JP2021185148A - 障害を治療するための5ht作動薬 - Google Patents
障害を治療するための5ht作動薬 Download PDFInfo
- Publication number
- JP2021185148A JP2021185148A JP2021128790A JP2021128790A JP2021185148A JP 2021185148 A JP2021185148 A JP 2021185148A JP 2021128790 A JP2021128790 A JP 2021128790A JP 2021128790 A JP2021128790 A JP 2021128790A JP 2021185148 A JP2021185148 A JP 2021185148A
- Authority
- JP
- Japan
- Prior art keywords
- receptor
- receptor agonist
- pharmaceutically acceptable
- epilepsy
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000952 serotonin receptor agonist Substances 0.000 title claims abstract description 267
- 150000003839 salts Chemical class 0.000 claims abstract description 210
- 206010015037 epilepsy Diseases 0.000 claims abstract description 155
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 88
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 68
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical group ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229960003991 trazodone Drugs 0.000 claims abstract description 22
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 claims abstract description 8
- 229960005060 lorcaserin Drugs 0.000 claims abstract description 8
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 174
- 206010010904 Convulsion Diseases 0.000 claims description 150
- 239000001961 anticonvulsive agent Substances 0.000 claims description 132
- 230000000694 effects Effects 0.000 claims description 122
- 229960003965 antiepileptics Drugs 0.000 claims description 104
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 claims description 76
- -1 2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl Chemical group 0.000 claims description 75
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 claims description 65
- 201000010099 disease Diseases 0.000 claims description 56
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 56
- 102000005962 receptors Human genes 0.000 claims description 55
- 108020003175 receptors Proteins 0.000 claims description 55
- 108091006146 Channels Proteins 0.000 claims description 51
- 208000036572 Myoclonic epilepsy Diseases 0.000 claims description 44
- 201000007547 Dravet syndrome Diseases 0.000 claims description 41
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 claims description 41
- 229940044601 receptor agonist Drugs 0.000 claims description 38
- 239000000018 receptor agonist Substances 0.000 claims description 38
- 238000011282 treatment Methods 0.000 claims description 37
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 32
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 32
- 208000035475 disorder Diseases 0.000 claims description 30
- 239000011734 sodium Substances 0.000 claims description 27
- 239000003772 serotonin uptake inhibitor Substances 0.000 claims description 25
- 229940049706 benzodiazepine Drugs 0.000 claims description 23
- 229940076279 serotonin Drugs 0.000 claims description 22
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 claims description 22
- 210000004556 brain Anatomy 0.000 claims description 21
- 230000007812 deficiency Effects 0.000 claims description 20
- 230000001037 epileptic effect Effects 0.000 claims description 20
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 claims description 20
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 19
- 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 claims description 19
- 229960000623 carbamazepine Drugs 0.000 claims description 19
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 19
- 229960002036 phenytoin Drugs 0.000 claims description 19
- 229960004394 topiramate Drugs 0.000 claims description 19
- 235000020887 ketogenic diet Nutrition 0.000 claims description 18
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 claims description 18
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims description 17
- 229960001848 lamotrigine Drugs 0.000 claims description 17
- 229960001897 stiripentol Drugs 0.000 claims description 17
- IBLNKMRFIPWSOY-FNORWQNLSA-N stiripentol Chemical compound CC(C)(C)C(O)\C=C\C1=CC=C2OCOC2=C1 IBLNKMRFIPWSOY-FNORWQNLSA-N 0.000 claims description 17
- 230000001419 dependent effect Effects 0.000 claims description 16
- 229960002870 gabapentin Drugs 0.000 claims description 16
- 230000001404 mediated effect Effects 0.000 claims description 16
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 claims description 16
- 229940094035 potassium bromide Drugs 0.000 claims description 16
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 15
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 15
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 claims description 14
- 229960001582 fenfluramine Drugs 0.000 claims description 14
- 229940084026 sodium valproate Drugs 0.000 claims description 14
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 claims description 14
- 208000024827 Alzheimer disease Diseases 0.000 claims description 13
- 206010003805 Autism Diseases 0.000 claims description 13
- 208000020706 Autistic disease Diseases 0.000 claims description 13
- 208000018737 Parkinson disease Diseases 0.000 claims description 12
- 229960001816 oxcarbazepine Drugs 0.000 claims description 12
- 229960002695 phenobarbital Drugs 0.000 claims description 12
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims description 12
- 229960001233 pregabalin Drugs 0.000 claims description 12
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 12
- 229960002393 primidone Drugs 0.000 claims description 12
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 claims description 12
- 229960005318 vigabatrin Drugs 0.000 claims description 12
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 claims description 12
- 229960002911 zonisamide Drugs 0.000 claims description 12
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 claims description 12
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 11
- PGTVWKLGGCQMBR-FLBATMFCSA-N Ganaxolone Chemical compound C([C@@H]1CC2)[C@](C)(O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 PGTVWKLGGCQMBR-FLBATMFCSA-N 0.000 claims description 11
- 229950006567 ganaxolone Drugs 0.000 claims description 11
- 102000012276 GABA Plasma Membrane Transport Proteins Human genes 0.000 claims description 10
- 108091006228 GABA transporters Proteins 0.000 claims description 10
- 208000005392 Spasm Diseases 0.000 claims description 10
- 229960005254 naratriptan Drugs 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 10
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 claims description 9
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 claims description 9
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 claims description 9
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 claims description 9
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
- 208000007101 Muscle Cramp Diseases 0.000 claims description 9
- 229960000571 acetazolamide Drugs 0.000 claims description 9
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 claims description 9
- 230000004913 activation Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- MLBHFBKZUPLWBD-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]-2-propanamine Chemical compound CC(N)CC1=CC=CC(C(F)(F)F)=C1 MLBHFBKZUPLWBD-UHFFFAOYSA-N 0.000 claims description 8
- PYJBJMIBANAOFJ-UHFFFAOYSA-N 1-[5-(thiophen-2-ylmethoxy)-1h-indol-3-yl]propan-2-amine;hydrochloride Chemical compound Cl.C1=C2C(CC(N)C)=CNC2=CC=C1OCC1=CC=CS1 PYJBJMIBANAOFJ-UHFFFAOYSA-N 0.000 claims description 8
- QJHCTHPYUOXOGM-UHFFFAOYSA-N 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)C(O)CN(CC1)CCN1C1=CC=CC(Cl)=C1 QJHCTHPYUOXOGM-UHFFFAOYSA-N 0.000 claims description 8
- PDWNVVUANMHHOR-UHFFFAOYSA-N 3-bromo-2,5-dimethoxy-N-methylbicyclo[4.2.0]octa-1(6),2,4,7-tetraen-7-amine hydrobromide Chemical compound Br.COC1=CC(Br)=C(OC)C2=C1C(NC)=C2 PDWNVVUANMHHOR-UHFFFAOYSA-N 0.000 claims description 8
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 claims description 8
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 claims description 8
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 claims description 8
