JP6668045B2 - ドラベ症候群を処置するための選択的5−ht受容体アゴニストおよびアンタゴニスト - Google Patents
ドラベ症候群を処置するための選択的5−ht受容体アゴニストおよびアンタゴニスト Download PDFInfo
- Publication number
- JP6668045B2 JP6668045B2 JP2015221719A JP2015221719A JP6668045B2 JP 6668045 B2 JP6668045 B2 JP 6668045B2 JP 2015221719 A JP2015221719 A JP 2015221719A JP 2015221719 A JP2015221719 A JP 2015221719A JP 6668045 B2 JP6668045 B2 JP 6668045B2
- Authority
- JP
- Japan
- Prior art keywords
- scn1lab
- receptor
- agonist
- epilepsy
- methyl
- 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.)
- Expired - Fee Related
Links
- 208000036572 Myoclonic epilepsy Diseases 0.000 title claims description 66
- 201000007547 Dravet syndrome Diseases 0.000 title claims description 65
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 title claims description 65
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 title description 29
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 title description 21
- 239000000018 receptor agonist Substances 0.000 title description 14
- 229940044601 receptor agonist Drugs 0.000 title description 13
- 229940044551 receptor antagonist Drugs 0.000 title description 3
- 239000002464 receptor antagonist Substances 0.000 title description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 564
- 206010010904 Convulsion Diseases 0.000 claims description 57
- 102000005962 receptors Human genes 0.000 claims description 49
- 108020003175 receptors Proteins 0.000 claims description 49
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 15
- BTTOYOKCLDAHHO-HNNXBMFYSA-N (2s)-n,n-dimethyl-5-(1,3,5-trimethylpyrazol-4-yl)-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C([C@@H](C1)N(C)C)CC2=C1C=CC=C2C=1C(C)=NN(C)C=1C BTTOYOKCLDAHHO-HNNXBMFYSA-N 0.000 claims description 8
- LBVZWEWTNUDWNS-YRNVUSSQSA-N (e)-3-[3-[2-(dimethylamino)ethyl]-1h-indol-5-yl]-n-[(4-methoxyphenyl)methyl]prop-2-enamide Chemical group C1=CC(OC)=CC=C1CNC(=O)\C=C\C1=CC=C(NC=C2CCN(C)C)C2=C1 LBVZWEWTNUDWNS-YRNVUSSQSA-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
- 239000003937 drug carrier Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- LMIQERWZRIFWNZ-UHFFFAOYSA-N 5-hydroxyindole Chemical compound OC1=CC=C2NC=CC2=C1 LMIQERWZRIFWNZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 description 54
- 206010015037 epilepsy Diseases 0.000 description 50
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 44
- 239000000556 agonist Substances 0.000 description 44
- 238000011282 treatment Methods 0.000 description 43
- 229960001582 fenfluramine Drugs 0.000 description 40
- 238000000034 method Methods 0.000 description 27
- 230000035772 mutation Effects 0.000 description 24
- 229940079593 drug Drugs 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- 241000252212 Danio rerio Species 0.000 description 21
- 230000006742 locomotor activity Effects 0.000 description 21
- 239000005557 antagonist Substances 0.000 description 18
- 230000001787 epileptiform Effects 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- 239000002858 neurotransmitter agent Substances 0.000 description 14
- 239000012634 fragment Substances 0.000 description 11
- 238000011866 long-term treatment Methods 0.000 description 11
- 239000003420 antiserotonin agent Substances 0.000 description 10
- 230000001186 cumulative effect Effects 0.000 description 9
- 230000001037 epileptic effect Effects 0.000 description 9
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical group C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 8
- 230000002068 genetic effect Effects 0.000 description 8
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 7
- 208000008589 Obesity Diseases 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 235000020824 obesity Nutrition 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 6
- 239000001961 anticonvulsive agent Substances 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 208000037824 growth disorder Diseases 0.000 description 6
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 5
- 208000002877 Epileptic Syndromes Diseases 0.000 description 5
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 5
- DBGIVFWFUFKIQN-SECBINFHSA-N Levofenfluramine Chemical compound CCN[C@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-SECBINFHSA-N 0.000 description 5
- 108010052164 Sodium Channels Proteins 0.000 description 5
- 102000018674 Sodium Channels Human genes 0.000 description 5
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229960000623 carbamazepine Drugs 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
- 229960004597 dexfenfluramine Drugs 0.000 description 5
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 5
- 229960004943 ergotamine Drugs 0.000 description 5
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 5
- 210000003128 head Anatomy 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229960001848 lamotrigine Drugs 0.000 description 5
- 230000001418 larval effect Effects 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 229960005060 lorcaserin Drugs 0.000 description 5
- 230000002035 prolonged effect Effects 0.000 description 5
- 210000004129 prosencephalon Anatomy 0.000 description 5
- 229940076279 serotonin Drugs 0.000 description 5
- 239000004003 serotonin 1D agonist Substances 0.000 description 5
- 239000002399 serotonin 2A agonist Substances 0.000 description 5
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 5
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 description 4
- 208000024658 Epilepsy syndrome Diseases 0.000 description 4
- 206010020880 Hypertrophy Diseases 0.000 description 4
- 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 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960001403 clobazam Drugs 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000003205 genotyping method Methods 0.000 description 4
- 210000003709 heart valve Anatomy 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- POGQSBRIGCQNEG-UHFFFAOYSA-N rufinamide Chemical compound N1=NC(C(=O)N)=CN1CC1=C(F)C=CC=C1F POGQSBRIGCQNEG-UHFFFAOYSA-N 0.000 description 4
- 239000003244 serotonin 2B agonist Substances 0.000 description 4
- 239000002485 serotonin 2C agonist Substances 0.000 description 4
- 239000003195 sodium channel blocking agent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229960005318 vigabatrin Drugs 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- USFUFHFQWXDVMH-UHFFFAOYSA-N 1-(1-methylindol-5-yl)-3-(3-methyl-1,2-thiazol-5-yl)urea Chemical compound S1N=C(C)C=C1NC(=O)NC1=CC=C(N(C)C=C2)C2=C1 USFUFHFQWXDVMH-UHFFFAOYSA-N 0.000 description 3
- KPXKZZURYAXZQE-UHFFFAOYSA-N 1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-6-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole;hydrochloride Chemical compound Cl.ClC1=C(OC)C(OC)=CC=C1CC1C(NC=2C3=CC(C)=CC=2)=C3CCN1 KPXKZZURYAXZQE-UHFFFAOYSA-N 0.000 description 3
- -1 4-fluoro-1-naphthalenyl Chemical group 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 101000631760 Homo sapiens Sodium channel protein type 1 subunit alpha Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010061334 Partial seizures Diseases 0.000 description 3
- 241001417523 Plesiopidae Species 0.000 description 3
- OJZZJTLBYXHUSJ-UHFFFAOYSA-N SB 200646 Chemical compound C=1C=C2N(C)C=CC2=CC=1NC(=O)NC1=CC=CN=C1 OJZZJTLBYXHUSJ-UHFFFAOYSA-N 0.000 description 3
- OQZOXHCRSXYSPM-UHFFFAOYSA-N SB 221284 Chemical compound C1=2C=C(C(F)(F)F)C(SC)=CC=2CCN1C(=O)NC1=CC=CN=C1 OQZOXHCRSXYSPM-UHFFFAOYSA-N 0.000 description 3
- RRJLJKRFFRZRAF-UHFFFAOYSA-N SB 228357 Chemical compound C1=2C=C(C(F)(F)F)C(OC)=CC=2CCN1C(=O)NC(C=1)=CC(F)=CC=1C1=CC=CN=C1 RRJLJKRFFRZRAF-UHFFFAOYSA-N 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940125681 anticonvulsant agent Drugs 0.000 description 3
- 229960003965 antiepileptics Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 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 3
- 201000010099 disease Diseases 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 3
- 210000001161 mammalian embryo Anatomy 0.000 description 3
- UMLARORAEPLXTC-UHFFFAOYSA-N n-ethyl-1-[3-(trifluoromethyl)phenyl]propan-2-amine;2-methyl-1-phenylpropan-2-amine Chemical compound CC(C)(N)CC1=CC=CC=C1.CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 UMLARORAEPLXTC-UHFFFAOYSA-N 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 3
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229960001897 stiripentol Drugs 0.000 description 3
- IBLNKMRFIPWSOY-FNORWQNLSA-N stiripentol Chemical compound CC(C)(C)C(O)\C=C\C1=CC=C2OCOC2=C1 IBLNKMRFIPWSOY-FNORWQNLSA-N 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 2
- VGEMBOFBPSNOIO-UHFFFAOYSA-N 1-methyl-n-pyridin-3-yl-6,7-dihydropyrrolo[2,3-f]indole-5-carboxamide;hydrochloride Chemical compound Cl.C1CC=2C=C3N(C)C=CC3=CC=2N1C(=O)NC1=CC=CN=C1 VGEMBOFBPSNOIO-UHFFFAOYSA-N 0.000 description 2
- MKJPYBJBPRFMHL-UHFFFAOYSA-N 4-(4-fluoronaphthalen-1-yl)-6-propan-2-ylpyrimidin-2-amine;hydrochloride Chemical compound Cl.NC1=NC(C(C)C)=CC(C=2C3=CC=CC=C3C(F)=CC=2)=N1 MKJPYBJBPRFMHL-UHFFFAOYSA-N 0.000 description 2
