JP2021529732A - 大うつ病性障害の処置方法 - Google Patents
大うつ病性障害の処置方法 Download PDFInfo
- Publication number
- JP2021529732A JP2021529732A JP2020569956A JP2020569956A JP2021529732A JP 2021529732 A JP2021529732 A JP 2021529732A JP 2020569956 A JP2020569956 A JP 2020569956A JP 2020569956 A JP2020569956 A JP 2020569956A JP 2021529732 A JP2021529732 A JP 2021529732A
- Authority
- JP
- Japan
- Prior art keywords
- administration
- escutamine
- less
- treatment
- days
- 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
- 208000024714 major depressive disease Diseases 0.000 title claims description 58
- 238000000034 method Methods 0.000 claims abstract description 59
- 238000011282 treatment Methods 0.000 claims description 66
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 claims description 39
- 229960000450 esketamine Drugs 0.000 claims description 37
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 claims description 35
- 229960003299 ketamine Drugs 0.000 claims description 34
- 239000000935 antidepressant agent Substances 0.000 claims description 23
- 229940005513 antidepressants Drugs 0.000 claims description 23
- 238000011269 treatment regimen Methods 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 14
- 230000001430 anti-depressive effect Effects 0.000 claims description 12
- 238000001990 intravenous administration Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000002249 anxiolytic agent Substances 0.000 claims description 4
- 230000000949 anxiolytic effect Effects 0.000 claims description 4
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 2
- 229960002464 fluoxetine Drugs 0.000 claims description 2
- 229960002073 sertraline Drugs 0.000 claims description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims 1
- 229960001653 citalopram Drugs 0.000 claims 1
- 229960004341 escitalopram Drugs 0.000 claims 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 claims 1
- 229960004038 fluvoxamine Drugs 0.000 claims 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims 1
- 229960002296 paroxetine Drugs 0.000 claims 1
- 238000010586 diagram Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 38
- 241001465754 Metazoa Species 0.000 description 31
- 239000003981 vehicle Substances 0.000 description 30
- 208000031404 Chromosome Aberrations Diseases 0.000 description 27
- 241000700159 Rattus Species 0.000 description 22
- 231100000005 chromosome aberration Toxicity 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 230000004913 activation Effects 0.000 description 11
- 230000002411 adverse Effects 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- YQEZLKZALYSWHR-CYBMUJFWSA-N (R)-(+)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O YQEZLKZALYSWHR-CYBMUJFWSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000902 placebo Substances 0.000 description 10
- 229940068196 placebo Drugs 0.000 description 10
- 206010036040 Polychromasia Diseases 0.000 description 9
- 210000005104 human peripheral blood lymphocyte Anatomy 0.000 description 9
- 230000008859 change Effects 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- BEQZHFIKTBVCAU-LBPRGKRZSA-N (2s)-2-amino-2-(2-chlorophenyl)cyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(N)CCCCC1=O BEQZHFIKTBVCAU-LBPRGKRZSA-N 0.000 description 7