- MPBCKKVERDTCEL-LURJTMIESA-N [(7r)-3-bromo-2,5-dimethoxy-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl]methanamine Chemical compound COC1=CC(Br)=C(OC)C2=C1[C@H](CN)C2 MPBCKKVERDTCEL-LURJTMIESA-N 0.000 claims description 8
- 230000033228 biological regulation Effects 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 8
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 claims description 8
- 229960002495 buspirone Drugs 0.000 claims description 8
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims description 8
- 229960003120 clonazepam Drugs 0.000 claims description 8
- 231100000867 compulsive behavior Toxicity 0.000 claims description 8
- 229940011871 estrogen Drugs 0.000 claims description 8
- 239000000262 estrogen Substances 0.000 claims description 8
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 claims description 8
- NIBOMXUDFLRHRV-UHFFFAOYSA-N hydron;8-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-8-azaspiro[4.5]decane-7,9-dione;dichloride Chemical compound Cl.Cl.COC1=CC=CC=C1N1CCN(CCN2C(CC3(CCCC3)CC2=O)=O)CC1 NIBOMXUDFLRHRV-UHFFFAOYSA-N 0.000 claims description 8
- 108010043412 neuropeptide Y-Y1 receptor Proteins 0.000 claims description 8
- POGQSBRIGCQNEG-UHFFFAOYSA-N rufinamide Chemical compound N1=NC(C(=O)N)=CN1CC1=C(F)C=CC=C1F POGQSBRIGCQNEG-UHFFFAOYSA-N 0.000 claims description 8
- 229960003014 rufinamide Drugs 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 229960003708 sumatriptan Drugs 0.000 claims description 8
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims description 8
- 238000009098 adjuvant therapy Methods 0.000 claims description 7
- 208000013257 developmental and epileptic encephalopathy Diseases 0.000 claims description 7
- 229960002053 flibanserin Drugs 0.000 claims description 7
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 claims description 7
- 229960001454 nitrazepam Drugs 0.000 claims description 7
- QVFDMWGKHUFODK-UHFFFAOYSA-N 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine;hydrochloride Chemical compound Cl.COC1=CC(CC(C)N)=C(OC)C=C1I QVFDMWGKHUFODK-UHFFFAOYSA-N 0.000 claims description 6
- WKNFADCGOAHBPG-UHFFFAOYSA-N 3-(1-methyl-4-piperidinyl)-1H-indol-5-ol Chemical compound C1CN(C)CCC1C1=CNC2=CC=C(O)C=C12 WKNFADCGOAHBPG-UHFFFAOYSA-N 0.000 claims description 6
- 201000008009 Early infantile epileptic encephalopathy Diseases 0.000 claims description 6
- 206010071545 Early infantile epileptic encephalopathy with burst-suppression Diseases 0.000 claims description 6
- 208000001914 Fragile X syndrome Diseases 0.000 claims description 6
- 239000000556 agonist Substances 0.000 claims description 6
- QIALRBLEEWJACW-INIZCTEOSA-N eslicarbazepine acetate Chemical compound CC(=O)O[C@H]1CC2=CC=CC=C2N(C(N)=O)C2=CC=CC=C12 QIALRBLEEWJACW-INIZCTEOSA-N 0.000 claims description 6
- 229960003233 eslicarbazepine acetate Drugs 0.000 claims description 6
- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical group FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 claims description 6
- 208000005809 status epilepticus Diseases 0.000 claims description 6
- INGCLXPSKXSYND-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-(1-methylpiperidin-4-yl)-1h-indol-5-ol Chemical compound OC(=O)\C=C/C(O)=O.C1CN(C)CCC1C1=CNC2=CC=C(O)C=C12 INGCLXPSKXSYND-BTJKTKAUSA-N 0.000 claims description 5
- MWJWBEUGJSWXGZ-UHFFFAOYSA-N 3-[4-(4-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)C(O)CN(CC1)CCN1C1=CC=C(Cl)C=C1 MWJWBEUGJSWXGZ-UHFFFAOYSA-N 0.000 claims description 5
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 claims description 5
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 claims description 5
- 208000019695 Migraine disease Diseases 0.000 claims description 5
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 claims description 5
- WTVNFKVGGUWHQC-UHFFFAOYSA-N decane-2,4-dione Chemical compound CCCCCCC(=O)CC(C)=O WTVNFKVGGUWHQC-UHFFFAOYSA-N 0.000 claims description 5
- 206010027599 migraine Diseases 0.000 claims description 5
- 201000001119 neuropathy Diseases 0.000 claims description 5
- 230000007823 neuropathy Effects 0.000 claims description 5
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 5
- 229960001130 urapidil Drugs 0.000 claims description 5
- 206010012289 Dementia Diseases 0.000 claims description 4
- 201000010769 Prader-Willi syndrome Diseases 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 3
- 208000037902 enteropathy Diseases 0.000 claims description 3
- 208000028774 intestinal disease Diseases 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 claims 11
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 claims 2
- 235000002639 sodium chloride Nutrition 0.000 description 202
- 150000001875 compounds Chemical class 0.000 description 110
- 241000252212 Danio rerio Species 0.000 description 98
- 239000000203 mixture Substances 0.000 description 65
- 108090000623 proteins and genes Proteins 0.000 description 62
- 239000003814 drug Substances 0.000 description 52
- 229940079593 drug Drugs 0.000 description 50
- 230000014509 gene expression Effects 0.000 description 49
- 230000033001 locomotion Effects 0.000 description 42
- 238000009472 formulation Methods 0.000 description 41
- 238000012360 testing method Methods 0.000 description 39
- 230000006399 behavior Effects 0.000 description 31
- 238000003556 assay Methods 0.000 description 30
- 241001465754 Metazoa Species 0.000 description 28
- 239000000243 solution Substances 0.000 description 24
- 230000035772 mutation Effects 0.000 description 23
- 230000006870 function Effects 0.000 description 22
- 239000004480 active ingredient Substances 0.000 description 21
- 239000011575 calcium Substances 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 21
- 230000002269 spontaneous effect Effects 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 210000003169 central nervous system Anatomy 0.000 description 19
- 238000012216 screening Methods 0.000 description 19
- 230000009182 swimming Effects 0.000 description 19
- 230000008859 change Effects 0.000 description 18
- 239000003112 inhibitor Substances 0.000 description 18
- 208000011580 syndromic disease Diseases 0.000 description 17
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 16
- 210000001161 mammalian embryo Anatomy 0.000 description 16
- 239000000725 suspension Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- 239000002775 capsule Substances 0.000 description 13
- 230000018109 developmental process Effects 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000011161 development Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 230000001629 suppression Effects 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 238000000692 Student's t-test Methods 0.000 description 11
- 230000001773 anti-convulsant effect Effects 0.000 description 11
- 239000000739 antihistaminic agent Substances 0.000 description 11
- 239000000839 emulsion Substances 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 231100000419 toxicity Toxicity 0.000 description 11
- 230000001988 toxicity Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 210000002216 heart Anatomy 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000002502 liposome Substances 0.000 description 10
- 210000004129 prosencephalon Anatomy 0.000 description 10
- 229940125715 antihistaminic agent Drugs 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 230000001418 larval effect Effects 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 108010052164 Sodium Channels Proteins 0.000 description 8
- 102000018674 Sodium Channels Human genes 0.000 description 8
- 230000003213 activating effect Effects 0.000 description 8
- 239000003086 colorant Substances 0.000 description 8
- 229960003529 diazepam Drugs 0.000 description 8
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000007937 lozenge Substances 0.000 description 8
- AMKVXSZCKVJAGH-UHFFFAOYSA-N naratriptan Chemical compound C12=CC(CCS(=O)(=O)NC)=CC=C2NC=C1C1CCN(C)CC1 AMKVXSZCKVJAGH-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- 239000002562 thickening agent Substances 0.000 description 8
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 7
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 7
- 102000006969 5-HT2B Serotonin Receptor Human genes 0.000 description 7
- 108010072584 5-HT2B Serotonin Receptor Proteins 0.000 description 7
- 241000251468 Actinopterygii Species 0.000 description 7
- 208000019901 Anxiety disease Diseases 0.000 description 7
- 208000008882 Benign Neonatal Epilepsy Diseases 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 206010061334 Partial seizures Diseases 0.000 description 7
- 230000036506 anxiety Effects 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 201000003452 benign familial neonatal epilepsy Diseases 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 230000003137 locomotive effect Effects 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 7
- 238000002703 mutagenesis Methods 0.000 description 7
- 231100000350 mutagenesis Toxicity 0.000 description 7
- 238000007911 parenteral administration Methods 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 239000006187 pill Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- 238000010200 validation analysis Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010047139 Vasoconstriction Diseases 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 238000007877 drug screening Methods 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 201000007186 focal epilepsy Diseases 0.000 description 6
- 235000013355 food flavoring agent Nutrition 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 230000002068 genetic effect Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000000366 juvenile effect Effects 0.000 description 6
- 229960002623 lacosamide Drugs 0.000 description 6
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 6
- 238000002493 microarray Methods 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- 229940102566 valproate Drugs 0.000 description 6
- 230000025033 vasoconstriction Effects 0.000 description 6
- 206010067866 Benign familial neonatal convulsions Diseases 0.000 description 5
- 208000014644 Brain disease Diseases 0.000 description 5
- 208000032274 Encephalopathy Diseases 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 5
- 230000002411 adverse Effects 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
- 238000013459 approach Methods 0.000 description 5
- 201000010295 benign neonatal seizures Diseases 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- CXOXHMZGEKVPMT-UHFFFAOYSA-N clobazam Chemical compound O=C1CC(=O)N(C)C2=CC=C(Cl)C=C2N1C1=CC=CC=C1 CXOXHMZGEKVPMT-UHFFFAOYSA-N 0.000 description 5
- 229960001403 clobazam Drugs 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 230000002920 convulsive effect Effects 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000007876 drug discovery Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 210000001153 interneuron Anatomy 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 229920000609 methyl cellulose Polymers 0.000 description 5
- 235000010981 methylcellulose Nutrition 0.000 description 5
- 239000001923 methylcellulose Substances 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 229960005152 pentetrazol Drugs 0.000 description 5
- 210000001428 peripheral nervous system Anatomy 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000007958 sleep Effects 0.000 description 5
- 238000012353 t test Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- FSKFPVLPFLJRQB-UHFFFAOYSA-N 2-methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone Chemical compound C=1C=C(C)C=CC=1C(=O)C(C)CN1CCCCC1 FSKFPVLPFLJRQB-UHFFFAOYSA-N 0.000 description 4
- VCCNKWWXYVWTLT-CYZBKYQRSA-N 7-[(2s,3r,4s,5s,6r)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2s,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-one Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 VCCNKWWXYVWTLT-CYZBKYQRSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- 108010071131 Autoreceptors Proteins 0.000 description 4
- 102000007527 Autoreceptors Human genes 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 208000002091 Febrile Seizures Diseases 0.000 description 4
- 206010020843 Hyperthermia Diseases 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
- 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 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- 208000037158 Partial Epilepsies Diseases 0.000 description 4
- 238000011529 RT qPCR Methods 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 101000783611 Takifugu rubripes 5-hydroxytryptamine receptor 1D Proteins 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 235000010419 agar Nutrition 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 230000003556 anti-epileptic effect Effects 0.000 description 4
- 230000036528 appetite Effects 0.000 description 4
- 235000019789 appetite Nutrition 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 208000029078 coronary artery disease Diseases 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 206010014599 encephalitis Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229960001903 ergotamine tartrate Drugs 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 229930195712 glutamate Natural products 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 208000019622 heart disease Diseases 0.000 description 4
- 238000013537 high throughput screening Methods 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 230000036031 hyperthermia Effects 0.000 description 4
- 238000007901 in situ hybridization Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000010208 microarray analysis Methods 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 229960001785 mirtazapine Drugs 0.000 description 4
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 4
- 230000036651 mood Effects 0.000 description 4
- 239000002547 new drug Substances 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 201000005070 reflex epilepsy Diseases 0.000 description 4
- 230000009329 sexual behaviour Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 229960005334 tolperisone Drugs 0.000 description 4
- 208000009575 Angelman syndrome Diseases 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 241000283070 Equus zebra Species 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 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 3
- 241000282412 Homo Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- 208000012641 Pigmentation disease Diseases 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 3
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 3
- 235000001537 Ribes X gardonianum Nutrition 0.000 description 3
- 235000001535 Ribes X utile Nutrition 0.000 description 3
- 235000016919 Ribes petraeum Nutrition 0.000 description 3
- 244000281247 Ribes rubrum Species 0.000 description 3
- 235000002355 Ribes spicatum Nutrition 0.000 description 3
- 101150022529 Scn1a gene Proteins 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229940125681 anticonvulsant agent Drugs 0.000 description 3
- 210000003050 axon Anatomy 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- 210000001772 blood platelet Anatomy 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000001638 cerebellum Anatomy 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229950002858 clorgiline Drugs 0.000 description 3
- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-UHFFFAOYSA-N 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 3
- 239000008393 encapsulating agent Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 229960002767 ethosuximide Drugs 0.000 description 3
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 208000013403 hyperactivity Diseases 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000007913 intrathecal administration Methods 0.000 description 3
- 235000015110 jellies Nutrition 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 230000013011 mating Effects 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000015654 memory Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 210000002460 smooth muscle Anatomy 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000007940 sugar coated tablet Substances 0.000 description 3
- 210000003863 superior colliculi Anatomy 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- 238000011285 therapeutic regimen Methods 0.000 description 3
- 230000004797 therapeutic response Effects 0.000 description 3
- 231100000440 toxicity profile Toxicity 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- 208000009999 tuberous sclerosis Diseases 0.000 description 3
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 3
- 229960000604 valproic acid Drugs 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- XBGUIVFBMBVUEG-UHFFFAOYSA-N 1-methyl-4-(1,5-dimethyl-4-hexenylidene)-1-cyclohexene Chemical compound CC(C)=CCCC(C)=C1CCC(C)=CC1 XBGUIVFBMBVUEG-UHFFFAOYSA-N 0.000 description 2
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- APWHJJLFCMBWQT-UHFFFAOYSA-N 3-methoxy-n-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ium-4-ylethoxy)phenyl]benzamide;chloride Chemical compound [Cl-].COC1=CC=CC(C(=O)NC=2C=C(C(OCC[NH+]3CCOCC3)=CC=2)C=2N(N=CC=2)C)=C1 APWHJJLFCMBWQT-UHFFFAOYSA-N 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 2
- AYYCFGDXLUPJAQ-UHFFFAOYSA-N 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione Chemical compound COC1=CC=CC=C1N1CCN(CCN2C(CC3(CCCC3)CC2=O)=O)CC1 AYYCFGDXLUPJAQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 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 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
- 206010003591 Ataxia Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010070666 Cortical dysplasia Diseases 0.000 description 2
- 244000163122 Curcuma domestica Species 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 229940124602 FDA-approved drug Drugs 0.000 description 2
- 201000009010 Frontal lobe epilepsy Diseases 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 102000005915 GABA Receptors Human genes 0.000 description 2
- 108010005551 GABA Receptors Proteins 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 208000017605 Hodgkin disease nodular sclerosis Diseases 0.000 description 2
- 101000631760 Homo sapiens Sodium channel protein type 1 subunit alpha Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- 206010021750 Infantile Spasms Diseases 0.000 description 2
- 208000035899 Infantile spasms syndrome Diseases 0.000 description 2
- 201000006347 Intellectual Disability Diseases 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 2
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 2
- 208000000676 Malformations of Cortical Development Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- FUSGACRLAFQQRL-UHFFFAOYSA-N N-Ethyl-N-nitrosourea Chemical compound CCN(N=O)C(N)=O FUSGACRLAFQQRL-UHFFFAOYSA-N 0.000 description 2
- JNNOSTQEZICQQP-UHFFFAOYSA-N N-desmethylclozapine Chemical compound N=1C2=CC(Cl)=CC=C2NC2=CC=CC=C2C=1N1CCNCC1 JNNOSTQEZICQQP-UHFFFAOYSA-N 0.000 description 2
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 101800001019 Non-structural protein 4B Proteins 0.000 description 2
- 108060005874 Parvalbumin Proteins 0.000 description 2
- 102000001675 Parvalbumin Human genes 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 206010036312 Post-traumatic epilepsy Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 206010071141 Rasmussen encephalitis Diseases 0.000 description 2
- 208000004160 Rasmussen subacute encephalitis Diseases 0.000 description 2
- 208000004974 Rolandic Epilepsy Diseases 0.000 description 2
- 102000003567 TRPV4 Human genes 0.000 description 2
- 101150098315 TRPV4 gene Proteins 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 201000006793 Walker-Warburg syndrome Diseases 0.000 description 2
- 201000006791 West syndrome Diseases 0.000 description 2
- YGCODSQDUUUKIV-UHFFFAOYSA-N Zoxazolamine Chemical compound ClC1=CC=C2OC(N)=NC2=C1 YGCODSQDUUUKIV-UHFFFAOYSA-N 0.000 description 2
- 208000003554 absence epilepsy Diseases 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 230000016571 aggressive behavior Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- YHBUQBJHSRGZNF-HNNXBMFYSA-N alpha-bisabolene Natural products CC(C)=CCC=C(C)[C@@H]1CCC(C)=CC1 YHBUQBJHSRGZNF-HNNXBMFYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 229930003493 bisabolene Natural products 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000006931 brain damage Effects 0.000 description 2
- 231100000874 brain damage Toxicity 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000009084 cardiovascular function Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 208000023397 cerebral cortical dysplasia Diseases 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 229960005132 cisapride Drugs 0.000 description 2
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000003255 drug test Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000012202 endocytosis Effects 0.000 description 2
- 229960003533 ethotoin Drugs 0.000 description 2
- SZQIFWWUIBRPBZ-UHFFFAOYSA-N ethotoin Chemical compound O=C1N(CC)C(=O)NC1C1=CC=CC=C1 SZQIFWWUIBRPBZ-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 206010016284 febrile convulsion Diseases 0.000 description 2
- 229960003472 felbamate Drugs 0.000 description 2
- WKGXYQFOCVYPAC-UHFFFAOYSA-N felbamate Chemical compound NC(=O)OCC(COC(N)=O)C1=CC=CC=C1 WKGXYQFOCVYPAC-UHFFFAOYSA-N 0.000 description 2
- 229960002464 fluoxetine Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000003371 gabaergic effect Effects 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 230000000887 hydrating effect Effects 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 229960004002 levetiracetam Drugs 0.000 description 2
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 235000014380 magnesium carbonate Nutrition 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000002175 menstrual effect Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- BYJYIKWMABSTKJ-ZNYNAASMSA-N migril Chemical compound Cl.OC(=O)[C@H](O)[C@@H](O)C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1.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(C=3C=CC=C4NC=C(C=34)C2)=C1)C)C1=CC=CC=C1.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(C=3C=CC=C4NC=C(C=34)C2)=C1)C)C1=CC=CC=C1 BYJYIKWMABSTKJ-ZNYNAASMSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 238000001422 normality test Methods 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- GZVBVBMMNFIXGE-CQSZACIVSA-N osu-6162 Chemical compound C1N(CCC)CCC[C@H]1C1=CC=CC(S(C)(=O)=O)=C1 GZVBVBMMNFIXGE-CQSZACIVSA-N 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 201000003040 photosensitive epilepsy Diseases 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 230000001144 postural effect Effects 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000013102 re-test Methods 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000002739 subcortical effect Effects 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 210000001587 telencephalon Anatomy 0.000 description 2
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- QAXBVGVYDCAVLV-UHFFFAOYSA-N tiletamine Chemical compound C=1C=CSC=1C1(NCC)CCCCC1=O QAXBVGVYDCAVLV-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 description 2
- 229960002301 trazodone hydrochloride Drugs 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N trimethylxanthine Natural products CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 208000034373 type A muscular dystrophy-dystroglycanopathy Diseases 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- 229950006967 zoxazolamine Drugs 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- YQGDEPYYFWUPGO-VKHMYHEASA-N (3s)-4-azaniumyl-3-hydroxybutanoate Chemical compound [NH3+]C[C@@H](O)CC([O-])=O YQGDEPYYFWUPGO-VKHMYHEASA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- IPANUAHQWFDVAG-BTJKTKAUSA-N (z)-4-hydroxy-4-oxobut-2-enoate;1-methyl-4-thioxanthen-9-ylidenepiperidin-1-ium Chemical compound OC(=O)\C=C/C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2SC2=CC=CC=C21 IPANUAHQWFDVAG-BTJKTKAUSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-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
- BGMZUEKZENQUJY-UHFFFAOYSA-N 2-(4-iodo-2,5-dimethoxyphenyl)-1-methylethylamine Chemical compound COC1=CC(CC(C)N)=C(OC)C=C1I BGMZUEKZENQUJY-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- LSYPVNHPFUQGON-UHFFFAOYSA-N 3-chloro-2h-pyran-2-amine Chemical compound NC1OC=CC=C1Cl LSYPVNHPFUQGON-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- 101150096316 5 gene Proteins 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 241000208223 Anacardiaceae Species 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 101150035467 BDNF gene Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 101100263837 Bovine ephemeral fever virus (strain BB7721) beta gene Proteins 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102100026548 Caspase-8 Human genes 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 208000031976 Channelopathies Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 201000001913 Childhood absence epilepsy Diseases 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010219 Compulsions Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 235000003392 Curcuma domestica Nutrition 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- 241000252208 Danio Species 0.000 description 1
- 101100329834 Danio rerio gja1 gene Proteins 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 208000035976 Developmental Disabilities Diseases 0.000 description 1
- 241000004297 Draba Species 0.000 description 1
- 101100401560 Drosophila melanogaster mib1 gene Proteins 0.000 description 1
- 102000013138 Drug Receptors Human genes 0.000 description 1
- 108010065556 Drug Receptors Proteins 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 206010013974 Dyspnoea paroxysmal nocturnal Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101100316840 Enterobacteria phage P4 Beta gene Proteins 0.000 description 1
- 208000024658 Epilepsy syndrome Diseases 0.000 description 1
- 208000002877 Epileptic Syndromes Diseases 0.000 description 1
- 101000706102 Esox lucius Parvalbumin alpha Proteins 0.000 description 1
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 101001105542 Gallus gallus Parvalbumin, thymic CPV3 Proteins 0.000 description 1
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 108010077223 Homer Scaffolding Proteins Proteins 0.000 description 1
- 102000010029 Homer Scaffolding Proteins Human genes 0.000 description 1
- 101000654381 Homo sapiens Sodium channel protein type 8 subunit alpha Proteins 0.000 description 1
- ZRJBHWIHUMBLCN-SEQYCRGISA-N Huperzine A Natural products N1C(=O)C=CC2=C1C[C@H]1/C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-SEQYCRGISA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010070511 Hypoxic-ischaemic encephalopathy Diseases 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 201000008189 Juvenile absence epilepsy Diseases 0.000 description 1
- 206010071082 Juvenile myoclonic epilepsy Diseases 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 241000761557 Lamina Species 0.000 description 1
- 101150083522 MECP2 gene Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 108010008364 Melanocortins Proteins 0.000 description 1
- 229940091512 Monoamine oxidase A inhibitor Drugs 0.000 description 1
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010031123 Orthopnoea Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 208000004327 Paroxysmal Dyspnea Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- 101150020107 SCN8A gene Proteins 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- ZRJBHWIHUMBLCN-UHFFFAOYSA-N Shuangyiping Natural products N1C(=O)C=CC2=C1CC1C(=CC)C2(N)CC(C)=C1 ZRJBHWIHUMBLCN-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100031371 Sodium channel protein type 8 subunit alpha Human genes 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 102000005890 Spectrin Human genes 0.000 description 1
- 108010019965 Spectrin Proteins 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 102000012275 Ubiquitin domains Human genes 0.000 description 1
- 108050002897 Ubiquitin domains Proteins 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 231100000569 acute exposure Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229940125516 allosteric modulator Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002298 aminohydroxybutyric acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical group O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 1
- 229960002430 atomoxetine Drugs 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 229960005200 beclamide Drugs 0.000 description 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 208000009973 brain hypoxia - ischemia Diseases 0.000 description 1
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 1
- 229950011318 cannabidiol Drugs 0.000 description 1
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000020226 cashew nut Nutrition 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- CJXAEXPPLWQRFR-UHFFFAOYSA-N clemizole Chemical compound C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2N=C1CN1CCCC1 CJXAEXPPLWQRFR-UHFFFAOYSA-N 0.000 description 1
- 229950002020 clemizole Drugs 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 238000007418 data mining Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 235000021045 dietary change Nutrition 0.000 description 1
- 235000020930 dietary requirements Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000137 effect on hyperthermia Effects 0.000 description 1
- 230000000792 effect on seizure Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 208000028329 epileptic seizure Diseases 0.000 description 1
- 230000008579 epileptogenesis Effects 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229960000693 fosphenytoin Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000037433 frameshift Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000003976 gap junction Anatomy 0.000 description 1
- 208000028326 generalized seizure Diseases 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004195 gingiva Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 238000007417 hierarchical cluster analysis Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 102000049589 human SCN1A Human genes 0.000 description 1
- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000035863 hyperlocomotion Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 208000015210 hypertensive heart disease Diseases 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 208000034287 idiopathic generalized susceptibility to 7 epilepsy Diseases 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 210000001926 inhibitory interneuron Anatomy 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- NKGYBXHAQAKSSG-UHFFFAOYSA-N iproheptine Chemical compound CC(C)CCCC(C)NC(C)C NKGYBXHAQAKSSG-UHFFFAOYSA-N 0.000 description 1
- 229950000120 iproheptine Drugs 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000010978 jasper Substances 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 208000030175 lameness Diseases 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 208000002741 leukoplakia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000020855 low-carbohydrate diet Nutrition 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002865 melanocortin Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 229960002441 nefazodone hydrochloride Drugs 0.000 description 1
- DYCKFEBIOUQECE-UHFFFAOYSA-N nefazodone hydrochloride Chemical compound [H+].[Cl-].O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 DYCKFEBIOUQECE-UHFFFAOYSA-N 0.000 description 1
- 230000010807 negative regulation of binding Effects 0.000 description 1
- 101150006061 neur gene Proteins 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000008062 neuronal firing Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 108091008700 nociceptors Proteins 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940016084 oleptro Drugs 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000026269 optomotor response Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000012144 orthopnea Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960005198 perampanel Drugs 0.000 description 1
- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000012660 pharmacological inhibitor Substances 0.000 description 1
- 238000012247 phenotypical assay Methods 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229960000399 pimethixene Drugs 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 235000020004 porter Nutrition 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- ZGHYCJFHASGYQY-UHFFFAOYSA-M potassium;2-propylpentanoate Chemical compound [K+].CCCC(C([O-])=O)CCC ZGHYCJFHASGYQY-UHFFFAOYSA-M 0.000 description 1
- 235000012015 potatoes Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- ZRJBHWIHUMBLCN-BMIGLBTASA-N rac-huperzine A Natural products N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-BMIGLBTASA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical group C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 101150043066 scn4aa gene Proteins 0.000 description 1
- 101150070019 scn4ab gene Proteins 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 230000009154 spontaneous behavior Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960004523 tiletamine Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000011311 validation assay Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical group C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 108700024526 zebrafish sox32 Proteins 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical group C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical group C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
Description
本願は癲癇症の治療方法を提供する。1態様において、前記方法は前記治療を必要とする対象に治療有効量の5−HT受容体作動薬又はその医薬的に許容される塩を投与することによる癲癇症の治療方法である。別の態様において、前記方法は前記治療を必要とする対象に本願に記載するような医薬組成物を投与することによる癲癇症の治療方法であり、前記医薬組成物は5−HT受容体作動薬又はその医薬的に許容される塩を含有する。対象はケト原性食を摂取しているものとすることができる(例えばケト原性食に従う食物を摂取しているものとすることができる)。対象は心血管疾患をもつものとすることができる。対象はセロトニン再取り込み阻害薬による治療に耐性のものとすることができる。対象はセロトニン再取り込み阻害薬を投与した場合の副作用に感受性のものとすることができる。対象は小児(例えば小児癲癇病態をもつ対象)とすることができる。
本願は上記疾患及び障害を治療するのに有用な5−HT受容体作動薬又はその医薬的に許容される塩を含有する医薬組成物を提供する。前記医薬組成物は本願に記載するように錠剤、散剤、カプセル剤、丸剤、カシェ剤又はロゼンジ剤として製剤化することができる。前記医薬組成物は経口投与用に錠剤、カプセル剤、丸剤、カシェ剤又はロゼンジ剤として製剤化することができる。前記医薬組成物は例えば静脈内投与等の技術により投与するために溶液に溶解させるように製剤化することができる。前記医薬組成物は本願に記載するように経口投与、坐剤投与、局所投与、静脈内投与、腹腔内投与、筋肉内投与、病変内投与、髄腔内投与、鼻腔内投与、皮下投与、移植、経皮投与又は経粘膜投与用に製剤化することができる。
本願に記載する5−HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は多様な経口、非経口及び局所剤形で製造及び投与することができる。従って、本願に記載する5−HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は注射により(例えば静脈内、筋肉内、皮内、皮下、十二指腸内又は腹腔内に)投与することができる。また、本願に記載する5−HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は吸入により例えば鼻腔内に投与することもできる。更に、前記5−HT受容体作動薬(その医薬的に許容される塩を含む)又は医薬組成物は経皮投与することもできる。前記5−HT受容体作動薬(その医薬的に許容される塩を含む)又はこれを含有する医薬組成物を投与するために複数の投与経路(例えば筋肉内、経口、経皮)を使用できるとも予想される。本願に記載する医薬組成物は医薬的に許容される担体又は賦形剤と、5−HT受容体作動薬(その医薬的に許容される塩を含む)の1種以上を含有することができる。本願に記載する医薬組成物は医薬的に許容される担体又は賦形剤と、5−HT受容体作動薬(その医薬的に許容される塩を含む)の1種以上と、本願に記載するような1種以上のAEDを含有することができる。
前記医薬組成物は治療有効量、即ちその所期目的を達成するために有効な量の前記5−HT受容体作動薬(その医薬的に許容される塩を含む)を含有することができる。特定の用途に有効な実際の量は特に治療する病態により異なる。例えば、癲癇症(例えばドラベ症候群)の治療方法で投与する場合、このような組成物は所望の結果(例えば発作の抑制)を達成するために有効な量の前記5−HT受容体作動薬(その医薬的に許容される塩を含む)又はその医薬組成物を含有する。
特定の化合物の毒性と治療効果の比はその治療指数であり、LD50(集団の50%が死亡する化合物の量)とED50(集団の50%で有効な化合物の量)の比として表すことができる。治療指数の高い化合物が好ましい。人体用投与量範囲を処方するには、細胞培養アッセイ及び/又は動物試験から得られた治療指数データを使用することができる。このような化合物の投与量は毒性を殆ど又は全く生じることなしにED50を含む血漿濃度の範囲内にあることが好ましい。用量は利用する剤形と利用する投与経路に応じてこの範囲内で変えることができる。例えばFingl et al.,In:THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,Ch.1,p.l,1975参照。厳密な処方、投与経路及び投与量は患者の病態と化合物を使用する特定の方法に鑑みて個々の医師が選択することができる。
癲癇は脳の損傷又は遺伝子突然変異の結果として生ずる。遺伝的癲癇としては、SCN1A遺伝子で650種類を超える変異体が同定されている(Harkin,L.A.et al.The spectrum of SCN1A−related infantile epileptic encephalopathies.Brain 130,843−852(2007);Mulley J.C.,et al.,SCN1A mutations and epilepsy.Hum.Mutat.25,535−542(2005))。この遺伝子のミスセンス又はフレームシフト突然変異は全般癲癇熱性痙攣プラス(GEFS+)(Ceulemans,B.P.,et al.,Clinical correlations of mutations in the SCN1A gene:from febrile seizures to severe myoclonic epilepsy in infancy.Pediatric Neurol.30,236−243(2004))と、ドラベ症候群と呼ばれるより重度の障害に関連している。DSの小児は最初に正常な発育を示すが、生後1年以内に熱性痙攣エピソードを生じることが多く、その結果、重度の自発性反復性発作、知的障害、運動失調及び精神運動機能障害に進行する。発作は入手可能な抗癲癇薬(AED)を使用して十分に管理されず、これらの小児は脳神経外科的切除の候補としては不適切である(Bender,A.C.,et al.,SCN1A mutations in Dravet syndrome:Impact of interneuron dysfunction on neural networks and cognitive outcome.Epilepsy Beh.23,177−186(2012))。
本発明者らのこれまでの検討と、マウスの定性的MESスクリーニングで100mg/kgと300mg/kgの用量で認められた若干の活性に基づき、MES/scMET/Toxマウスモデルで定量的試験を進め、ED50/TD50を求めた。MESモデルでTPEを求める間に、300mg/kgの出発時の用量で活性は認められなかった。一方、500mg/kgの用量では活性が認められ、4匹のうちの2匹が0.25分、4匹のうちの4匹が30分で保護された。試験した他のどの用量又は試験時点でも活性又は毒性(回転棒を掴めない)は認められなかった。scMETモデルでは活性が認められなかった。MESモデルのデータによると、このマウスモデルではASP469016により有意な活性/保護が得られ、ED50<400mg/kgである。
本発明者らの初期T31(MES/scMET/Tox)スクリーニングではASP469016を30mg/kg、100mg/kg及び300mg/kgで試験した。各条件のデータをN/Fとして表し、ここでNは保護された動物数であり、Fは試験した動物数である。毒性(TOX)試験では、Nは毒性作用を示す動物数であり、Fは試験した動物数である。C列のコードは実験を実施する技術者からのコメントを意味し、必要に応じてコメントセクションに定義する。死亡は認められない。6Hz(32mA)モデルに示すように、100mg/kgで30分にて4匹中の1匹のみが保護された。MESにより誘発させた発作モデルでは、100mg/kgと300mg/kgで30分にて4匹中の1匹のみが保護された。試験した他のどの用量又は時点でも毒性(回転棒を掴めない)又は活性は検出されなかった。
139種類の異なるインビトロ受容体結合アッセイ及び酵素アッセイの集合であるCEREP BioPrint Profileでクレミゾール(149934−L6)を試験した。初期BioPrintスクリーニングには、10μΜ(1.0E−5M)の遊離化合物濃度を使用した。各標的に特異的な放射性標識リガンドの結合の阻害率%として化合物結合性を計算した。対照酵素活性の阻害率%として化合物酵素阻害効果を計算した。各実験で夫々の基準化合物をクレミゾール(149934−L6)と同時に試験し、CEREPで測定された歴史的数値とデータを比較した。実験はCEREPの検証標準操作手順に従って承認された。50%よりも高い阻害(又は基礎条件で実施したアッセイの刺激)を示す結果が試験化合物の有意な効果に相当するとみなされる。これらの結果をまとめたものを以下に示す。
クレミゾールは抗ヒスタミン薬の作用機序により抗癲癇活性を発揮するものではない。32種類の異なる抗ヒスタミン化合物(図10)をscn1Labゼブラフィッシュアッセイでスクリーニングした処、クレミゾールの抗癲癇作用と似ている化合物は皆無であった。化合物のうちの3種類は毒性であり、抗ヒスタミン薬が小児癲癇患者における発作を悪化させるという臨床報告通りに、5種類の化合物は発作行動を亢進させた。
出願人らはセロトニンシグナル伝達経路に作用する62種類の薬物を含むSelleck Customized Libraryをスクリーニングした。これらの化合物を先ずゼブラフィッシュ移動運動アッセイでスクリーニングした処、図11に示すように、15種類の化合物が初回通過移動運動アッセイ(アッセイの詳細についてはBaraban et al.Nat.Comm.2013及びDinday and Baraban,eNeuro 2015を参酌できる)で陽性ヒットと認定された。これらの試験は、5HTシグナル伝達の調節、特にシナプス後部5HT受容体の活性化が潜在的な抗癲癇効果をもつことを示唆している。
実施形態1.癲癇症の治療方法であって、前記治療を必要とする対象に治療有効量の5HT受容体作動薬又はその医薬的に許容される塩を投与することを含む前記方法。
Claims (58)
- 癲癇症の治療方法であって、前記治療を必要とする対象に治療有効量の5HT受容体作動薬又はその医薬的に許容される塩を投与することを含む前記方法。
- 前記5HT受容体作動薬が、5HT2A受容体作動薬又は5HT2B受容体作動薬である請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT2A受容体と5HT2B受容体の両方の作動薬である請求項2に記載の方法。
- 前記5HT受容体作動薬が、クレミゾール又はフェンフルラミン以外のものである請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体と直接結合する請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体を特異的に活性化させる請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT2C受容体により介在される活性を同等以下にしながら5HT2A受容体又は5HT2B受容体により介在される活性を増加させる請求項1に記載の方法。
- 前記5HT受容体作動薬が、セロトニン再取り込み阻害薬以外のものである請求項1に記載の方法。
- 前記5HT受容体作動薬が、5HT1A、5HT1B、5HT1D、5HT2C、5HT3、5HT4、5HT6、5HT7、NPY Y1受容体、L型Caチャネル、N型Caチャネル、SK−Caチャネル、GABA依存性Clチャネル、GABAトランスポーター、GABA−A1受容体、GABA−B1b受容体、Naチャネル、5HTトランスポーター、CB1受容体、CB2受容体、BZD又はエストロゲンERαの少なくとも1種と有意に結合しないか又はその活性を調節しない請求項1に記載の方法。
- 前記5HT受容体作動薬が、フリバンセリン、DOI HCl、ノルフェンフルラミン又はBW723C86である請求項1に記載の方法。
- 前記5HT受容体作動薬が、スマトリプタン、ナラトリプタン、リザトリプタン、ゾルミトリプタン、ウラピジル、BRL−54443(3−(1−メチルピペリジン−4−イル)−1H−インドール−5−オール)、ロルカセリン、ブスピロン、ジプラシドン、TCB−2((4−ブロモ−3,6−ジメトキシベンゾシクロブテン−1−イル)メチルアミン臭化水素酸塩)、BRL−15572(3−(4−(4−クロロフェニル)ピペラジン−1−イル)−1,1−ジフェニル−2−プロパノール)、トラゾドン、BMY7378(8−(2−[4−(2−メトキシフェニル)−1−ピペラジニル]エチル)−8−アザスピロ[4.5]デカン−7,9−ジオン)、アトモキセチン又はベンラファキシンである請求項1に記載の方法。
- 前記5HT受容体作動薬が、トラゾドンである請求項1に記載の方法。
- 前記癲癇症が、ドラベ症候群、レノックス・ガストー症候群、点頭癲癇又は大田原症候群である請求項1に記載の方法。
- 前記癲癇症が、ドラベ症候群である請求項13に記載の方法。
- 前記癲癇症が、小児癲癇症である請求項1に記載の方法。
- 前記対象が、心血管疾患をもつ請求項1に記載の方法。
- 前記対象が、セロトニン再取り込み阻害薬による治療に耐性である請求項1に記載の方法。
- 前記対象が、セロトニン再取り込み阻害薬を投与した場合の副作用に感受性である請求項1に記載の方法。
- 前記セロトニン再取り込み阻害薬が、フェンフルラミンである請求項17又は18に記載の方法。
- 前記対象が、ケト原性食を摂取している請求項1に記載の方法。
- 前記5HT受容体作動薬が、癲癇対象、アルツハイマー病対象、自閉症対象又はパーキンソン病対象における強迫行為又はエレクトログラフ発作を抑制する請求項1に記載の方法。
- 前記5HT受容体作動薬が、前記5HT受容体作動薬の不在下と比較した場合に前記対象における非誘発性発作の発生を抑制する請求項1に記載の方法。
- 前記5HT受容体作動薬の前記投与が、5HT受容体作動薬の不在下と比較した場合に前記対象におけるミオクローヌス発作又は癲癇重積状態を抑制又は予防する請求項1に記載の方法。
- 前記5HT受容体作動薬を体重1kg当たり約0.1mg〜約1000mgの量で前記対象に投与する請求項1に記載の方法。
- 前記5HT受容体作動薬を体重1kg当たり約0.1mg〜約1000mgの1日用量で前記対象に投与する請求項22に記載の方法。
- 前記5HT受容体作動薬を抗癲癇薬(AED)と併用投与する請求項1に記載の方法。
- 前記5HT受容体作動薬が、抗癲癇薬(AED)の補助療法である請求項1に記載の方法。
- 前記AEDが、アセタゾラミド、ベンゾジアゼピン、カンナビジオール、カルバマゼピン、クロバザム、クロナゼパム、エスリカルバゼピン酢酸塩、エトスクシミド、エトトイン、フェルバメート、フェンフルラミン、フォスフェニトイン、ガバペンチン、ガナキソロン、フペルジンA、ラコサミド、ラモトリギン、レベチラセタム、ニトラゼパム、オクスカルバゼピン、ペランパネル、ピラセタム、フェノバルビタール、フェニトイン、臭化カリウム、プレガバリン、プリミドン、レチガビン、ルフィナミド、バルプロ酸、バルプロ酸ナトリウム、スチリペントール、チアガビン、トピラマート、ビガバトリン又はゾニサミドである請求項26又は27に記載の方法。
- 前記AEDが、バルプロ酸、バルプロ酸ナトリウム、クロナゼパム、エトスクシミド、フェルバメート、ガバペンチン、カルバマゼピン、オクスカルバゼピン、ラモトリギン、レベチラセタム、ベンゾジアゼピン、フェノバルビタール、プレガバリン、プリミドン、チアガビン、トピラマート、臭化カリウム、フェニトイン、スチリペントール、ビガバトリン又はゾニサミドである請求項28に記載の方法。
- 前記AEDが、バルプロ酸、バルプロ酸ナトリウム、ガバペンチン、トピラマート、カルバマゼピン、オクスカルバゼピン又はビガバトリンである請求項29に記載の方法。
- 前記AEDが、フェンフルラミン又はトピラマート以外のものである請求項26に記載の方法。
- 前記AEDを前記5HT受容体作動薬と同時又は順次投与する請求項26に記載の方法。
- 癲癇症の治療方法であって、前記方法が前記治療を必要とする対象に治療有効量の5HT受容体作動薬又はその医薬的に許容される塩を投与することを含み、前記対象が心血管疾患をもつか、セロトニン再取り込み阻害薬による治療に耐性であるか、又はセロトニン再取り込み阻害薬を投与した場合の副作用に感受性である前記方法。
- 前記5HT受容体作動薬が、5HT2A受容体作動薬又は5HT2B受容体作動薬である請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT2A受容体と5HT2B受容体の両方の作動薬である請求項32に記載の方法。
- 前記5HT受容体作動薬が、クレミゾール、クレミゾールアナログ又はその医薬的に許容される塩である請求項33に記載の方法。
- 前記医薬的に許容される塩がクレミゾールHClである請求項36に記載の方法。
- 前記クレミゾール、前記クレミゾールアナログ又は前記その医薬的に許容される塩が医薬組成物の一部を形成する請求項36に記載の方法。
- 前記医薬組成物が更に医薬的に許容される賦形剤を含有する請求項38に記載の方法。
- 前記医薬組成物が、治療有効量のクレミゾール、前記クレミゾールアナログ又は前記その医薬的に許容される塩を含有する請求項38に記載の方法。
- 前記医薬組成物を抗癲癇薬(AED)と併用投与する請求項40に記載の方法。
- 前記医薬組成物が、クレミゾール、前記クレミゾールアナログ又は前記その医薬的に許容される塩と、AEDを含有する請求項41に記載の方法。
- 前記5HT受容体作動薬が、フェンフルラミン以外のものである請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体と直接結合する請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT受容体を特異的に活性化させる請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT2C受容体により介在される活性を同等以下にしながら5HT2A受容体又は5HT2B受容体により介在される活性を増加させる請求項33に記載の方法。
- 前記5HT受容体作動薬が、セロトニン再取り込み阻害薬以外のものである請求項33に記載の方法。
- 前記5HT受容体作動薬が、5HT1A、5HT1B、5HT1D、5HT2C、5HT3、5HT4、5HT6、5HT7、NPY Y1受容体、L型Caチャネル、N型Caチャネル、SK−Caチャネル、GABA依存性Clチャネル、GABAトランスポーター、GABA−A1受容体、GABA−B1b受容体、Naチャネル、5HTトランスポーター、CB1受容体、CB2受容体、BZD又はエストロゲンERαの少なくとも1種と有意に結合しないか又はその活性を調節しない請求項33に記載の方法。
- 前記5HT受容体作動薬が、スマトリプタン、ナラトリプタン、リザトリプタン、ゾルミトリプタン、ウラピジル、BRL−54443(3−(1−メチルピペリジン−4−イル)−1H−インドール−5−オール)、ロルカセリン、ブスピロン、ジプラシドン、TCB−2((4−ブロモ−3,6−ジメトキシベンゾシクロブテン−1−イル)メチルアミン臭化水素酸塩)、BRL−15572(3−(4−(4−クロロフェニル)ピペラジン−1−イル)−1,1−ジフェニル−2−プロパノール)、トラゾドン、BMY7378(8−(2−[4−(2−メトキシフェニル)−1−ピペラジニル]エチル)−8−アザスピロ[4.5]デカン−7,9−ジオン)、アトモキセチン又はベンラファキシンである請求項33に記載の方法。
- 前記5HT受容体作動薬が、トラゾドン又はその医薬的に許容される塩である請求項33に記載の方法。
- 5HT受容体をクレミゾール、クレミゾールアナログ又はその医薬的に許容される塩と接触させることを含む5HT受容体の活性の調節方法。
- 前記調節が、活性化である請求項51に記載の方法。
- 前記5HT受容体が、5HT2A受容体又は5HT2B受容体である請求項51に記載の方法。
- 脳内のセロトニンの不足により又は1種以上の5HT受容体の活動下で生じる疾患又は障害の治療方法であって、前記治療を必要とする対象に治療有効量のクレミゾール、クレミゾールアナログ又はその医薬的に許容される塩を投与することを含む前記方法。
- 前記疾患又は障害が、癲癇以外のものである請求項54に記載の方法。
- 前記疾患又は障害が、ドラベ症候群以外のものである請求項54に記載の方法。
- 前記疾患又は障害が、片頭痛、脆弱X症候群、プラダー・ウィリー症候群、統合失調症、鬱病、アルツハイマー病、自閉症、神経障害性疼痛、パーキンソン病、過敏性腸症及び認知症から構成される群から選択される請求項51に記載の方法。
- 前記医薬的に許容される塩が、クレミゾールHClである請求項50に記載の方法。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022091363A JP2022116307A (ja) | 2015-02-25 | 2022-06-06 | 障害を治療するための5ht作動薬 |
JP2023169390A JP2024009839A (ja) | 2015-02-25 | 2023-09-29 | 障害を治療するための5ht作動薬 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562120726P | 2015-02-25 | 2015-02-25 | |
US62/120,726 | 2015-02-25 | ||
JP2020081127A JP2020143087A (ja) | 2015-02-25 | 2020-05-01 | 障害を治療するための5ht作動薬 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020081127A Division JP2020143087A (ja) | 2015-02-25 | 2020-05-01 | 障害を治療するための5ht作動薬 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022091363A Division JP2022116307A (ja) | 2015-02-25 | 2022-06-06 | 障害を治療するための5ht作動薬 |
JP2023169390A Division JP2024009839A (ja) | 2015-02-25 | 2023-09-29 | 障害を治療するための5ht作動薬 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2021185148A true JP2021185148A (ja) | 2021-12-09 |
Family
ID=56789223
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017544887A Active JP6884703B2 (ja) | 2015-02-25 | 2016-02-24 | 障害を治療するための5ht作動薬 |
JP2020081127A Pending JP2020143087A (ja) | 2015-02-25 | 2020-05-01 | 障害を治療するための5ht作動薬 |
JP2021128790A Pending JP2021185148A (ja) | 2015-02-25 | 2021-08-05 | 障害を治療するための5ht作動薬 |
JP2022091363A Pending JP2022116307A (ja) | 2015-02-25 | 2022-06-06 | 障害を治療するための5ht作動薬 |
JP2023169390A Pending JP2024009839A (ja) | 2015-02-25 | 2023-09-29 | 障害を治療するための5ht作動薬 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017544887A Active JP6884703B2 (ja) | 2015-02-25 | 2016-02-24 | 障害を治療するための5ht作動薬 |
JP2020081127A Pending JP2020143087A (ja) | 2015-02-25 | 2020-05-01 | 障害を治療するための5ht作動薬 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022091363A Pending JP2022116307A (ja) | 2015-02-25 | 2022-06-06 | 障害を治療するための5ht作動薬 |
JP2023169390A Pending JP2024009839A (ja) | 2015-02-25 | 2023-09-29 | 障害を治療するための5ht作動薬 |
Country Status (19)
Country | Link |
---|---|
US (4) | US10874643B2 (ja) |
EP (3) | EP4043016A1 (ja) |
JP (5) | JP6884703B2 (ja) |
KR (3) | KR102385665B1 (ja) |
CN (2) | CN113546174A (ja) |
AU (3) | AU2016222804C1 (ja) |
BR (1) | BR112017018297B1 (ja) |
CA (2) | CA3204599A1 (ja) |
DK (1) | DK3261640T3 (ja) |
EA (2) | EA201791882A1 (ja) |
ES (1) | ES2920886T3 (ja) |
HR (1) | HRP20220822T1 (ja) |
HU (1) | HUE059559T2 (ja) |
LT (1) | LT3261640T (ja) |
PL (1) | PL3261640T3 (ja) |
PT (1) | PT3261640T (ja) |
RS (1) | RS63426B1 (ja) |
SI (1) | SI3261640T1 (ja) |
WO (1) | WO2016138138A1 (ja) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9549909B2 (en) | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
EA201791882A1 (ru) | 2015-02-25 | 2018-02-28 | Дзе Риджентс Оф Дзе Юниверсити Оф Калифорниа | Агонисты 5ht для лечения нарушений |
EP3393470B1 (en) | 2015-12-22 | 2021-01-20 | Zogenix International Limited | Metabolism resistant fenfluramine analogs and methods of using the same |
EP3800177A1 (en) | 2015-12-22 | 2021-04-07 | Zogenix International Limited | Fenfluramine compositions and methods of preparing the same |
KR20230021172A (ko) | 2016-08-24 | 2023-02-13 | 조게닉스 인터내셔널 리미티드 | 5-ht2b 작용물질의 형성을 억제하기 위한 제제 및 그것의 사용 방법 |
KR102614709B1 (ko) | 2016-12-20 | 2023-12-18 | 에르테에스 로만 테라피-시스테메 아게 | 아세나핀 및 폴리실록산 또는 폴리이소부틸렌을 함유하는 경피흡수 치료 시스템 |
CN115813888A (zh) | 2016-12-20 | 2023-03-21 | 罗曼治疗系统股份公司 | 包含阿塞那平的透皮治疗系统 |
JP2020525545A (ja) | 2017-06-26 | 2020-08-27 | エルテーエス ローマン テラピー−ジステーメ アーゲー | アセナピンおよびシリコーンアクリルハイブリッドポリマーを含有する経皮治療システム |
US10682317B2 (en) * | 2017-09-26 | 2020-06-16 | Zogenix International Limited | Ketogenic diet compatible fenfluramine formulation |
CA3097335A1 (en) | 2018-05-11 | 2019-11-14 | Zogenix International Limited | Compositions and methods for treating seizure-induced sudden death |
EP3806835A1 (en) | 2018-06-14 | 2021-04-21 | Zogenix International Limited | Compositions and methods for treating respiratory depression with fenfluramine |
KR20210022656A (ko) | 2018-06-20 | 2021-03-03 | 에르테에스 로만 테라피-시스테메 아게 | 아세나핀을 함유하는 경피 치료 시스템 |
WO2020023923A1 (en) * | 2018-07-27 | 2020-01-30 | Xenon Pharmaceuticals Inc. | Method for treating epilepsy |
AU2020284577A1 (en) * | 2019-05-29 | 2021-12-16 | The Regents Of The University Of California | Methods and compositions for treating epilepsy |
EP3791873A1 (en) * | 2019-09-16 | 2021-03-17 | Universite De Bordeaux | Methods of treatment and/or prevention of disorders and symptoms related to bkca and/or sk channelophathies |
WO2021081376A1 (en) * | 2019-10-23 | 2021-04-29 | Maplight Therapeutics, Inc. | Methods of treating the symptoms of autism spectrum disorder |
KR20210054684A (ko) | 2019-11-06 | 2021-05-14 | 동국대학교 경주캠퍼스 산학협력단 | 라미나린을 유효성분으로 함유하는 허혈성 뇌혈관 질환 예방용 조성물 |
CA3158280A1 (en) * | 2019-12-06 | 2021-06-10 | Alex Aimetti | Ganaxolone for use in treating tuberous sclerosis complex |
KR102476771B1 (ko) * | 2020-05-08 | 2022-12-13 | 광운대학교 산학협력단 | 뇌질환 검증용 eeg 바이오 마커 분석 알고리즘을 통하여 소아 뇌전증 환자 미주신경자극술 효과를 예측하는 방법 |
US11612574B2 (en) | 2020-07-17 | 2023-03-28 | Zogenix International Limited | Method of treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) |
IL307194A (en) * | 2021-03-25 | 2023-11-01 | Maplight Therapeutics Inc | Pharmaceutical preparations containing zolmitriptan |
EP4346804A1 (en) * | 2021-06-01 | 2024-04-10 | Arena Pharmaceuticals, Inc. | Methods of treatment |
EP4351586A1 (en) * | 2021-06-10 | 2024-04-17 | Neurelis, Inc. | Methods and compositions for treating seizure disorders in pediatric patients |
KR20240042485A (ko) * | 2021-07-30 | 2024-04-02 | 에피제닉스 테라퓨틱스, 인크. | 클레미졸 제제 |
WO2023107965A1 (en) * | 2021-12-06 | 2023-06-15 | Terran Biosciences, Inc. | Salt and solid forms of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (dom), 2,5-dimethoxy-4-iodoamphetamine (doi), 2,5-dimethoxy-4-bromoamphetamine (dob), and 2,5-dimethoxy-4-chloroamphetamine (doc) |
WO2023144166A1 (en) | 2022-01-26 | 2023-08-03 | Neurolixis | Use of serotonin 5-ht1a receptor agonists to treat diseases associated with sudden unexpected death in epilepsy |
WO2023212244A1 (en) * | 2022-04-27 | 2023-11-02 | Tessellate Therapeutics, Inc. | Methods of treating 5ht2a receptor-mediated conditions |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011518154A (ja) * | 2008-04-16 | 2011-06-23 | アリーナ ファーマシューティカルズ, インコーポレイテッド | (r)−1−{2−[4’−(3−メトキシプロパン−1−スルホニル)−ビフェニル−4−イル]−エチル}−2−メチル−ピロリジンの合成に有用なプロセス |
JP2011520900A (ja) * | 2008-05-16 | 2011-07-21 | アルボー ビータ コーポレーション | てんかんの治療 |
JP2012526847A (ja) * | 2009-05-13 | 2012-11-01 | ネクター セラピューティックス | オリゴマー含有の置換芳香族トリアジン化合物 |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2436883C2 (de) | 1974-07-29 | 1985-08-22 | Schering AG, 1000 Berlin und 4709 Bergkamen | Benzimidazol-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel |
US4911920A (en) | 1986-07-30 | 1990-03-27 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
FR2588189B1 (fr) | 1985-10-03 | 1988-12-02 | Merck Sharp & Dohme | Composition pharmaceutique de type a transition de phase liquide-gel |
DK0495421T3 (da) | 1991-01-15 | 1996-12-09 | Alcon Lab Inc | Anvendelse af carragenaner i topiske ophthalmiske sammensætninger |
US5212162A (en) | 1991-03-27 | 1993-05-18 | Alcon Laboratories, Inc. | Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions |
US6309853B1 (en) | 1994-08-17 | 2001-10-30 | The Rockfeller University | Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof |
US6323237B1 (en) * | 1997-03-17 | 2001-11-27 | Btg International Limited | Therapeutic compositions |
GB9927844D0 (en) | 1999-11-26 | 2000-01-26 | Glaxo Group Ltd | Chemical compounds |
WO2002089731A2 (en) | 2001-05-03 | 2002-11-14 | Stanford University | Agents for treatment of hcv and methods of use |
US6559293B1 (en) | 2002-02-15 | 2003-05-06 | Transform Pharmaceuticals, Inc. | Topiramate sodium trihydrate |
US7582428B2 (en) | 2003-08-22 | 2009-09-01 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for identifying anti-HCV agents |
US20050215589A1 (en) * | 2003-09-03 | 2005-09-29 | Roger Crossley | Inhibitors of 5-HT2A receptor |
EP1787679A1 (en) * | 2005-07-29 | 2007-05-23 | Laboratorios Del Dr. Esteve, S.A. | Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain |
US7635710B2 (en) * | 2006-02-15 | 2009-12-22 | Neurim Pharmaceuticals (1991) Ltd. | Pyrone-indole derivatives and process for their preparation |
US7998971B2 (en) | 2006-09-08 | 2011-08-16 | Braincells Inc. | Combinations containing a 4-acylaminopyridine derivative |
US8642351B2 (en) | 2006-09-20 | 2014-02-04 | Waters Technologies Corporation | Apparatus and methods of fluid chromatography |
EP2134556B1 (en) | 2007-04-06 | 2012-07-18 | Koninklijke Philips Electronics N.V. | Air pollution sensor system |
WO2008133884A2 (en) | 2007-04-23 | 2008-11-06 | Combinatorx, Incorporated | Methods and compositions for the treatment of neurodegenerative disorders |
CA2687715A1 (en) | 2007-05-09 | 2008-11-20 | Traffick Therapeutics Inc. | Screening assay to identify correctors of protein trafficking defects |
WO2010107742A2 (en) | 2009-03-18 | 2010-09-23 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions of treating a flaviviridae family viral infection |
WO2009039246A2 (en) | 2007-09-18 | 2009-03-26 | Stanford University | Methods of treating a flaviviridae family viral infection, compositions for treating a flaviviridae family viral infection, and screening assays for identifying compositions for treating a flaviviridae family viral infection |
KR100925176B1 (ko) | 2007-09-21 | 2009-11-05 | 한국전자통신연구원 | 지리 정보를 이용한 네트워크 상태 표시장치 및 방법 |
NZ594937A (en) * | 2008-02-19 | 2013-03-28 | Adolor Corp | Beloxepin, its enantiomers, and analogs thereof for the treatment of pain |
US20110217265A1 (en) | 2008-09-23 | 2011-09-08 | Glenn Jeffrey S | Screening for Inhibitors of HCV Amphipathic Helix (AH) Function |
JP2012520884A (ja) | 2009-03-18 | 2012-09-10 | ザ ボード オブ トラスティーズ オブ ザ リランド スタンフォード ジュニア ユニバーシティー | フラビウイルス科ウイルス感染症を治療する方法および組成物 |
EP2491033A4 (en) | 2009-10-20 | 2013-03-13 | Eiger Biopharmaceuticals Inc | AZAINDAZOLES FOR THE TREATMENT OF FLAVIVIRIDAE VIRUS INFECTION |
WO2014123909A1 (en) * | 2013-02-05 | 2014-08-14 | University Of Washington Through Its Center For Commercialization | Positive allosteric modulators of the gaba-a receptor in the treatment of autism |
US9549909B2 (en) * | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
LT3035926T (lt) * | 2013-08-19 | 2020-11-25 | The Regents Of The University Of California | Junginiai ir būdai, skirti epileptinio sutrikimo gydymui |
WO2015066344A1 (en) * | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
WO2015096119A1 (zh) | 2013-12-27 | 2015-07-02 | 杭州普晒医药科技有限公司 | 氯卡色林盐及其晶体、其制备方法和用途 |
EA201791882A1 (ru) | 2015-02-25 | 2018-02-28 | Дзе Риджентс Оф Дзе Юниверсити Оф Калифорниа | Агонисты 5ht для лечения нарушений |
GB2539472A (en) | 2015-06-17 | 2016-12-21 | Gw Res Ltd | Use of cannabinoids in the treatment of epilepsy |
-
2016
- 2016-02-24 EA EA201791882A patent/EA201791882A1/ru unknown
- 2016-02-24 SI SI201631545T patent/SI3261640T1/sl unknown
- 2016-02-24 PL PL16756282.6T patent/PL3261640T3/pl unknown
- 2016-02-24 JP JP2017544887A patent/JP6884703B2/ja active Active
- 2016-02-24 DK DK16756282.6T patent/DK3261640T3/da active
- 2016-02-24 US US15/552,784 patent/US10874643B2/en active Active
- 2016-02-24 CN CN202111041649.4A patent/CN113546174A/zh active Pending
- 2016-02-24 LT LTEPPCT/US2016/019368T patent/LT3261640T/lt unknown
- 2016-02-24 PT PT167562826T patent/PT3261640T/pt unknown
- 2016-02-24 RS RS20220598A patent/RS63426B1/sr unknown
- 2016-02-24 HR HRP20220822TT patent/HRP20220822T1/hr unknown
- 2016-02-24 HU HUE16756282A patent/HUE059559T2/hu unknown
- 2016-02-24 ES ES16756282T patent/ES2920886T3/es active Active
- 2016-02-24 KR KR1020177026528A patent/KR102385665B1/ko active IP Right Grant
- 2016-02-24 KR KR1020227011498A patent/KR20220048045A/ko active Application Filing
- 2016-02-24 EA EA201992474A patent/EA201992474A3/ru unknown
- 2016-02-24 CA CA3204599A patent/CA3204599A1/en active Pending
- 2016-02-24 CN CN201680023991.2A patent/CN107530326B/zh active Active
- 2016-02-24 CA CA2977135A patent/CA2977135C/en active Active
- 2016-02-24 EP EP22157142.5A patent/EP4043016A1/en active Pending
- 2016-02-24 EP EP16756282.6A patent/EP3261640B1/en active Active
- 2016-02-24 BR BR112017018297-1A patent/BR112017018297B1/pt active IP Right Grant
- 2016-02-24 EP EP19211183.9A patent/EP3632434A1/en not_active Withdrawn
- 2016-02-24 WO PCT/US2016/019368 patent/WO2016138138A1/en active Application Filing
- 2016-02-24 KR KR1020237037303A patent/KR20230152844A/ko not_active Application Discontinuation
- 2016-02-24 AU AU2016222804A patent/AU2016222804C1/en active Active
-
2019
- 2019-11-08 US US16/679,112 patent/US11648237B2/en active Active
-
2020
- 2020-05-01 JP JP2020081127A patent/JP2020143087A/ja active Pending
- 2020-10-28 US US17/082,929 patent/US20210154171A1/en active Pending
-
2021
- 2021-06-23 AU AU2021204261A patent/AU2021204261B2/en active Active
- 2021-08-05 JP JP2021128790A patent/JP2021185148A/ja active Pending
-
2022
- 2022-05-16 AU AU2022203274A patent/AU2022203274A1/en active Pending
- 2022-06-06 JP JP2022091363A patent/JP2022116307A/ja active Pending
-
2023
- 2023-03-30 US US18/192,955 patent/US20230346750A1/en active Pending
- 2023-09-29 JP JP2023169390A patent/JP2024009839A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011518154A (ja) * | 2008-04-16 | 2011-06-23 | アリーナ ファーマシューティカルズ, インコーポレイテッド | (r)−1−{2−[4’−(3−メトキシプロパン−1−スルホニル)−ビフェニル−4−イル]−エチル}−2−メチル−ピロリジンの合成に有用なプロセス |
JP2011520900A (ja) * | 2008-05-16 | 2011-07-21 | アルボー ビータ コーポレーション | てんかんの治療 |
JP2012526847A (ja) * | 2009-05-13 | 2012-11-01 | ネクター セラピューティックス | オリゴマー含有の置換芳香族トリアジン化合物 |
Non-Patent Citations (2)
Title |
---|
CNS NEUROSCIENCE & THERAPEUTICS, vol. 20, no. 7, JPN6019042517, July 2014 (2014-07-01), pages 651 - 661, ISSN: 0004854969 * |
PHARMACOLOGYONLINE, vol. 3, JPN6019042515, 2011, pages 214 - 221, ISSN: 0004854968 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2021185148A (ja) | 障害を治療するための5ht作動薬 | |
US11291653B2 (en) | Compounds and methods for treating an epileptic disorder | |
EA040818B1 (ru) | Способ лечения эпилептического расстройства с помощью агониста рецептора 5ht |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210903 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210903 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220823 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20221117 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230530 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230929 |