- 206010052075 Acquired epileptic aphasia Diseases 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- 108091093088 Amplicon Proteins 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 239000004475 Arginine Substances 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
- 208000002381 Brain Hypoxia Diseases 0.000 description 2
- MSXFEKRSKBQMGJ-QMMMGPOBSA-N C[C@H]1CNCCC2=C1C(=CC=C2)Cl Chemical compound C[C@H]1CNCCC2=C1C(=CC=C2)Cl MSXFEKRSKBQMGJ-QMMMGPOBSA-N 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
- 206010019196 Head injury Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 201000005802 Landau-Kleffner Syndrome Diseases 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
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- 102100028910 Sodium channel protein type 1 subunit alpha Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000016571 aggressive behavior Effects 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 238000009360 aquaculture Methods 0.000 description 2
- 244000144974 aquaculture Species 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- FAIMGWSOSCFGRU-UHFFFAOYSA-N atc-0175 Chemical compound N=1C2=CC=CC=C2C(N(C)C)=NC=1NC(CC1)CCC1NC(=O)C1=CC=C(F)C(F)=C1 FAIMGWSOSCFGRU-UHFFFAOYSA-N 0.000 description 2
- 230000007177 brain activity Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229960003120 clonazepam Drugs 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 230000009540 excitatory neurotransmission Effects 0.000 description 2
- 201000007186 focal epilepsy Diseases 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 229960002623 lacosamide Drugs 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000001422 normality test Methods 0.000 description 2
- 229960001816 oxcarbazepine Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 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 2
- 230000002085 persistent effect Effects 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 229960002036 phenytoin Drugs 0.000 description 2
- 230000000270 postfertilization Effects 0.000 description 2
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 2
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 229960003014 rufinamide Drugs 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 239000002400 serotonin 2A antagonist Substances 0.000 description 2
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 2
- 231100000161 signs of toxicity Toxicity 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 230000007958 sleep Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 208000005809 status epilepticus Diseases 0.000 description 2
- 230000028016 temperature homeostasis Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229940102566 valproate Drugs 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 2
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- TYMMXVZAUGQKRF-UHFFFAOYSA-N (3-bromo-2,5-dimethoxy-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl)methanamine;hydrobromide Chemical compound Br.COC1=CC(Br)=C(OC)C2=C1C(CN)C2 TYMMXVZAUGQKRF-UHFFFAOYSA-N 0.000 description 1
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- DXUZZRDHJMOLTN-QKBLNNHISA-N (E)-but-2-enedioic acid (2S,7R)-4-methyl-4,9-diazatetracyclo[7.6.1.02,7.012,16]hexadeca-1(15),12(16),13-triene Chemical compound OC(=O)\C=C\C(O)=O.CN1CC[C@H]2CN3CCc4cccc([C@H]2C1)c34 DXUZZRDHJMOLTN-QKBLNNHISA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- BMPDWHIDQYTSHX-AWEZNQCLSA-N (S)-MHD Chemical compound C1[C@H](O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 BMPDWHIDQYTSHX-AWEZNQCLSA-N 0.000 description 1
- GDAJGLDMCDMPIR-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole Chemical compound C1=C(OC)C(OC)=CC=C1CC1C(NC=2C3=CC(C)=CC=2)=C3CCN1 GDAJGLDMCDMPIR-UHFFFAOYSA-N 0.000 description 1
- BKAZOTIBKRWLQA-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1C(NC=2C3=CC(C)=CC=2)=C3CCN1 BKAZOTIBKRWLQA-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 206010004954 Birth trauma Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 0 COC1=C(CC2**)C2C(*)C=C1Br Chemical compound COC1=C(CC2**)C2C(*)C=C1Br 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- HUUPKFUYSQNNLO-FAESNJTISA-N Cl.N([C@H]1CC[C@H](CC1)NC=1N=C(C2=CC=CC=C2N=1)N(C)C)C(=O)C1=CC=C(F)C(F)=C1 Chemical compound Cl.N([C@H]1CC[C@H](CC1)NC=1N=C(C2=CC=CC=C2N=1)N(C)C)C(=O)C1=CC=C(F)C(F)=C1 HUUPKFUYSQNNLO-FAESNJTISA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000032065 Convulsion neonatal Diseases 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010012559 Developmental delay Diseases 0.000 description 1
- 241000004297 Draba Species 0.000 description 1
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 206010016173 Fall Diseases 0.000 description 1
- 208000002091 Febrile Seizures Diseases 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
- 201000009010 Frontal lobe epilepsy Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 102000017706 GABRD Human genes 0.000 description 1
- 102000017703 GABRG2 Human genes 0.000 description 1
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001000686 Homo sapiens 4-aminobutyrate aminotransferase, mitochondrial Proteins 0.000 description 1
- 101001073587 Homo sapiens Gamma-aminobutyric acid receptor subunit delta Proteins 0.000 description 1
- 101000926813 Homo sapiens Gamma-aminobutyric acid receptor subunit gamma-2 Proteins 0.000 description 1
- 101100028812 Homo sapiens PCDH19 gene Proteins 0.000 description 1
- 101000684826 Homo sapiens Sodium channel protein type 2 subunit alpha Proteins 0.000 description 1
- 101000684820 Homo sapiens Sodium channel protein type 3 subunit alpha Proteins 0.000 description 1
- 101000654386 Homo sapiens Sodium channel protein type 9 subunit alpha Proteins 0.000 description 1
- 101000684813 Homo sapiens Sodium channel subunit beta-1 Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010021750 Infantile Spasms Diseases 0.000 description 1
- 208000035899 Infantile spasms syndrome Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 102000006835 Lamins Human genes 0.000 description 1
- 108010047294 Lamins Proteins 0.000 description 1
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 description 1
- DIWRORZWFLOCLC-UHFFFAOYSA-N Lorazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010027727 Mitral valve incompetence Diseases 0.000 description 1
- 241000234479 Narcissus Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 101150105943 PCDH19 gene Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000037158 Partial Epilepsies Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 206010036312 Post-traumatic epilepsy Diseases 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 206010071141 Rasmussen encephalitis Diseases 0.000 description 1
- 208000004160 Rasmussen subacute encephalitis Diseases 0.000 description 1
- 230000010757 Reduction Activity Effects 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 108010063499 Sigma Factor Proteins 0.000 description 1
- 102100023150 Sodium channel protein type 2 subunit alpha Human genes 0.000 description 1
- 102100023720 Sodium channel protein type 3 subunit alpha Human genes 0.000 description 1
- 102100031367 Sodium channel protein type 9 subunit alpha Human genes 0.000 description 1
- 102100023732 Sodium channel subunit beta-1 Human genes 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 102400000096 Substance P Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 201000006791 West syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 208000003554 absence epilepsy Diseases 0.000 description 1
- 208000028311 absence seizure Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026802 afebrile Diseases 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000007953 anoxia 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
- 210000000709 aorta Anatomy 0.000 description 1
- 229940075225 aptiom Drugs 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 229940072698 ativan Drugs 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 229940000221 banzel Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 230000008236 biological pathway Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940057922 carbatrol Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229940029783 cerebyx Drugs 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 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 1
- 229960005132 cisapride Drugs 0.000 description 1
- 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 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000001609 comparable effect Effects 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 229940075922 depacon Drugs 0.000 description 1
- 229940089052 depakene Drugs 0.000 description 1
- 229940075925 depakote Drugs 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229940074202 diastat Drugs 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 229940064790 dilantin Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000005059 dormancy Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229940089063 epitol Drugs 0.000 description 1
- 229940051493 equetro Drugs 0.000 description 1
- 229960004028 eslicarbazepine Drugs 0.000 description 1
- 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 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 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 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- WKGXYQFOCVYPAC-UHFFFAOYSA-N felbamate Chemical compound NC(=O)OCC(COC(N)=O)C1=CC=CC=C1 WKGXYQFOCVYPAC-UHFFFAOYSA-N 0.000 description 1
- 229940099239 felbatol Drugs 0.000 description 1
- 229940024040 fycompa Drugs 0.000 description 1
- 239000002843 gaba uptake inhibitor Substances 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- TZDUHAJSIBHXDL-UHFFFAOYSA-N gabapentin enacarbil Chemical compound CC(C)C(=O)OC(C)OC(=O)NCC1(CC(O)=O)CCCCC1 TZDUHAJSIBHXDL-UHFFFAOYSA-N 0.000 description 1
- 229940084457 gabitril Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229910021397 glassy carbon Inorganic materials 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229940015456 gralise Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- YASBOGFWAMXINH-TZMCWYRMSA-N gtpl195 Chemical compound C1CC2=CC=CC3=C2N1C[C@H]1CCN(C)C[C@H]13 YASBOGFWAMXINH-TZMCWYRMSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229940074066 horizant Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000009539 inhibitory neurotransmission Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 1
- 229960005417 ketanserin Drugs 0.000 description 1
- 229940073092 klonopin Drugs 0.000 description 1
- 229940072170 lamictal Drugs 0.000 description 1
- 210000005053 lamin Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 229940009697 lyrica Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 229940090010 mysoline Drugs 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003705 neurological process Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229940072228 neurontin Drugs 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229940044442 onfi Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 229940065847 oxtellar Drugs 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000018052 penile erection Effects 0.000 description 1
- 229960005198 perampanel Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940017430 potiga Drugs 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000008132 psychomotor development Effects 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229940106773 sabril Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- DXUZZRDHJMOLTN-MRYVXRNOSA-N ser-082 Chemical compound OC(=O)\C=C\C(O)=O.C1CC2=CC=CC3=C2N1C[C@H]1CCN(C)C[C@H]13 DXUZZRDHJMOLTN-MRYVXRNOSA-N 0.000 description 1
- 239000003723 serotonin 1A agonist Substances 0.000 description 1
- 239000004002 serotonin 1B agonist Substances 0.000 description 1
- 239000004000 serotonin 1B antagonist Substances 0.000 description 1
- 239000004001 serotonin 1D antagonist Substances 0.000 description 1
- 239000002484 serotonin 2C antagonist Substances 0.000 description 1
- 239000000198 serotonin 5-HT3 receptor agonist Substances 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- AIMUHNZKNFEZSN-UHFFFAOYSA-M sodium;decane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCS([O-])(=O)=O AIMUHNZKNFEZSN-UHFFFAOYSA-M 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229940010817 stavzor Drugs 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 229940090016 tegretol Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 229940035305 topamax Drugs 0.000 description 1
- 229940115663 topiragen Drugs 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 229940072040 tricaine Drugs 0.000 description 1
- FQZJYWMRQDKBQN-UHFFFAOYSA-N tricaine methanesulfonate Chemical compound CS([O-])(=O)=O.CCOC(=O)C1=CC=CC([NH3+])=C1 FQZJYWMRQDKBQN-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229940061414 trileptal Drugs 0.000 description 1
- 229940072690 valium Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940089285 vimpat Drugs 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229940063682 zarontin Drugs 0.000 description 1
- 229940061639 zonegran Drugs 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15/265,062 US20170071949A1 (en) | 2015-09-14 | 2016-09-14 | Combination treatment of specific forms of epilepsy |
| US15/989,812 US20180325909A1 (en) | 2015-09-14 | 2018-05-25 | Combination treatment of specific forms of epilepsy |
| US17/579,135 US20220193082A1 (en) | 2015-09-14 | 2022-01-19 | Combination treatment of specific forms of epilepsy |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562162544P | 2015-05-15 | 2015-05-15 | |
| US62/162,544 | 2015-05-15 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2016216438A JP2016216438A (ja) | 2016-12-22 |
| JP2016216438A5 JP2016216438A5 (enExample) | 2018-07-26 |
| JP6668045B2 true JP6668045B2 (ja) | 2020-03-18 |
Family
ID=57579762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015221719A Expired - Fee Related JP6668045B2 (ja) | 2015-05-15 | 2015-11-12 | ドラベ症候群を処置するための選択的5−ht受容体アゴニストおよびアンタゴニスト |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6668045B2 (enExample) |
Families Citing this family (9)
| 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 |
| JP2019507111A (ja) | 2015-12-22 | 2019-03-14 | ゾゲニクス インターナショナル リミテッド | 代謝抵抗性フェンフルラミン類縁体およびその使用法 |
| KR102688278B1 (ko) | 2015-12-22 | 2024-07-26 | 조게닉스 인터내셔널 리미티드 | 펜플루라민 조성물 및 그 제조 방법 |
| CA3032996C (en) | 2016-08-24 | 2025-05-06 | Zogenix International Ltd | Formulation for inhibiting formation of 5-ht 2b agonists and methods of using same |
| US20190091179A1 (en) * | 2017-09-26 | 2019-03-28 | Zogenix International Limited | Congnitive function with fenfluramine |
| JP2021530541A (ja) * | 2018-07-27 | 2021-11-11 | ゼノン・ファーマシューティカルズ・インコーポレイテッドXenon Pharmaceuticals Inc. | てんかんの治療方法 |
| AU2019384963B2 (en) | 2018-11-19 | 2022-05-26 | Zogenix International Limited | Methods of treating Rett syndrome using fenfluramine |
| WO2020112460A1 (en) * | 2018-11-30 | 2020-06-04 | Zogenix International Limited | A method of treating refractory epilepsy syndromes using fenfluramine enantiomers |
| CN113897399A (zh) * | 2021-08-31 | 2022-01-07 | 浙江赛微思生物科技有限公司 | 一种scn1lab基因敲除斑马鱼癫痫模型及其应用 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009051747A1 (en) * | 2007-10-15 | 2009-04-23 | Concert Pharmaceuticals, Inc. | Deuterated lorcaserin |
| US9549909B2 (en) * | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
| WO2015066344A1 (en) * | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
-
2015
- 2015-11-12 JP JP2015221719A patent/JP6668045B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016216438A (ja) | 2016-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6668045B2 (ja) | ドラベ症候群を処置するための選択的5−ht受容体アゴニストおよびアンタゴニスト | |
| US20180325909A1 (en) | Combination treatment of specific forms of epilepsy | |
| JP5675650B2 (ja) | 向精神薬の働きを向上させるソルビン酸、安息香酸及びその誘導体 | |
| US20220193082A1 (en) | Combination treatment of specific forms of epilepsy | |
| EP3606525B1 (en) | Compositions for treating aging-associated impairments using ccr3-inhibitors | |
| KR101612563B1 (ko) | 도파민 수용체 리간드를 함유하는 약학적 조성물 및 도파민 수용체 리간드를 사용한 치료 방법 | |
| AU2011316225B2 (en) | Combinations of serotonin receptor agonists for treatment of movement disorders | |
| JP2021526507A (ja) | 発作により誘発される突然死を処置するための組成物および方法 | |
| EA017915B1 (ru) | Kcnq-открыватели калиевых каналов, применяемые для лечения или ослабления симптомов шизофрении | |
| US20200054622A1 (en) | Methods and Compositions for Treating Aging-Associated Impairments Using CCR3-Inhibitors | |
| WO2012163365A1 (en) | Combinations of serotonin receptor agonists for treatment of movement disorders | |
| TWI457123B (zh) | 4-{3-[順式-六氫環戊并[c]吡咯-2(1h)-基]丙氧基}苯甲醯胺與nmda受體拮抗劑之新結合及包含彼等之醫藥組合物 | |
| JP2024153742A (ja) | Ccr3阻害剤を用いて、加齢性機能障害を治療するための方法および組成物 | |
| JP2017057188A (ja) | 特別な形態のてんかんの併用療法 | |
| AU2022418280A1 (en) | Use of aminopyrazole compounds | |
| EA041892B1 (ru) | Способы и композиции для лечения ассоциированных со старением нарушений с применением ccr3-ингибиторов | |
| HK40053020A (en) | Methods and compositions for treating aging-associated impairments using ccr3-inhibitors | |
| HK40047615A (en) | New uses of a 5-ht4 receptor agonist | |
| CN108785304A (zh) | 一种ampa受体激动剂的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A80 | Written request to apply exceptions to lack of novelty of invention |
Free format text: JAPANESE INTERMEDIATE CODE: A80 Effective date: 20151127 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180615 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180615 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190513 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190809 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191023 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191219 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200106 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200116 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200214 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200226 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6668045 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |