成されるエピトープと特異的に結合する、請求項1から18のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、前記ヒトCGRP受容体と、KD≦100nMで特異的に結合する、請求項1から18のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号14の配列を有するCDRH1、配列番号23の配列を有するCDRH2、配列番号34の配列を有するCDRH3、配列番号44の配列を有するCDRL1、配列番号55の配列を有するCDRL2、及び配列番号65の配列を有するCDRL3を含む、請求項1から20のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号92の配列を含む重鎖可変領域(VH)、及び配列番号80の配列を含む軽鎖可変領域(VL)を含む、請求項1から20のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体は、配列番号105の配列を含む重鎖、及び配列番号123の配列を含む軽鎖を含む、請求項1から20のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体は、モノクローナルIgG1またはモノクローナルIgG2抗体である、請求項1から23のいずれか1項に記載の方法。
- 前記医薬組成物は、さらに、緩衝剤を含む、請求項1から24のいずれか1項に記載の方法。
- 前記緩衝剤は、酢酸緩衝剤である、請求項25に記載の方法。
- 前記医薬組成物は、さらに、界面活性剤を含む、請求項1から26のいずれか1項に記載の方法。
- 前記界面活性剤は、ポリソルベート20またはポリソルベート80である、請求項27に記載の方法。
- 前記医薬組成物は、さらに、安定剤を含む、請求項1から28のいずれか1項に記載の方法。
- 前記安定剤は、スクロースである、請求項29に記載の方法。
- 患者の片頭痛の予防的治療方法であって、前記患者に、抗CGRP受容体抗体またはその抗原結合断片を含む医薬組成物を、1ヶ月あたり約35mg〜約210mgの用量で投与することを含む、前記方法。
- 前記用量は、1ヶ月あたり約70mg〜約140mgである、請求項31に記載の方法。
- 前記用量は、1ヶ月あたり約70mgである、請求項31に記載の方法。
- 前記用量は、1ヶ月あたり約140mgである、請求項31に記載の方法。
- 前記医薬組成物は、1ヶ月に1回投与される、請求項31から34のいずれか1項に記載の方法。
- 前記医薬組成物は、非経口で投与される、請求項31から35のいずれか1項に記載の方法。
- 前記非経口投与は、皮下投与である、請求項36に記載の方法。
- 前記医薬組成物は、前記医薬組成物を充填済であるシリンジを用いて、前記患者に投与される、請求項31から37のいずれか1項に記載の方法。
- 前記医薬組成物は、自己注射器を用いて、前記患者に投与される、請求項31から37のいずれか1項に記載の方法。
- 前記患者が経験する月々の片頭痛日数は、前記医薬組成物を投与されない患者が経験する月々の片頭痛日数と比較して、前記医薬組成物の投与後に減少する、請求項31から39のいずれか1項に記載の方法。
- 前記患者が経験する月々の片頭痛時間数は、前記医薬組成物を投与されない患者が経験する月々の片頭痛時間数と比較して、前記医薬組成物の投与後に減少する、請求項31から39のいずれか1項に記載の方法。
- 前記患者が経験する月々の片頭痛専用薬物使用日数は、前記医薬組成物を投与されない患者が経験する月々の片頭痛専用薬物使用日数と比較して、前記医薬組成物の投与後に減少する、請求項31から39のいずれか1項に記載の方法。
- 前記医薬組成物の投与は、前記患者に有害副作用を実質的に引き起こさない、請求項31から42のいずれか1項に記載の方法。
- 前記片頭痛は、反復性片頭痛である、請求項31から43のいずれか1項に記載の方法。
- 前記片頭痛は、慢性片頭痛である、請求項31から43のいずれか1項に記載の方法。
- 前記患者は、以前に片頭痛の予防的治療を受けたことがない、請求項31から45のいずれか1項に記載の方法。
- 前記患者は、少なくとも1つの他の片頭痛予防的治療に失敗したことがあるか、それに対して不耐性である、請求項31から45のいずれか1項に記載の方法。
- 前記他の片頭痛予防的治療は、抗癲癇薬、三環系抗鬱薬、またはベータ遮断薬である、請求項47に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、ヒトCGRP受容体のヒトCRLRポリペプチド構成要素及びヒトRAMP1ポリペプチド構成要素の両方のアミノ酸から形成されるエピトープと特異的に結合する、請求項31から48のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、前記ヒトCGRP受容体と、KD≦100nMで特異的に結合する、請求項31から48のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号14の配列を有するCDRH1、配列番号23の配列を有するCDRH2、配列番号34の配列を有するCDRH3、配列番号44の配列を有するCDRL1、配列番号55の配列を有するCDRL2、及び配列番号65の配列を有するCDRL3を含む、請求項31から50のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号92の配列を含む重鎖可変領域(VH)、及び配列番号80の配列を含む軽鎖可変領域(VL)を含む、請求項31から50のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体は、配列番号105の配列を含む重鎖、及び配列番号123の配列を含む軽鎖を含む、請求項31から50のいずれか1項に記載の方法。
- 前記抗CGRP受容体抗体は、モノクローナルIgG1またはモノクローナルIgG2抗体である、請求項31から53のいずれか1項に記載の方法。
- 前記医薬組成物は、さらに、緩衝剤を含む、請求項31から54のいずれか1項に記載の方法。
- 前記緩衝剤は、酢酸緩衝剤である、請求項55に記載の方法。
- 前記医薬組成物は、さらに、界面活性剤を含む、請求項31から56のいずれか1項に記載の方法。
- 前記界面活性剤は、ポリソルベート20またはポリソルベート80である、請求項57に記載の方法。
- 前記医薬組成物は、さらに、安定剤を含む、請求項31から58のいずれか1項に記載の方法。
- 前記安定剤は、スクロースである、請求項59に記載の方法。
- 片頭痛の発生を予防または減少させる必要がある患者における片頭痛の発生の予防または減少方法で使用するための抗CGRP受容体抗体またはその抗原結合断片であって、前記方法は、前記患者に、前記抗CGRP受容体抗体またはその抗原結合断片を、1ヶ月あたり約35mg〜約210mgの用量で、投与することを含む、前記抗CGRP受容体抗体またはその抗原結合断片。
- 患者の片頭痛の予防的治療方法で使用するための抗CGRP受容体抗体またはその抗原結合断片であって、前記方法は、前記患者に、前記抗CGRP受容体抗体またはその抗原結合断片を、1ヶ月あたり約35mg〜約210mgの用量で投与することを含む、前記抗CGRP受容体抗体またはその抗原結合断片。
- 前記用量は、1ヶ月あたり約70mg〜約140mgである、請求項61または62に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記用量は、1ヶ月あたり約70mgである、請求項61または62に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記用量は、1ヶ月あたり約140mgである、請求項61または62に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、1ヶ月に1回投与される、請求項61から65のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、非経口で投与される、請求項61から66のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記非経口投与は、皮下投与である、請求項67に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、前記抗CGRP受容体抗体またはその抗原結合断片を充填済であるシリンジを用いて、前記患者に投与される、請求項61から68のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、自己注射器を用いて、前記患者に投与される、請求項61から68のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者が経験する月々の片頭痛日数は、前記抗CGRP受容体抗体またはその抗原結合断片を投与されない患者が経験する月々の片頭痛日数と比較して、前記抗CGRP受容体抗体またはその抗原結合断片の投与後に減少する、請求項61から70のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者が経験する月々の片頭痛時間数は、前記抗CGRP受容体抗体またはその抗原結合断片を投与されない患者が経験する月々の片頭痛時間数と比較して、前記抗CGRP受容体抗体またはその抗原結合断片の投与後に減少する、請求項61から70のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者が経験する月々の片頭痛専用薬物使用日数は、前記抗CGRP受容体抗体またはその抗原結合断片を投与されない患者が経験する月々の片頭痛専用薬物使用日数と比較して、前記抗CGRP受容体抗体またはその抗原結合断片の投与後に減少する、請求項61から70のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片の用量は、前記患者に有害副作用を実質的に引き起こさない、請求項61から73のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者は、反復性片頭痛を有しているか、反復性片頭痛と診断されている、請求項61から74のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者は、慢性片頭痛を有しているか、慢性片頭痛と診断されている、請求項61から74のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者は、以前に片頭痛の予防的治療を受けたことがない、請求項61から76のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記患者は、少なくとも1つの他の片頭痛予防的治療に失敗したことがあるか、それに対して不耐性である、請求項61から76のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記他の片頭痛予防的治療は、抗癲癇薬、三環系抗鬱薬、またはベータ遮断薬である、請求項78に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、ヒトCGRP受容体のヒトCRLRポリペプチド構成要素及びヒトRAMP1ポリペプチド構成要素の両方のアミノ酸から形成されるエピトープと特異的に結合する、請求項61から79のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、前記ヒトCGRP受容体と、KD≦100nMで特異的に結合する、請求項61から79のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号14の配列を有するCDRH1、配列番号23の配列を有するCDRH2、配列番号34の配列を有するCDRH3、配列番号44の配列を有するCDRL1、配列番号55の配列を有するCDRL2、及び配列番号65の配列を有するCDRL3を含む、請求項61から81のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号92の配列を含む重鎖可変領域(VH)、及び配列番号80の配列を含む軽鎖可変領域(VL)を含む、請求項61から81のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体は、配列番号105の配列を含む重鎖、及び配列番号123の配列を含む軽鎖を含む、請求項61から81のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体は、モノクローナルIgG1またはモノクローナルIgG2抗体である、請求項61から84のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、緩衝剤を含む医薬組成物に入れられて投与される、請求項61から85のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記緩衝剤は、酢酸緩衝剤である、請求項86に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、界面活性剤を含む医薬組成物に入れられて投与される、請求項61から87のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記界面活性剤は、ポリソルベート20またはポリソルベート80である、請求項88に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、安定剤を含む医薬組成物に入れられて投与される、請求項61から89のいずれか1項に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 前記安定剤は、スクロースである、請求項90に記載の抗CGRP受容体抗体またはその抗原結合断片。
- 片頭痛の発生を予防または減少させる必要がある患者における片頭痛の発生の予防または減少用医薬の調製における、抗CGRP受容体抗体またはその抗原結合断片の使用であって、前記医薬は、1ヶ月あたり約35mg〜約210mgの用量での投与用に配合される、前記使用。
- 患者の片頭痛の予防的治療用医薬の調製における、抗CGRP受容体抗体またはその抗原結合断片の使用であって、前記医薬は、1ヶ月あたり約35mg〜約210mgの用量での投与用に配合される、前記使用。
- 前記用量は、1ヶ月あたり約70mg〜約140mgである、請求項92または93に記載の使用。
- 前記用量は、1ヶ月あたり約70mgである、請求項92または93に記載の使用。
- 前記用量は、1ヶ月あたり約140mgである、請求項92または93に記載の使用。
- 前記医薬は、1ヶ月に1回投与される、請求項92から96のいずれか1項に記載の使用。
- 前記医薬は、非経口で投与される、請求項92から97のいずれか1項に記載の使用。
- 前記非経口投与は、皮下投与である、請求項98に記載の使用。
- 前記医薬は、シリンジを用いた投与用に配合される、請求項92から99のいずれか1項に記載の使用。
- 前記医薬は、自己注射器を用いた投与用に配合される、請求項92から99のいずれか1項に記載の使用。
- 前記医薬は、前記患者が経験する月々の片頭痛日数を、前記医薬を投与されない患者が経験する月々の片頭痛日数と比較して、減少させる、請求項92から101のいずれか1項に記載の使用。
- 前記医薬は、前記患者が経験する月々の片頭痛時間数を、前記医薬を投与されない患者が経験する月々の片頭痛時間数と比較して、減少させる、請求項92から101のいずれか1項に記載の使用。
- 前記医薬は、前記患者が経験する月々の片頭痛専用薬物使用日数を、前記医薬を投与されない患者が経験する月々の片頭痛専用薬物使用日数と比較して、減少させる、請求項92から101のいずれか1項に記載の使用。
- 前記医薬は、前記患者に有害副作用を実質的に引き起こさない、請求項92から104のいずれか1項に記載の使用。
- 前記患者は、反復性片頭痛を有しているか、反復性片頭痛と診断されている、請求項92から105のいずれか1項に記載の使用。
- 前記患者は、慢性片頭痛を有しているか、慢性片頭痛と診断されている、請求項92から105のいずれか1項に記載の使用。
- 前記患者は、以前に片頭痛の予防的治療を受けたことがない、請求項92から107のいずれか1項に記載の使用。
- 前記患者は、少なくとも1つの他の片頭痛予防的治療に失敗したことがあるか、それに対して不耐性である、請求項92から107のいずれか1項に記載の使用。
- 前記他の片頭痛予防的治療は、抗癲癇薬、三環系抗鬱薬、またはベータ遮断薬である、請求項109に記載の使用。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、ヒトCGRP受容体のヒトCRLRポリペプチド構成要素及びヒトRAMP1ポリペプチド構成要素の両方のアミノ酸から形成されるエピトープと特異的に結合する、請求項92から110のいずれか1項に記載の使用。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、前記ヒトCGRP受容体と、KD≦100nMで特異的に結合する、請求項92から110のいずれか1項に記載の使用。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号14の配列を有するCDRH1、配列番号23の配列を有するCDRH2、配列番号34の配列を有するCDRH3、配列番号44の配列を有するCDRL1、配列番号55の配列を有するCDRL2、及び配列番号65の配列を有するCDRL3を含む、請求項92から112のいずれか1項に記載の使用。
- 前記抗CGRP受容体抗体またはその抗原結合断片は、配列番号92の配列を含む重鎖可変領域(VH)、及び配列番号80の配列を含む軽鎖可変領域(VL)を含む、請求項92から112のいずれか1項に記載の使用。
- 前記抗CGRP受容体抗体は、配列番号105の配列を含む重鎖、及び配列番号123の配列を含む軽鎖を含む、請求項92から112のいずれか1項に記載の使用。
- 前記抗CGRP受容体抗体は、モノクローナルIgG1またはモノクローナルIgG2抗体である、請求項92から115のいずれか1項に記載の使用。
- 前記医薬は、さらに、緩衝剤を含む、請求項92から116のいずれか1項に記載の使用。
- 前記緩衝剤は、酢酸緩衝剤である、請求項117に記載の使用。
- 前記医薬組成物は、界面活性剤を含む、請求項92から118のいずれか1項に記載の使用。
- 前記界面活性剤は、ポリソルベート20またはポリソルベート80である、請求項119に記載の使用。
- 前記医薬は、安定剤を含む、請求項92から120のいずれか1項に記載の使用。
- 前記安定剤は、スクロースである、請求項121に記載の使用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562152708P | 2015-04-24 | 2015-04-24 | |
US62/152,708 | 2015-04-24 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017555506A Division JP6392471B2 (ja) | 2015-04-24 | 2015-08-10 | 片頭痛の治療または予防法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020087893A Division JP2020143115A (ja) | 2015-04-24 | 2020-05-20 | 片頭痛の治療または予防法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019001800A true JP2019001800A (ja) | 2019-01-10 |
JP6707590B2 JP6707590B2 (ja) | 2020-06-10 |
Family
ID=53969433
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017555506A Active JP6392471B2 (ja) | 2015-04-24 | 2015-08-10 | 片頭痛の治療または予防法 |
JP2018154482A Active JP6707590B2 (ja) | 2015-04-24 | 2018-08-21 | 片頭痛の治療または予防法 |
JP2020087893A Pending JP2020143115A (ja) | 2015-04-24 | 2020-05-20 | 片頭痛の治療または予防法 |
JP2022095538A Pending JP2022126724A (ja) | 2015-04-24 | 2022-06-14 | 片頭痛の治療または予防法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017555506A Active JP6392471B2 (ja) | 2015-04-24 | 2015-08-10 | 片頭痛の治療または予防法 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020087893A Pending JP2020143115A (ja) | 2015-04-24 | 2020-05-20 | 片頭痛の治療または予防法 |
JP2022095538A Pending JP2022126724A (ja) | 2015-04-24 | 2022-06-14 | 片頭痛の治療または予防法 |
Country Status (30)
Country | Link |
---|---|
US (3) | US10259877B2 (ja) |
EP (2) | EP3653225A1 (ja) |
JP (4) | JP6392471B2 (ja) |
KR (1) | KR102464415B1 (ja) |
CN (2) | CN108156814B (ja) |
AU (2) | AU2015392215B2 (ja) |
BR (1) | BR112017022772A2 (ja) |
CA (1) | CA2984254C (ja) |
CL (1) | CL2017002686A1 (ja) |
CY (1) | CY1123211T1 (ja) |
DK (1) | DK3285803T3 (ja) |
ES (1) | ES2771925T3 (ja) |
HK (1) | HK1250914A1 (ja) |
HR (1) | HRP20200056T1 (ja) |
HU (1) | HUE048528T2 (ja) |
IL (2) | IL255114B (ja) |
JO (2) | JOP20200116A1 (ja) |
LT (1) | LT3285803T (ja) |
MA (2) | MA41932B1 (ja) |
MX (2) | MX2017013627A (ja) |
PH (1) | PH12017501934A1 (ja) |
PL (1) | PL3285803T3 (ja) |
PT (1) | PT3285803T (ja) |
RS (1) | RS59912B1 (ja) |
RU (1) | RU2707745C2 (ja) |
SG (2) | SG10202004282RA (ja) |
SI (1) | SI3285803T1 (ja) |
TW (2) | TWI799849B (ja) |
WO (1) | WO2016171742A1 (ja) |
ZA (1) | ZA201707179B (ja) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100266638A1 (en) * | 2004-02-26 | 2010-10-21 | Allergan, Inc. | Headache treatment method |
JO3382B1 (ar) * | 2008-12-23 | 2019-03-13 | Amgen Inc | أجسام مضادة ترتبط مع مستقبل cgrp بشري |
US11844720B2 (en) | 2011-02-04 | 2023-12-19 | Seed Health, Inc. | Method and system to reduce the likelihood of dental caries and halitosis |
US11951140B2 (en) | 2011-02-04 | 2024-04-09 | Seed Health, Inc. | Modulation of an individual's gut microbiome to address osteoporosis and bone disease |
US11951139B2 (en) | 2015-11-30 | 2024-04-09 | Seed Health, Inc. | Method and system for reducing the likelihood of osteoporosis |
US11833177B2 (en) | 2013-12-20 | 2023-12-05 | Seed Health, Inc. | Probiotic to enhance an individual's skin microbiome |
US11839632B2 (en) | 2013-12-20 | 2023-12-12 | Seed Health, Inc. | Topical application of CRISPR-modified bacteria to treat acne vulgaris |
US11826388B2 (en) | 2013-12-20 | 2023-11-28 | Seed Health, Inc. | Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation |
US11969445B2 (en) | 2013-12-20 | 2024-04-30 | Seed Health, Inc. | Probiotic composition and method for controlling excess weight, obesity, NAFLD and NASH |
US11980643B2 (en) | 2013-12-20 | 2024-05-14 | Seed Health, Inc. | Method and system to modify an individual's gut-brain axis to provide neurocognitive protection |
US10556945B2 (en) | 2014-03-21 | 2020-02-11 | Teva Pharmaceuticals International Gmbh | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
CN111973740A (zh) | 2014-03-21 | 2020-11-24 | 泰华制药国际有限公司 | 针对降钙素基因相关肽的拮抗剂抗体及其使用方法 |
SG10201913032TA (en) | 2016-09-23 | 2020-02-27 | Teva Pharmaceuticals Int Gmbh | Treating refractory migraine |
WO2018160897A1 (en) | 2017-03-02 | 2018-09-07 | Beth Israel Deaconess Medical Center, Inc. | Preventing post-ictal headaches |
WO2019055399A1 (en) * | 2017-09-12 | 2019-03-21 | Igc Bio, Inc. | ANTI-VEGF ANTIBODIES |
BR112020013621A2 (pt) | 2018-01-12 | 2020-12-01 | Amgen Inc. | anticorpos contra pac1 e usos dos mesmos |
US11407838B2 (en) * | 2018-04-02 | 2022-08-09 | Amgen Inc. | Erenumab compositions and uses thereof |
EP4302828A3 (en) * | 2018-07-05 | 2024-01-17 | Allergan Pharmaceuticals International Limited | Combination therapy with cgrp antagonists and clostridial derivatives |
JP2022516956A (ja) | 2019-01-08 | 2022-03-03 | ハー・ルンドベック・アクチエゼルスカベット | 抗cgrp抗体を用いた頭痛の急性治療及び迅速治療 |
AU2020267107A1 (en) * | 2019-05-02 | 2021-10-07 | H. Lundbeck A/S | Treatment of headache using anti-CGRP antibodies |
US20210121541A1 (en) | 2019-07-05 | 2021-04-29 | Allergan Pharmaceuticals International Limited | CGRP Antagonists and Clostridial Derivatives for the Treatment of Neuropsychiatric and Neurological Disorders |
US20210128724A1 (en) | 2019-07-05 | 2021-05-06 | Allergan Pharmaceuticals International Limited | Cgrp antagonists and clostridial derivatives for the treatment of cortical spreading depression associated disorders |
WO2021005493A1 (en) | 2019-07-05 | 2021-01-14 | Allergan Pharmaceuticals International Limited | Cgrp antagonists and botulinum toxins for the treatment of inflammatory and neurologic disorders |
CA3161376A1 (en) * | 2019-12-18 | 2021-06-24 | Anthony P. FORD | Methods for improving neurological diseases and disorders |
KR20230157986A (ko) | 2021-03-02 | 2023-11-17 | 체게에르페 다이어그노스틱스 게엠베하 | 편투통 발생의 치료 및/또는 저감 |
WO2023026205A1 (en) | 2021-08-24 | 2023-03-02 | Cgrp Diagnostics Gmbh | Preventative treatment of migraine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012513214A (ja) * | 2008-12-23 | 2012-06-14 | アムジェン インコーポレイテッド | ヒトcgrp受容体結合タンパク質 |
JP2014515375A (ja) * | 2011-05-20 | 2014-06-30 | アルダーバイオ・ホールディングズ・エルエルシー | 羞明または光嫌悪症を予防または抑制する抗cgrp抗体および抗体断片のそれを必要とする対象、特に片頭痛患者における使用 |
Family Cites Families (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4740461A (en) | 1983-12-27 | 1988-04-26 | Genetics Institute, Inc. | Vectors and methods for transformation of eucaryotic cells |
US4959455A (en) | 1986-07-14 | 1990-09-25 | Genetics Institute, Inc. | Primate hematopoietic growth factors IL-3 and pharmaceutical compositions |
US4912040A (en) | 1986-11-14 | 1990-03-27 | Genetics Institute, Inc. | Eucaryotic expression system |
US4965195A (en) | 1987-10-26 | 1990-10-23 | Immunex Corp. | Interleukin-7 |
US4968607A (en) | 1987-11-25 | 1990-11-06 | Immunex Corporation | Interleukin-1 receptors |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
WO1990005183A1 (en) | 1988-10-31 | 1990-05-17 | Immunex Corporation | Interleukin-4 receptors |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US6713610B1 (en) | 1990-01-12 | 2004-03-30 | Raju Kucherlapati | Human antibodies derived from immunized xenomice |
US6673986B1 (en) | 1990-01-12 | 2004-01-06 | Abgenix, Inc. | Generation of xenogeneic antibodies |
DK0710719T3 (da) | 1990-01-12 | 2007-07-09 | Amgen Fremont Inc | Frembringelse af xenogene antistoffer |
AU651596B2 (en) | 1990-06-05 | 1994-07-28 | Immunex Corporation | Type II interleukin-1 receptors |
US5874299A (en) | 1990-08-29 | 1999-02-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US6255458B1 (en) | 1990-08-29 | 2001-07-03 | Genpharm International | High affinity human antibodies and human antibodies against digoxin |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
EP0814159B1 (en) | 1990-08-29 | 2005-07-27 | GenPharm International, Inc. | Transgenic mice capable of producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US6300129B1 (en) | 1990-08-29 | 2001-10-09 | Genpharm International | Transgenic non-human animals for producing heterologous antibodies |
US5789650A (en) | 1990-08-29 | 1998-08-04 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
EP0590076A4 (en) | 1991-06-14 | 1997-02-12 | Dnx Corp | Production of human hemoglobin in transgenic pigs |
DE69224906T2 (de) | 1991-07-08 | 1998-10-29 | Univ Massachusetts | Thermotropes flüssig-kristallines segment-blockcopolymer |
DE69324579T2 (de) | 1992-03-17 | 1999-09-23 | Novartis Ag | Gentechnologisch hergestellte antikörper |
JPH07509137A (ja) | 1992-07-24 | 1995-10-12 | セル ジェネシス,インク. | 異種抗体の生産 |
WO1996005221A1 (en) | 1994-08-16 | 1996-02-22 | Human Genome Sciences, Inc. | Calcitonin receptor |
US5785682A (en) | 1995-03-22 | 1998-07-28 | Abbott Laboratories | Pre-filled syringe drug delivery system |
ATE390933T1 (de) | 1995-04-27 | 2008-04-15 | Amgen Fremont Inc | Aus immunisierten xenomäusen stammende menschliche antikörper gegen il-8 |
AU6596096A (en) | 1996-07-23 | 1998-02-10 | Smithkline Beecham Corporation | Calcitonin gene-related peptide receptor component factor (houdc44) |
US6255455B1 (en) | 1996-10-11 | 2001-07-03 | The Trustees Of The University Of Pennsylvania | Rh(D)-binding proteins and magnetically activated cell sorting method for production thereof |
EP0942968B1 (en) | 1996-12-03 | 2008-02-27 | Amgen Fremont Inc. | Fully human antibodies that bind EGFR |
CA2196496A1 (en) | 1997-01-31 | 1998-07-31 | Stephen William Watson Michnick | Protein fragment complementation assay for the detection of protein-protein interactions |