- 206010008805 Chromosomal abnormalities Diseases 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 239000013641 positive control Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- -1 that is Inorganic materials 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 230000000394 mitotic effect Effects 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 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 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010041349 Somnolence Diseases 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 230000031864 metaphase Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 231100000946 Benchmark Dose Toxicity 0.000 description 3
- 206010005063 Bladder pain Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010007269 Carcinogenicity Diseases 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 208000020584 Polyploidy Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 231100000260 carcinogenicity Toxicity 0.000 description 3
- 230000007670 carcinogenicity Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000019771 cognition Effects 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 230000009849 deactivation Effects 0.000 description 3
- 230000000994 depressogenic effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000036651 mood Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- 238000002562 urinalysis Methods 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 206010010144 Completed suicide Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 206010011971 Decreased interest Diseases 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 206010013470 Dissociative states Diseases 0.000 description 2
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 2
- 241000027355 Ferocactus setispinus Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 2
- 231100000264 OECD 451 Carcinogenicity Study Toxicity 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 239000000228 antimanic agent Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 239000007894 caplet Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000013256 coordination polymer Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000000763 evoking effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000007897 gelcap Substances 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 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
- 229960002695 phenobarbital Drugs 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000009182 swimming Effects 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 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
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- LAXBNTIAOJWAOP-UHFFFAOYSA-N 2-chlorobiphenyl Chemical compound ClC1=CC=CC=C1C1=CC=CC=C1 LAXBNTIAOJWAOP-UHFFFAOYSA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- SDWAACKJISOIGZ-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one;2,2,2-trichloroethane-1,1-diol Chemical compound OC(O)C(Cl)(Cl)Cl.N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SDWAACKJISOIGZ-UHFFFAOYSA-N 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- VMIYHDSEFNYJSL-UHFFFAOYSA-N Bromazepam Chemical compound C12=CC(Br)=CC=C2NC(=O)CN=C1C1=CC=CC=N1 VMIYHDSEFNYJSL-UHFFFAOYSA-N 0.000 description 1
- 231100001074 DNA strand break Toxicity 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 235000017309 Hypericum perforatum Nutrition 0.000 description 1
- 244000141009 Hypericum perforatum Species 0.000 description 1
- 206010021030 Hypomania Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 231100000177 OECD 474 Mammalian Erythrocyte Micronucleus Test Toxicity 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000016787 Piper methysticum Nutrition 0.000 description 1
- 240000005546 Piper methysticum Species 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229960001570 ademetionine Drugs 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 229960002519 amoxapine Drugs 0.000 description 1
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008503 anti depressant like effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 208000027119 bilirubin metabolic disease Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229960002729 bromazepam Drugs 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- 229960002495 buspirone Drugs 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 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 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000003927 comet assay Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 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 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 208000037870 generalized anxiety Diseases 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 229960000647 gepirone Drugs 0.000 description 1
- QOIGKGMMAGJZNZ-UHFFFAOYSA-N gepirone Chemical compound O=C1CC(C)(C)CC(=O)N1CCCCN1CCN(C=2N=CC=CN=2)CC1 QOIGKGMMAGJZNZ-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 208000036796 hyperbilirubinemia Diseases 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 239000006204 intramuscular dosage form Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000006207 intravenous dosage form Substances 0.000 description 1
- 229940039412 ketalar Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960001432 lurasidone Drugs 0.000 description 1
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- 229960004644 moclobemide Drugs 0.000 description 1
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000037324 pain perception Effects 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 231100000773 point of departure Toxicity 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 229960002601 protriptyline Drugs 0.000 description 1
- BWPIARFWQZKAIA-UHFFFAOYSA-N protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 238000005353 urine analysis Methods 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 229960002263 vortioxetine Drugs 0.000 description 1
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
- A61P25/24—Antidepressants
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
この出願は、2018年6月27日に出願された米国仮出願第62/690,419号、2018年7月16日に出願された62/698,323号、2018年10月5日に出願された62/741,564号、および2018年11月19日に出願された62/769,264の利益を主張し、それぞれの全体が引用により本明細書に包含される。
●任意の水素原子または水素原子の基は、水素の同位体、すなわち重水素に適切に置換することができ、
●任意の炭素原子または炭素原子の基は、炭素の同位体、すなわち13Cの同位体に置換することができ、かつ
●任意の窒素原子または窒素原子の基は、窒素の同位体、すなわち、15Nに適切に置換することができる。
実施例1a:エスケタミン
エスケタミンの染色体異常誘発能を、誘発代謝活性化系(Aroclor−1254に曝露されたラットからの肝臓ホモジネートの9000g上清[S9]ミクロソーム画分)の非存在下および存在下の両方で、ヒト末梢血リンパ球(HPBL)を使用するインビトロ哺乳類染色体異常試験で評価した。染色体異常誘発性を、中期のHPBLの顕微鏡検査によって評価し、有糸***指数(MI)および数値的および/または構造的染色体異常を伴う中期細胞の割合を決定した。
S−ノルケタミンの染色体異常誘発能を、誘発代謝活性化系(フェノバルビタール/5,6−ベンゾフラボンに暴露されたラットからの肝臓ホモジネートの9000g上清[S9]ミクロソーム画分)の非存在下と存在下の両方で、ヒト末梢血リンパ球(HPBL)を使用したインビトロ哺乳類染色体異常試験で評価した。染色体異常誘発性を、中期におけるHPBLの顕微鏡検査によって評価し、数値的および/または構造的染色体異常を伴う中期細胞の割合を決定した。
エスケタミンが、肝臓でDNA鎖切断を誘発する可能性、およびCrl:CD(SD)ラットの骨髄細胞で微小核を誘発する可能性を評価する。動物にエスケタミンを3回経口投与し、2回目の投与は1回目の投与の約24時間後に投与し、3回目の投与は2回目の投与の約21時間後、サンプリングの3時間前に投与した。すべての動物に、10mL/kgの投与容量を使用する強制給餌により経口投与した。
この試験の目的は、エスケタミンをSprague Dawleyラットに強制給餌により28日にわたり経口投与した場合の潜在的毒性、神経行動学的影響、および毒物動態(TK)を評価し、14日間の無薬期間中の回復を評価することであった。50匹のオスおよび50匹のメスラットをランダムに4つの群に分けた(15匹/雌雄/群1および4、10匹/雌雄/群2および3)。エスケタミンを、0(ビヒクル対照)、6、10または30mg/kg/日でオスに、および0(ビヒクル対照)、2、10または20mg/kg/日でメスに、28日間連続して1日1回、10mL/kgの用量容量で強制給餌により経口投与した。29日目(10匹/雌雄/群)または43日目(5匹/群1および4からの雌雄)を安楽死させて剖検するまで、動物を観察した。毒性を、死亡率、臨床観察、体重、食物消費、眼科、運動活性、機能的観察バッテリー、臨床病理学(臨床化学、血液学、凝固および尿検査)、臓器重量、解剖学的(肉眼的または顕微鏡的)病理学に基づいて評価した。毒物動態学分析のために、毒物動態動物(3匹/雌雄/群1、6匹/雌雄/群2、3、および4)に同様に投与し、1日目と4週目に採血した。
Sprague Dawley Ratに、強制給餌により経口投与したエスケタミンの104週間の発がん性試験を実施し、発がん性の可能性を評価し、エスケタミンの毒物動態を測定する。
6〜7週齢のオスのSprague Dawleyラットの群に、エスケタミンを腹腔内注射によって投与し、行動の断念を強制水泳試験によって評価した。10コホートの動物に、15mg/kgのエスケタミンの単回用量、7.5または15mg/kgのエスケタミンまたはビヒクル対照の7回の1日用量のいずれかを投与し、投与の30分後に試験を実施した。統計学的評価を、通常の一元配置分散分析、t検定、および未修正のフィッシャーのLSD比較検定を使用して実施した。
16人の健康な男性および女性の被験者において、ランダム化、非盲検4方向クロスオーバー試験を実施し、ここで当該被験者をランダムに割り当てられた順序で配置し、エスケタミンを投与した。各被験者を、4人の被験者が各処置配列に割り当てられるように、ランダム化コードに従って4つの処置配列のうちの1つに割り当てた。経口または静脈内エスケタミン塩酸塩からなる投与による投与期間の間に、少なくとも7日間のウォッシュアウト期間があった。この試験は、28日間の適格性スクリーニング期間、エスケタミン塩酸塩の単回用量を含む4つの試験期間、続いて治験薬投与後72時間までのPK目的の採血による安全性評価、治験薬投与後72時間での退院、4日目に最後のPK血液サンプルを採取してから7〜14日後のフォローアップ訪問からなった。
フェーズII、用量範囲の所見、多国籍、二重ランダム化、二重盲検、プラセボ対照試験は、抗うつ治療に不十分な応答を有する204人のMDD被験者を対象において、1日1回の10、20、または40mg経口エスケタミンの有効性、安全性、および耐容性を、プラセボ処置と比較する。すべての被験者は、現在の彼らの抗うつ薬を、試験中に用量を変更することなく使用したままとする。
Claims (23)
- 大うつ病性障害(MDD)の処置を必要とするヒト患者においてMDDを処置する方法であって、少なくとも28日間の処置レジメンにわたるエスケタミンの前記患者への投与を含み、
a.前記投与のエスケタミンCmaxが30ng/ml以下であり、または
b.前記投与のエスケタミンAUC0−tが60ng*h/ml以下であり、または
c.前記投与の前記エスケタミンCmaxが、30ng/ml以下であり、かつ前記投与の前記AUC0−tが60ng*h/ml以下である、方法。 - 前記処置レジメンが、28日から約730日である、請求項1に記載の方法。
- 前記処置レジメンが、28日から約365日である、請求項1に記載の方法。
- 前記投与が毎日である、請求項1から3のいずれか一項に記載の方法。
- 前記投与が、2日ごとに1回から月に1回の期間にわたって断続的である、請求項1から3のいずれか一項に記載の方法。
- 前記投与が週に2回である、請求項5に記載の投与。
- 前記投与が週に1回である、請求項5に記載の投与。
- 前記投与が月に1回である、請求項5に記載の投与。
- 前記断続的な投与の頻度が、前記処置レジメンにわたって変化する、請求項5に記載の投与。
- 前記投与が経口的である、請求項1から9のいずれか一項に記載の方法。
- 前記投与が非経口的である、請求項1から9のいずれか一項に記載の方法。
- 前記投与が静脈内である、請求項11に記載の方法。
- 前記投与が鼻腔内である、請求項11に記載の方法。
- 前記投与が直腸である、請求項11に記載の方法。
- 前記投与が舌下である、請求項11に記載の方法。
- 前記投与が頬側である、請求項11に記載の方法。
- (R)−ケタミン以外の第2の薬剤の投与をさらに含む、請求項1から16のいずれか一項に記載の方法。
- 前記第2の薬物が、抗うつ薬、抗躁薬、または抗不安薬である、請求項17に記載の方法。
- 前記抗うつ薬が、フルオキセチン、セルトラリン、パロキセチン、シタロプラム、エスシタロプラムおよびフルボキサミンからなる群から選択される、請求項18に記載の方法。
- 前記投与の前記エスケタミンCmaxが、15ng/ml以下である、請求項1から19のいずれか一項に記載の方法。
- 前記投与の前記エスケタミンAUC0−tが、30ng*h/ml以下である、請求項1から20のいずれか一項に記載の方法。
- 前記投与の前記エスケタミンCmaxが、30ng/ml以下であり、かつ前記投与の前記エスケタミンAUC0−tが60ng*h/ml以下である、請求項1から21のいずれか一項に記載の方法。
- 前記投与の前記エスケタミンCmaxが、15ng/ml以下であり、かつ前記投与の前記エスケタミンAUC0−tが30ng*h/ml以下である、請求項1から22のいずれか一項に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2024000939A JP2024041855A (ja) | 2018-06-27 | 2024-01-09 | 大うつ病性障害の処置方法 |
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862690419P | 2018-06-27 | 2018-06-27 | |
US62/690,419 | 2018-06-27 | ||
US201862698323P | 2018-07-16 | 2018-07-16 | |
US62/698,323 | 2018-07-16 | ||
US201862741564P | 2018-10-05 | 2018-10-05 | |
US62/741,564 | 2018-10-05 | ||
US201862769264P | 2018-11-19 | 2018-11-19 | |
US62/769,264 | 2018-11-19 | ||
PCT/IB2019/055453 WO2020003195A1 (en) | 2018-06-27 | 2019-06-27 | Method of treating major depressive disorder |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024000939A Division JP2024041855A (ja) | 2018-06-27 | 2024-01-09 | 大うつ病性障害の処置方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021529732A true JP2021529732A (ja) | 2021-11-04 |
JPWO2020003195A5 JPWO2020003195A5 (ja) | 2022-04-25 |
Family
ID=67909427
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020569956A Pending JP2021529732A (ja) | 2018-06-27 | 2019-06-27 | 大うつ病性障害の処置方法 |
JP2024000939A Pending JP2024041855A (ja) | 2018-06-27 | 2024-01-09 | 大うつ病性障害の処置方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024000939A Pending JP2024041855A (ja) | 2018-06-27 | 2024-01-09 | 大うつ病性障害の処置方法 |
Country Status (11)
Country | Link |
---|---|
US (1) | US12036189B2 (ja) |
EP (1) | EP3813807A1 (ja) |
JP (2) | JP2021529732A (ja) |
KR (1) | KR20210028159A (ja) |
CN (1) | CN112188889A (ja) |
AU (1) | AU2019293515A1 (ja) |
BR (1) | BR112020023882A2 (ja) |
CA (1) | CA3103440A1 (ja) |
IL (1) | IL278759A (ja) |
MX (1) | MX2020012475A (ja) |
WO (1) | WO2020003195A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2019160057A1 (ja) | 2018-02-15 | 2021-02-04 | 国立大学法人千葉大学 | 炎症性疾患若しくは骨疾患の予防又は治療剤及び医薬組成物 |
CA3099293A1 (en) | 2018-05-04 | 2019-11-07 | Perception Neuroscience, Inc. | Methods of treating substance abuse |
JP2022504036A (ja) | 2018-10-05 | 2022-01-13 | クレキシオ バイオサイエンシーズ エルティーディー. | 大うつ病性障害を治療するためのエスケタミンの投与計画 |
WO2021137147A1 (en) * | 2019-12-30 | 2021-07-08 | Clexio Biosciences Ltd. | Dosage regime with esketamine for treating major depressive disorder |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016531913A (ja) * | 2013-08-26 | 2016-10-13 | アモーサ セラピューティックス, インコーポレイテッドAmorsa Therapeutics, Inc. | 神経抑制性ケタミンの単層による経口投与 |
JP2018515557A (ja) * | 2015-05-20 | 2018-06-14 | ヤンセン ファーマシューティカ エヌ.ベー. | うつ病を治療するための方法及びキット |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH535201A (de) | 1969-12-19 | 1973-03-31 | Bristol Myers Co | Verfahren zur Spaltung von racemischen 2-(o-Chlorphenyl)-2-methylaminocyclohexanon in die optisch-aktiven Isomeren |
EP1594467A4 (en) | 2002-07-05 | 2008-10-22 | Collegium Pharmaceutical Inc | MISUSE OF PHARMACEUTICAL COMPOSITIONS OF OPIOIDES AND OTHER MEDICAMENTS |
JP2009530385A (ja) | 2006-03-22 | 2009-08-27 | マウント シナイ スクール オブ メディシン | うつ病の治療のためのケタミンの鼻内投与 |
US20080069891A1 (en) | 2006-09-15 | 2008-03-20 | Cima Labs, Inc. | Abuse resistant drug formulation |
SA07280459B1 (ar) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني |
DE102007009888A1 (de) | 2007-02-28 | 2008-09-04 | Hermann, Holger Lars, Dr. | Verwendung von S-(+)-Ketamin zur Behandlung von Depressionen |
PL2187873T3 (pl) | 2007-08-13 | 2019-01-31 | Abuse Deterrent Pharmaceutical Llc | Leki odporne na nadużywanie, metoda stosowania i metoda wytwarzania |
WO2009137843A2 (en) | 2008-05-09 | 2009-11-12 | Emory University | Nmda receptor antagonists for the treatment of neuropsychiatric disorders |
US20110038807A1 (en) | 2009-08-14 | 2011-02-17 | Demitri Papolos | Compositions and methods for treating bipolar disorder |
PE20141906A1 (es) * | 2012-03-12 | 2014-12-05 | Janssen Pharmaceutica Nv | Esketamina para el tratamiento de la depresion refractaria al tratamiento o resistente al tratamiento |
KR20150059167A (ko) | 2012-07-06 | 2015-05-29 | 에갈렛 리미티드 | 제어된 방출을 위한 남용 제지 약학적 조성물 |
WO2014020155A1 (en) | 2012-08-02 | 2014-02-06 | Clinpharm Reform Gmbh | Oral transmucosal adminstration forms of s-ketamine |
US9468611B2 (en) | 2012-09-27 | 2016-10-18 | Relmada Therapeutics, Inc. | d-Methadone for the treatment of psychiatric symptoms |
US10555916B2 (en) | 2013-01-25 | 2020-02-11 | Case Western Reserve University | NMDAR antagonist for the treatment of pervasive development disorders |
KR20220044380A (ko) | 2013-04-12 | 2022-04-07 | 이칸 스쿨 오브 메디슨 엣 마운트 시나이 | 외상후 스트레스 장애의 치료 방법 |
WO2015051259A1 (en) | 2013-10-04 | 2015-04-09 | Impax Laboratories, Inc. | Pharmaceutical compositions and methods of use |
CA2900858C (en) | 2013-10-31 | 2017-05-02 | Cima Labs Inc. | Immediate release abuse-deterrent granulated dosage forms |
PL3131533T3 (pl) | 2014-04-17 | 2019-12-31 | Develco Pharma Schweiz Ag | Doustna postać dawkowania ketaminy |
CA2961208A1 (en) | 2014-09-15 | 2016-03-24 | Janssen Pharmaceutica Nv | Val66met (snp rs6265) genotype specific dosing regimens and methods for the treatment of depression |
SI3215147T1 (sl) | 2014-11-04 | 2024-05-31 | Acadia Pharmaceuticals Inc. | Nevroatenuacijske spojine norketamina in postopki |
CA2970065A1 (en) | 2014-12-08 | 2016-06-16 | Cima Labs Inc. | Immediate release abuse-deterrent granulated dosage forms |
US20160332962A1 (en) * | 2015-05-13 | 2016-11-17 | Janssen Pharmaceutica Nv | (s)-csa salt of s-ketamine, (r)-csa salt of s-ketamine and processes for the preparation of s-ketamine |
WO2017041112A1 (en) | 2015-09-04 | 2017-03-09 | Cyprus Therapeutics, Inc. | Ketamine and cytochrome p 450 inhibitor combinations |
WO2017087691A1 (en) | 2015-11-17 | 2017-05-26 | The Trustees Of Columbia University In The City Of New York | Pharmacological prophylactics against stress-induced affective disorders and their associated symptoms |
WO2018079693A1 (ja) | 2016-10-27 | 2018-05-03 | 国立大学法人 千葉大学 | (s)-ノルケタミンおよびその塩の医薬品としての応用 |
EP3548014B1 (en) | 2016-11-30 | 2024-07-31 | Philip E. Wolfson | Ketamine for the treatment of menstrually related symptoms |
US11723883B2 (en) | 2017-06-23 | 2023-08-15 | Ketabon Gmbh | Hydroxynorketamine for the use in the treatment of depression |
EP3694832A4 (en) | 2017-10-10 | 2021-07-14 | Douglas Pharmaceuticals Limited | EXTENDED-RELEASE PHARMACEUTICAL FORMULATION AND TREATMENT METHODS |
KR20240011237A (ko) | 2017-12-22 | 2024-01-25 | 얀센 파마슈티카 엔브이 | 우울증 치료를 위한 에스케타민 |
JP2022504036A (ja) | 2018-10-05 | 2022-01-13 | クレキシオ バイオサイエンシーズ エルティーディー. | 大うつ病性障害を治療するためのエスケタミンの投与計画 |
US20220151955A1 (en) | 2019-08-05 | 2022-05-19 | The Ketamine Research Foundation | Ketamine for the treatment of postpartum symptoms and disorders |
TW202135787A (zh) | 2019-12-12 | 2021-10-01 | 比利時商健生藥品公司 | 艾***調配物及製備與儲存的方法 |
WO2021137147A1 (en) | 2019-12-30 | 2021-07-08 | Clexio Biosciences Ltd. | Dosage regime with esketamine for treating major depressive disorder |
-
2019
- 2019-06-27 CA CA3103440A patent/CA3103440A1/en active Pending
- 2019-06-27 JP JP2020569956A patent/JP2021529732A/ja active Pending
- 2019-06-27 KR KR1020207036721A patent/KR20210028159A/ko unknown
- 2019-06-27 AU AU2019293515A patent/AU2019293515A1/en active Pending
- 2019-06-27 BR BR112020023882-1A patent/BR112020023882A2/pt unknown
- 2019-06-27 EP EP19766075.6A patent/EP3813807A1/en active Pending
- 2019-06-27 US US16/454,399 patent/US12036189B2/en active Active
- 2019-06-27 MX MX2020012475A patent/MX2020012475A/es unknown
- 2019-06-27 CN CN201980034997.3A patent/CN112188889A/zh active Pending
- 2019-06-27 WO PCT/IB2019/055453 patent/WO2020003195A1/en active Application Filing
-
2020
- 2020-11-17 IL IL278759A patent/IL278759A/en unknown
-
2024
- 2024-01-09 JP JP2024000939A patent/JP2024041855A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016531913A (ja) * | 2013-08-26 | 2016-10-13 | アモーサ セラピューティックス, インコーポレイテッドAmorsa Therapeutics, Inc. | 神経抑制性ケタミンの単層による経口投与 |
JP2018515557A (ja) * | 2015-05-20 | 2018-06-14 | ヤンセン ファーマシューティカ エヌ.ベー. | うつ病を治療するための方法及びキット |
Also Published As
Publication number | Publication date |
---|---|
MX2020012475A (es) | 2021-04-28 |
US12036189B2 (en) | 2024-07-16 |
AU2019293515A1 (en) | 2020-12-03 |
CN112188889A (zh) | 2021-01-05 |
JP2024041855A (ja) | 2024-03-27 |
WO2020003195A1 (en) | 2020-01-02 |
KR20210028159A (ko) | 2021-03-11 |
CA3103440A1 (en) | 2020-01-02 |
US20200000748A1 (en) | 2020-01-02 |
IL278759A (en) | 2021-01-31 |
BR112020023882A2 (pt) | 2021-02-09 |
EP3813807A1 (en) | 2021-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2021529732A (ja) | 大うつ病性障害の処置方法 | |
JP2022504036A (ja) | 大うつ病性障害を治療するためのエスケタミンの投与計画 | |
Zisook et al. | Nefazodone in patients with treatment-refractory posttraumatic stress disorder | |
EP3863617A1 (en) | Esketamine for use in treating major depressive disorder | |
WO2021137147A1 (en) | Dosage regime with esketamine for treating major depressive disorder | |
CN113710319A (zh) | 用于治疗焦虑相关病症的组合物和方法 | |
JP2023507926A (ja) | 神経精神状態または神経学的状態を治療するためのエスケタミンを用いた投与計画 | |
DK2694065T3 (en) | COMPOSITION FOR TREATMENT OF DISORDER WITH SEXUAL SEXUAL LISTENING | |
WO2020070706A1 (en) | Dosage regime of esketamine for treating major depressive disorder | |
WO2021137148A1 (en) | Dosage regime with esketamine for treating neuropsychiatric or neurological conditions | |
US20230255953A1 (en) | Use of roluperidone in preventing relapse in schizophrenia patients | |
US20210113494A1 (en) | Method Of Treating Post-Traumatic Stress Syndrome | |
WO2020070547A1 (en) | Dosage regime of esketamine for treating major depressive disorder | |
Cutler et al. | An evaluation of the anxiolytic SC 48,274 in generalized anxiety disorder (GAD) | |
JP2008273954A (ja) | うつ病の予防及び/又は治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220415 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220415 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230228 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230228 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230502 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230708 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230912 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240109 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20240109 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20240126 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20240209 |