FR2821080B1 (fr) | 2001-02-20 | 2003-12-19 | Sanofi Synthelabo | Anticorps specifique de l'adrenomedulline humaine, composition pharmaceutique le contenant, ses applications therapeutiques |
EP1438325B1 (en) | 2001-09-27 | 2009-12-30 | Merck & Co., Inc. | Isolated dna molecules encoding humanized calcitonin gene-related peptide receptor, related non-human transgenic animals and assay methods |
US7658924B2 (en) | 2001-10-11 | 2010-02-09 | Amgen Inc. | Angiopoietin-2 specific binding agents |
AR039067A1 (es) | 2001-11-09 | 2005-02-09 | Pfizer Prod Inc | Anticuerpos para cd40 |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
US20040110170A1 (en) | 2002-05-18 | 2004-06-10 | The Regents Of The University Of California | Cloning and characterization of calcitonin gene related peptide receptors |
US7842808B2 (en) | 2002-06-05 | 2010-11-30 | Bristol-Myers Squibb Company | Anti-migraine spirocycles |
US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
ES2323170T3 (es) | 2002-08-12 | 2009-07-08 | Birkir Sveinsson | Uso de compuestos antagonistas del cgrp para el tratamiento de la psoriasis. |
US20040176577A1 (en) | 2002-09-10 | 2004-09-09 | Eva Rojer | Immunoassays for specific determination of SCCA isoforms |
WO2004097421A2 (en) | 2003-04-29 | 2004-11-11 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with calcitonin receptor-like receptor (calcrl) |
US7569578B2 (en) | 2003-12-05 | 2009-08-04 | Bristol-Meyers Squibb Company | Heterocyclic anti-migraine agents |
KR20120034237A (ko) | 2004-02-11 | 2012-04-10 | 아밀린 파마슈티칼스, 인크. | 선택가능한 특성을 갖는 하이브리드 폴리펩티드 |
TW200533398A (en) | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
US7423128B2 (en) | 2004-11-03 | 2008-09-09 | Amgen Fremont Inc. | Anti-properdin antibodies, and methods for making and using same |
EP2284194A1 (en) | 2004-12-21 | 2011-02-16 | AstraZeneca AB | Antibodies directed to angiopoietin-2 and uses thereof |
DE102004063753A1 (de) | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung ausgewählter CGRP-Antagonisten in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne |
US9072777B2 (en) | 2005-06-16 | 2015-07-07 | Takayuki Shindo | Method for screening substance having proangiogenic effect |
GB0521139D0 (en) | 2005-10-18 | 2005-11-23 | Univ Sheffield | Therapeutic agent |
US8168592B2 (en) | 2005-10-21 | 2012-05-01 | Amgen Inc. | CGRP peptide antagonists and conjugates |
JP5123197B2 (ja) * | 2005-11-14 | 2013-01-16 | ライナット ニューロサイエンス コーポレイション | カルシトニン遺伝子関連ペプチドに対するアンタゴニスト抗体およびその使用方法 |
AU2006316642A1 (en) | 2005-11-18 | 2007-05-31 | Merck Sharp & Dohme Corp. | Spirolactam tricyclic CGRP receptor antagonists |
WO2007076336A1 (en) | 2005-12-22 | 2007-07-05 | Eli Lilly And Company | Treatment of migraine with anti-cgrp antibodies |
JP4435288B2 (ja) | 2006-05-09 | 2010-03-17 | メルク エンド カムパニー インコーポレーテッド | 置換スピロ環cgrp受容体アンタゴニスト |
CA2658612C (en) | 2006-08-03 | 2015-11-17 | Astrazeneca Ab | Antibodies directed to .alpha.v.beta.6 and uses thereof |
AU2008239754A1 (en) | 2007-04-11 | 2008-10-23 | Merck Sharp & Dohme Corp. | CGRP receptor antagonists with tertiary amide, sulfonamide, carbamate and urea end groups |
JP2010524934A (ja) | 2007-04-16 | 2010-07-22 | メルク・シャープ・エンド・ドーム・コーポレイション | アリール複素環式cgrp受容体アンタゴニスト |
GB0708002D0 (en) | 2007-04-25 | 2007-06-06 | Univ Sheffield | Antibodies |
NZ587297A (en) | 2008-03-04 | 2012-10-26 | Pfizer Ltd | Use of anti-CGRP (calcitonin gene-related peptide) antagonists to treat inflammatory pain |
AU2009257733A1 (en) | 2008-06-12 | 2009-12-17 | Merck Sharp & Dohme Corp. | Branched 3- and 6-substituted quinolines as CGRP receptor antagonists |
FR2934597B1 (fr) | 2008-07-31 | 2013-04-19 | Univ Aix Marseille Ii | Anticorps se liant aux recepteurs de l'adrenomedulline et leurs utilisations comme medicament. |
CA2737711A1 (en) | 2008-09-18 | 2010-03-25 | Merck Sharp & Dohme Corp. | Bicyclic dihydroimidazolone cgrp receptor antagonists |
EP2340025B1 (en) | 2008-10-03 | 2014-10-15 | Merck Sharp & Dohme Corp. | Cgrp receptor antagonists |
EP2470207A1 (en) | 2009-08-28 | 2012-07-04 | Rinat Neuroscience Corporation | Methods for treating visceral pain by administering antagonist antibodies directed against calcitonin gene-related peptide |
AR081434A1 (es) | 2010-06-10 | 2012-08-29 | Lilly Co Eli | Anticuerpo del peptido relacionado con el gen calcitonina (cgrp), composicion farmaceutica que lo comprende, uso de dicho anticuerpo para preparar un medicamento util para tratar dolor de osteoartritis o migranas y fragmento de union a antigeno de dicho anticuerpo |
JOP20190250A1 (ar) * | 2010-07-14 | 2017-06-16 | Regeneron Pharma | صيغ مستقرة تحتوي على الأجسام المضادة لمضاد عامل نمو الأعصاب |
PL2710039T3 (pl) | 2011-05-20 | 2019-07-31 | Alderbio Holdings Llc | Kompozycje przeciwko CGRP i ich zastosowanie |
EP2709662B1 (en) * | 2011-05-20 | 2019-07-31 | AlderBio Holdings LLC | Use of anti-cgrp or anti-cgrp-r antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea |
EA032830B1 (ru) | 2013-03-15 | 2019-07-31 | Эмджен Инк. | Антитела к pac1 человека и их применение для лечения головной боли |
US10556945B2 (en) | 2014-03-21 | 2020-02-11 | Teva Pharmaceuticals International Gmbh | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
CN111973740A (zh) | 2014-03-21 | 2020-11-24 | 泰华制药国际有限公司 | 针对降钙素基因相关肽的拮抗剂抗体及其使用方法 |
MX2017003247A (es) * | 2014-09-15 | 2017-11-30 | Amgen Inc | Proteina de union a antigenos, bi-especificos del receptor anti-cgrp/receptor pac1 y usos de las mismas. |
-
2015
- 2015-04-24 JO JOP/2020/0116A patent/JOP20200116A1/ar unknown
- 2015-08-07 TW TW110115984A patent/TWI799849B/zh active
- 2015-08-07 TW TW104125845A patent/TWI728953B/zh active
- 2015-08-10 CN CN201580081186.0A patent/CN108156814B/zh active Active
- 2015-08-10 MA MA41932A patent/MA41932B1/fr unknown
- 2015-08-10 PT PT157540717T patent/PT3285803T/pt unknown
- 2015-08-10 JP JP2017555506A patent/JP6392471B2/ja active Active
- 2015-08-10 SG SG10202004282RA patent/SG10202004282RA/en unknown
- 2015-08-10 MA MA051815A patent/MA51815A/fr unknown
- 2015-08-10 BR BR112017022772-0A patent/BR112017022772A2/pt not_active Application Discontinuation
- 2015-08-10 EP EP19212188.7A patent/EP3653225A1/en active Pending
- 2015-08-10 HU HUE15754071A patent/HUE048528T2/hu unknown
- 2015-08-10 RS RS20200165A patent/RS59912B1/sr unknown
- 2015-08-10 SI SI201531065T patent/SI3285803T1/sl unknown
- 2015-08-10 PL PL15754071T patent/PL3285803T3/pl unknown
- 2015-08-10 KR KR1020177034051A patent/KR102464415B1/ko active IP Right Grant
- 2015-08-10 LT LTEP15754071.7T patent/LT3285803T/lt unknown
- 2015-08-10 SG SG11201708607WA patent/SG11201708607WA/en unknown
- 2015-08-10 CA CA2984254A patent/CA2984254C/en active Active
- 2015-08-10 EP EP15754071.7A patent/EP3285803B1/en active Active
- 2015-08-10 AU AU2015392215A patent/AU2015392215B2/en active Active
- 2015-08-10 RU RU2017140789A patent/RU2707745C2/ru active
- 2015-08-10 WO PCT/US2015/044479 patent/WO2016171742A1/en active Application Filing
- 2015-08-10 MX MX2017013627A patent/MX2017013627A/es unknown
- 2015-08-10 CN CN202110748961.0A patent/CN113908268A/zh active Pending
- 2015-08-10 ES ES15754071T patent/ES2771925T3/es active Active
- 2015-08-10 DK DK15754071.7T patent/DK3285803T3/da active
-
2016
- 2016-03-03 JO JOP/2016/0034A patent/JO3559B1/ar active
- 2016-04-22 US US15/136,736 patent/US10259877B2/en active Active
-
2017
- 2017-10-18 IL IL255114A patent/IL255114B/en unknown
- 2017-10-23 CL CL2017002686A patent/CL2017002686A1/es unknown
- 2017-10-23 PH PH12017501934A patent/PH12017501934A1/en unknown
- 2017-10-23 MX MX2021013327A patent/MX2021013327A/es unknown
- 2017-10-23 ZA ZA2017/07179A patent/ZA201707179B/en unknown
-
2018
- 2018-08-10 HK HK18110282.6A patent/HK1250914A1/zh unknown
- 2018-08-21 JP JP2018154482A patent/JP6707590B2/ja active Active
-
2019
- 2019-02-27 US US16/287,533 patent/US11466090B2/en active Active
-
2020
- 2020-01-14 HR HRP20200056TT patent/HRP20200056T1/hr unknown
- 2020-02-11 CY CY20201100128T patent/CY1123211T1/el unknown
- 2020-05-20 JP JP2020087893A patent/JP2020143115A/ja active Pending
-
2022
- 2022-03-07 IL IL291153A patent/IL291153B2/en unknown
- 2022-06-14 JP JP2022095538A patent/JP2022126724A/ja active Pending
- 2022-07-06 AU AU2022204866A patent/AU2022204866A1/en active Pending
- 2022-09-02 US US17/902,168 patent/US20230020514A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012513214A (ja) * | 2008-12-23 | 2012-06-14 | アムジェン インコーポレイテッド | ヒトcgrp受容体結合タンパク質 |
JP2014515375A (ja) * | 2011-05-20 | 2014-06-30 | アルダーバイオ・ホールディングズ・エルエルシー | 羞明または光嫌悪症を予防または抑制する抗cgrp抗体および抗体断片のそれを必要とする対象、特に片頭痛患者における使用 |
Non-Patent Citations (5)
Title |
---|
EDVINSSON L, HO TW: "CGRP receptor antagonism and migraine", NEUROTHERAPEUTICS, vol. 7, no. 2, JPN6018009119, April 2010 (2010-04-01), pages 164 - 175, XP027030854, ISSN: 0004066495 * |
VECSEI L, ET AL.: "CGRP antagonists and antibodies for the treatment of migraine", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 24, no. 1, JPN6018009120, 15 September 2014 (2014-09-15), pages 31 - 41, XP009186473, ISSN: 0004066496, DOI: 10.1517/13543784.2015.960921 * |
WALTER S, BIGAL ME: "TEV-48125: a review of a monoclonal CGRP antibody in development for the preventive treatment of mig", CURRENT PAIN AND HEADACHE REPORTS, vol. 19, no. 3, JPN6018009115, 10 March 2015 (2015-03-10), pages 6, ISSN: 0004066494 * |
伊藤 康男,荒木 信夫: "各種薬剤の選び方と上手な使い方 片頭痛治療薬", 臨牀と研究, vol. 第91巻,第3号, JPN6018009123, March 2014 (2014-03-01), pages 365 - 370, ISSN: 0004066493 * |
柴田 興一: "片頭痛予防療法", 最新医学, vol. 第69巻,第6号, JPN6018009122, June 2014 (2014-06-01), pages 1130 - 1136, ISSN: 0004066492 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6707590B2 (ja) | 片頭痛の治療または予防法 | |
EP2074149B1 (en) | Compositions and methods relating to glucagon receptor antibodies | |
JP4840939B2 (ja) | Dkk−1に対する抗体 | |
AU2015331602A1 (en) | Antibodies directed to angiopoietin-1 and angiopoietin-2 for ocular therapies | |
US20240026036A1 (en) | Compounds and methods for treating pain | |
AU2018266324B2 (en) | Methods of treating eye disorders with APLNR antagonists and VEGF inhibitors | |
TW202126685A (zh) | 抗nrp1a抗體及其用於治療眼或眼部疾病之用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180910 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180910 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190702 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190926 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191105 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200421 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200520 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6707590 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |