CN103249407B - 用于治疗抑郁症和其他非感染性疾病的联合疗法 - Google Patents
用于治疗抑郁症和其他非感染性疾病的联合疗法 Download PDFInfo
- Publication number
- CN103249407B CN103249407B CN201180058704.9A CN201180058704A CN103249407B CN 103249407 B CN103249407 B CN 103249407B CN 201180058704 A CN201180058704 A CN 201180058704A CN 103249407 B CN103249407 B CN 103249407B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- acid
- glycine
- disorder
- vitamin
- 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.)
- Active
Links
- 208000031662 Noncommunicable disease Diseases 0.000 title claims abstract description 33
- 238000011282 treatment Methods 0.000 title claims description 62
- 208000020401 Depressive disease Diseases 0.000 title description 2
- 238000002648 combination therapy Methods 0.000 title 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 64
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 49
- 239000011715 vitamin B12 Substances 0.000 claims abstract description 43
- 239000000203 mixture Substances 0.000 claims abstract description 29
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims abstract description 25
- 239000004471 Glycine Substances 0.000 claims description 60
- JCZPMGDSEAFWDY-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanamide Chemical compound NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO JCZPMGDSEAFWDY-SQOUGZDYSA-N 0.000 claims description 53
- 239000011149 active material Substances 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 206010012289 Dementia Diseases 0.000 claims description 23
- 208000019901 Anxiety disease Diseases 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 208000019022 Mood disease Diseases 0.000 claims description 18
- -1 hydroxyl cobalamin Chemical compound 0.000 claims description 18
- 230000006872 improvement Effects 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 10
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 10
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000019771 cognition Effects 0.000 claims description 5
- 206010034912 Phobia Diseases 0.000 claims description 4
- MTDHILKWIRSIHB-UHFFFAOYSA-N (5-azaniumyl-3,4,6-trihydroxyoxan-2-yl)methyl sulfate Chemical compound NC1C(O)OC(COS(O)(=O)=O)C(O)C1O MTDHILKWIRSIHB-UHFFFAOYSA-N 0.000 claims description 3
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 3
- 229960002849 glucosamine sulfate Drugs 0.000 claims description 3
- 208000019906 panic disease Diseases 0.000 claims description 3
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 3
- 201000001716 specific phobia Diseases 0.000 claims description 3
- MDJWGFJOKVZUOD-KAQMDTKVSA-N (2r,3s,4r,5r)-2-amino-2,3,4,5,6-pentahydroxyhexanamide Chemical compound NC(=O)[C@](N)(O)[C@@H](O)[C@H](O)[C@H](O)CO MDJWGFJOKVZUOD-KAQMDTKVSA-N 0.000 claims description 2
- 206010041250 Social phobia Diseases 0.000 claims description 2
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 claims description 2
- 239000011585 methylcobalamin Substances 0.000 claims description 2
- 235000007672 methylcobalamin Nutrition 0.000 claims description 2
- 150000002301 glucosamine derivatives Chemical class 0.000 claims 2
- 125000003346 cobalamin group Chemical group 0.000 claims 1
- 150000001867 cobalamins Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 53
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 abstract description 10
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 abstract description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 abstract description 2
- 229960002442 glucosamine Drugs 0.000 abstract description 2
- 229940016409 methylsulfonylmethane Drugs 0.000 abstract description 2
- 229930003779 Vitamin B12 Natural products 0.000 abstract 1
- 235000019163 vitamin B12 Nutrition 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 51
- 150000001875 compounds Chemical class 0.000 description 48
- 208000024891 symptom Diseases 0.000 description 37
- 201000010099 disease Diseases 0.000 description 23
- 238000011160 research Methods 0.000 description 23
- 230000035882 stress Effects 0.000 description 19
- 230000001575 pathological effect Effects 0.000 description 17
- 230000002996 emotional effect Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 230000000770 proinflammatory effect Effects 0.000 description 12
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 206010061218 Inflammation Diseases 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- 230000006399 behavior Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 230000036506 anxiety Effects 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 9
- 230000036651 mood Effects 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 102000010909 Monoamine Oxidase Human genes 0.000 description 8
- 108010062431 Monoamine oxidase Proteins 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 8
- 238000003745 diagnosis Methods 0.000 description 8
- 208000024714 major depressive disease Diseases 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 208000020016 psychiatric disease Diseases 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 239000000935 antidepressant agent Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000994 depressogenic effect Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000011720 vitamin B Substances 0.000 description 7
- 235000019156 vitamin B Nutrition 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229930003270 Vitamin B Natural products 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940005513 antidepressants Drugs 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000003931 cognitive performance Effects 0.000 description 6
- 235000015872 dietary supplement Nutrition 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 208000020925 Bipolar disease Diseases 0.000 description 5
- 208000001640 Fibromyalgia Diseases 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 230000001976 improved effect Effects 0.000 description 5
- 229940100601 interleukin-6 Drugs 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 229940076279 serotonin Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NYMGNSNKLVNMIA-UHFFFAOYSA-N Iproniazid Chemical compound CC(C)NNC(=O)C1=CC=NC=C1 NYMGNSNKLVNMIA-UHFFFAOYSA-N 0.000 description 4
- 206010033799 Paralysis Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229940099112 cornstarch Drugs 0.000 description 4
- 230000003001 depressive effect Effects 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002651 drug therapy Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical class O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 208000006373 Bell palsy Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 208000016192 Demyelinating disease Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229930195725 Mannitol Chemical class 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000003930 cognitive ability Effects 0.000 description 3
- 230000001149 cognitive effect Effects 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 230000009615 deamination Effects 0.000 description 3
- 238000006481 deamination reaction Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000006735 deficit Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000012055 enteric layer Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 208000019622 heart disease Diseases 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000000594 mannitol Chemical class 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229960004644 moclobemide Drugs 0.000 description 3
- 239000004050 mood stabilizer Substances 0.000 description 3
- 229940127237 mood stabilizer 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
- 229960002748 norepinephrine Drugs 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000008447 perception Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 235000015424 sodium Nutrition 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 229940032330 sulfuric acid Drugs 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- LCTORNIWLGOBPB-GASJEMHNSA-N (3r,4s,5s,6r)-2-amino-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound NC1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LCTORNIWLGOBPB-GASJEMHNSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZSTKHSQDNIGFLM-UHFFFAOYSA-N 5-methoxy-N,N-dimethyltryptamine Chemical compound COC1=CC=C2NC=C(CCN(C)C)C2=C1 ZSTKHSQDNIGFLM-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 208000000013 Hammer Toe Syndrome Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 240000005373 Panax quinquefolius Species 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 238000004617 QSAR study Methods 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- BEWNZPMDJIGBED-UHFFFAOYSA-N benmoxin Chemical compound C=1C=CC=CC=1C(C)NNC(=O)C1=CC=CC=C1 BEWNZPMDJIGBED-UHFFFAOYSA-N 0.000 description 2
- 229950011271 benmoxin Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- 208000025307 bipolar depression Diseases 0.000 description 2
- WZXHSWVDAYOFPE-UHFFFAOYSA-N brofaromine Chemical compound C=1C2=CC(OC)=CC(Br)=C2OC=1C1CCNCC1 WZXHSWVDAYOFPE-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 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 2
- 229960003529 diazepam Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 229960002598 fumaric acid Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940070023 iproniazide Drugs 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229940098895 maleic acid Drugs 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920001206 natural gum Polymers 0.000 description 2
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960004838 phosphoric acid Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229940107700 pyruvic acid Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229960005137 succinic acid Drugs 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- XRNCALBVXMOHDX-GASJEMHNSA-N (3R,4R,5S,6R)-2,3-diamino-6-(hydroxymethyl)oxane-2,4,5-triol Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(N)O XRNCALBVXMOHDX-GASJEMHNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- YBJCDTIWNDBNTM-UHFFFAOYSA-N 1-methylsulfonylethane Chemical compound CCS(C)(=O)=O YBJCDTIWNDBNTM-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical class OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 1
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 0.000 description 1
- VVINERCPKRFEOL-UHFFFAOYSA-N 4-(7-chloro-1,3-benzoxazol-2-yl)-2,6-diiodophenol Chemical compound Oc1c(I)cc(cc1I)-c1nc2cccc(Cl)c2o1 VVINERCPKRFEOL-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical class OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- MXUNKHLAEDCYJL-UHFFFAOYSA-N 5-(hydroxymethyl)-3-(3-methylphenyl)-1,3-oxazolidin-2-one Chemical compound CC1=CC=CC(N2C(OC(CO)C2)=O)=C1 MXUNKHLAEDCYJL-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- GHEZNRQAMLNCNT-UHFFFAOYSA-N C(=O)OCCC.OC1=CC=CC=C1 Chemical compound C(=O)OCCC.OC1=CC=CC=C1 GHEZNRQAMLNCNT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000522254 Cassia Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 208000018458 Colitis-Associated Neoplasms Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical class OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 229920001353 Dextrin Chemical class 0.000 description 1
- 239000004375 Dextrin Chemical class 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical class OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102000018170 Lymphotoxin beta Receptor Human genes 0.000 description 1
- 108010091221 Lymphotoxin beta Receptor Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 102000055008 Matrilin Proteins Human genes 0.000 description 1
- 108010072582 Matrilin Proteins Proteins 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 208000027382 Mental deterioration Diseases 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010014632 NF-kappa B kinase Proteins 0.000 description 1
- 102000008125 NF-kappa B p52 Subunit Human genes 0.000 description 1
- 108010074852 NF-kappa B p52 Subunit Proteins 0.000 description 1
- 102000019148 NF-kappaB-inducing kinase activity proteins Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101710171573 Primary amine oxidase Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 240000000203 Salix gracilistyla Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000018594 Tumour necrosis factor Human genes 0.000 description 1
- 108050007852 Tumour necrosis factor Proteins 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- UHXWLHYMUGRLKG-UHFFFAOYSA-N [Mg].O[Si](O)(O)O Chemical compound [Mg].O[Si](O)(O)O UHXWLHYMUGRLKG-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000011861 anti-inflammatory therapy Methods 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 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
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical class OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 229950004068 brofaromine Drugs 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- ALELTFCQZDXAMQ-UHFFFAOYSA-N butriptyline Chemical compound C1CC2=CC=CC=C2C(CC(C)CN(C)C)C2=CC=CC=C21 ALELTFCQZDXAMQ-UHFFFAOYSA-N 0.000 description 1
- 229960004301 butriptyline Drugs 0.000 description 1
- 239000011575 calcium Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 208000030251 communication disease Diseases 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000011262 co‐therapy Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960001393 dosulepin Drugs 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008103 glucose Chemical class 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002589 iproclozide Drugs 0.000 description 1
- GGECDTUJZOXAAR-UHFFFAOYSA-N iproclozide Chemical compound CC(C)NNC(=O)COC1=CC=C(Cl)C=C1 GGECDTUJZOXAAR-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229950005862 lazabemide Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000004558 lewy body Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- SAPNXPWPAUFAJU-UHFFFAOYSA-N lofepramine Chemical compound C12=CC=CC=C2CCC2=CC=CC=C2N1CCCN(C)CC(=O)C1=CC=C(Cl)C=C1 SAPNXPWPAUFAJU-UHFFFAOYSA-N 0.000 description 1
- 229960002813 lofepramine Drugs 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000863 loss of memory Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical class [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical class CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- JZXRLKWWVNUZRB-UHFFFAOYSA-N n-(2-aminoethyl)-5-chloropyridine-2-carboxamide Chemical compound NCCNC(=O)C1=CC=C(Cl)C=N1 JZXRLKWWVNUZRB-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 208000018360 neuromuscular disease Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960003057 nialamide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940074355 nitric acid Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical class CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical class CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000002310 reflectometry Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 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 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 108010050939 thrombocytin Proteins 0.000 description 1
- 229960002309 toloxatone Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- PHTUQLWOUWZIMZ-GZTJUZNOSA-N trans-dothiepin Chemical compound C1SC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 PHTUQLWOUWZIMZ-GZTJUZNOSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229940046001 vitamin b complex Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及用治疗有效量的药物组合物治疗非感染性疾病的方法、用途和组合物,所述药物组合物包含甲磺酰基甲烷、葡糖胺、L‑甘氨酸和维生素B12(或其任何一种的衍生物)。
Description
发明领域
本发明涉及炎症的控制,以治疗或预防非感染性疾病,特别是精神疾病(psychiatric disorders)。更具体地讲,本发明涉及用于治疗或预防非感染性疾病特别是精神疾病的方法、用途及营养补剂的组合物,所述营养补剂包含治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)。
发明背景
促炎细胞因子肿瘤坏死因子-α(TNF-a)、白细胞介素-l(IL-1)和白细胞介素-6(IL-6)是炎症反应中的重要参与者。机体具有一套系统,其用于:启动炎症,即所谓的促炎症反应,以及当其工作完成时关掉炎症,即抗炎症反应。细胞因子TNF、IL-1和IL-6是一些主要的促炎细胞因子。如果抗炎症反应不能有效地终止炎症,炎症反应能够并确实能引起重大疾病表现。最近的证据已表明促炎细胞因子应对世界范围内越来越多的非感染性疾病的出现负责。非感染性疾病例如类风湿性关节炎(rheumatoid arthritis)、脑瘫、贝尔(Bell)麻痹、重性抑郁(major depression)、克罗恩氏病、焦虑、自杀观念、双相障碍(bipolardiseases)、成瘾行为、早老症、心脏疾病、帕金森病、糖尿病、注意力缺陷伴多动症(ADHD)、自闭症、阿尔茨海默病,以及其他所述过程引起的相关疾病。大量的数据表明暴露于应激(stress)(众所周知的心境障碍沉淀剂)下,还可激活外周和脑中的炎症反应。
尽管疾病过程中的促炎症反应的作用的证据是强有力的,但是其还未转化为治疗方案。已用于降低促炎症反应水平的少数治疗涉及抗TNF和IL-6的单克隆抗体的生产和应用。结果是令人鼓舞的,但是治疗方法本身是侵入性的,需要注射抗体,并且已鉴定严重不良反应,这使得其用于非威胁生命的疾病的广泛应用未成为被认真考虑的选项。因此,需要有效的、非侵入性的治疗(其能预防、延缓、终止和/逆转促炎症反应),特别是几乎没有消极的副作用的疗法。
发明简述
广泛来讲,本发明涉及用于治疗或预防由促炎症反应引起的非感染性疾病特别是精神疾病的方法和营养补剂的组合物,所述营养补剂包含治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)。甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12的治疗组合还称作GMGB1。
第一方面,本发明提供在有需要的个体中治疗非感染性疾病的方法,所述方法包括施用治疗有效量的药物组合物至个体的步骤,该药物组合物包含(a)甲磺酰基甲烷或其衍生物,(b)葡糖胺或其衍生物,(c)L-甘氨酸或其衍生物和(d)维生素B12或其衍生物。
在一实施方案中,本发明提供在有需要的个体中治疗心境障碍、焦虑性障碍、注意缺陷障碍、痴呆或应激(stress)的方法,所述方法包括施用治疗有效量的药物组合物至个体的步骤,该药物组合物包含(a)甲磺酰基甲烷或其衍生物,(b)葡糖胺或其衍生物,(c)L-甘氨酸或其衍生物和(d)维生素B12或其衍生物。
适应地,根据上述方面,药物组合物包含甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素Β12。
适应地,根据上述实施方案,在有需要的个体中治疗心境障碍、焦虑性障碍、注意缺陷障碍、痴呆或应激包括在个体中降低心境障碍、焦虑性障碍、注意缺陷障碍、痴呆或应激的严重性。
在上述方面的一些实施方案中,所述方法还包括施用一种或多种其他活性物质例如去甲肾上腺素再摄取抑制剂、选择性血清素再摄取抑制剂、三环抗抑郁药和/或单胺氧化酶抑制剂至个体。
第二方面,本发明提供改善个体认知性能(cognitive performance)的方法,所述方法包括将治疗有效量的药物组合物施用至个体的步骤,所述药物组合物包含(a)甲磺酰基甲烷或其衍生物,(b)葡糖胺或其衍生物,(c)L-甘氨酸或其衍生物和(d)维生素B12或其衍生物。
适应地,根据上述方面,药物组合物包含甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12。
适应地,根据上述方面,个体是人。
第三方面,本发明提供甲磺酰基甲烷或其衍生物、葡糖胺或其衍生物、L-甘氨酸或其衍生物和维生素B12或其衍生物在制备用于治疗个体非感染性疾病的药物中的用途。
适应地,根据上述方面,使用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12。
适应地,根据上述方面,个体是人。
第四方面,本发明提供用于治疗非感染性疾病的药物组合物,其包含甲磺酰基甲烷或其衍生物、葡糖胺或其衍生物、L-甘氨酸或其衍生物和维生素B12或其衍生物,以及药学上可接受的载体、稀释剂或赋形剂。
适应地,根据上述方面,药物组合物包含甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12。
第五方面,本发明提供用于改善认知性能的药物组合物,其包含甲磺酰基甲烷或其衍生物、葡糖胺或其衍生物、L-甘氨酸或其衍生物和维生素B12或其衍生物,以及药学上可接受的载体、稀释剂或赋形剂。
适应地,根据上述方面,药物组合物包含甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12。
附图说明
图1.在GMGB1试验的第1天、第14天和第28天研究参与者的平均BDI得分。
图2.第1天,BDI测试中四种抑郁程度的每一程度中的参与者的百分数。
图3.第14天,BDI测试中四种抑郁程度的每一程度中的参与者的百分数。
图4.第28天,BDI测试中四种抑郁程度的每一程度中的参与者的百分数。
图5.具有已报道的所述作用的研究参与者的百分数。
发明详述
本发明涉及由促炎症反应引起的非感染性疾病,特别是用于控制炎症以治疗或预防非感染性疾病特别是精神疾病、心境障碍、焦虑性障碍、注意缺陷障碍、痴呆和应激的营养补剂的方法和用途,所述营养补剂包含作为活性物质的治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)。
在整个说明书中,除非上下文另外要求,词“包含”应理解为意指包含所述的整体(integers)或整体的组,但是不排除任何其他的整体或整体的组。
在一方面,本发明提供在有需要的个体中治疗和/或预防非感染性疾病的方法,所述方法包括施用治疗有效量的药物组合物至个体的步骤,该药物组合物包含(a)甲磺酰基甲烷或其衍生物,(b)葡糖胺或其衍生物,(c)L-甘氨酸或其衍生物和(d)维生素B12或其衍生物。
各种非感染性疾病和病患以促炎细胞因子作为其表现(presentation)的主要诱因,所述非感染性疾病和病患包括例如精神疾病(例如双相抑郁症、精神分裂症和自杀观念);心境障碍(例如抑郁症);焦虑性障碍;注意缺陷障碍;痴呆(例如阿尔茨海默病);成瘾行为及相关的戒断问题;应激;焦虑;脑瘫;贝尔麻痹;早老症;类风湿性关节炎;心脏病;帕金森病;1型和2型糖尿病;脱髓鞘疾病;纤维肌痛;炎性肠病(例如克罗恩氏病);哮喘;变应性鼻炎;深静脉血栓形成;和血小板聚集。非感染性疾病可通过抗促炎细胞因子治疗而得到控制。GMGB1具有主要对于细胞因子TNF、IL-1和IL-6的抗炎作用,使其可用于治疗文中所述的非感染性疾病。
如文中所用,“治疗”指在其开始出现之后,改善不希望的身体或精神/情绪状态的征兆或症状或者病理情况的治疗介入。所述术语包括积极治疗(active treatment),也就是说特别涉及改善个体的身体或精神/情绪状态或者病理情况的治疗,并且所述术语还包括病因治疗(causal treatment),也就是说涉及消除个体的不希望的身体或精神/情绪状态或者病理情况的治疗。此外,所述术语包括姑息治疗,也就是说,设计用于减轻症状而不是治愈个体的不希望的身体或精神/情绪状态或者病理情况的治疗;预防治疗,也就是说,涉及预防个体的不希望的身体或精神/情绪状态或者病理情况的治疗;和支持性疗法,也就是说,用于补充另一种旨在改善进个体身体或精神/情绪状态或者病理情况的具体治疗的治疗。
关于不希望的身体或精神/情绪状态或者病理情况,术语“改善”指治疗的任何可观察到的有益效果。所述有益效果可例如通过下述证实:敏感个体中不希望的身体或精神/情绪状态或者病理情况的症状的延迟发作,不希望的身体或精神/情绪状态或者病理情况的一些或所有症状的严重性的减轻,个体整体健康或幸福状态的改善,或者对于特定状态或情况特异的本领域众所周知的其他参数。应该理解:所述治疗不需对个体是绝对有益的。
如文中所用,“预防”指在不希望的身体或精神/情绪状态或者病理情况的症状、外观(aspect)或特征出现之前,启动作用过程(例如施用治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12),以便预防或减轻症状、外观或特征。应该理解:所述预防不需对个体是绝对有利的。“预防”治疗是施用至未显示不希望的身体或精神/情绪状态或者病理情况的征兆或者仅显示早期征兆的个体的治疗,用于降低形成不希望的身体或精神/情绪状态或者病理情况的风险。
在一实施方案中,本发明提供在有需要的个体中治疗和/或预防心境障碍(例如抑郁症),焦虑性障碍(例如惊恐障碍、强迫性障碍、创伤后应激障碍、社会恐怖症、特异恐怖症和广泛性焦虑症),注意缺陷障碍(例如注意力缺陷伴多动症和自闭症),痴呆(例如阿尔茨海默病)或应激的方法,所述方法包括将治疗有效量的药物组合物施用至个体的步骤,所述药物组合物包含(a)甲磺酰基甲烷或其衍生物,(b)葡糖胺或其衍生物,(c)L-甘氨酸或其衍生物和(d)维生素B12或其衍生物。
当个体显示所述病症的某些症状时,可诊断为心境障碍例如抑郁症。心境障碍的症状可包括情感淡漠、持久性的悲伤感、感到绝望或无助、低自尊、感觉不适、过度内疚、想死的感觉、对惯常活动或曾经喜欢的活动丧失兴趣、联系困难、睡眠障碍、食欲或体重变化、精力下降、难以专注、做决定的能力降低、自杀想法或企图、频繁的身体抱怨(例如头痛、胃疼和疲劳)、离家或威胁离家出走、对失败或拒绝高度敏感、易激惹、敌对和侵犯性。
因此,根据本发明的心境障碍的治疗可包括消除或降低任何所述的症状或依赖于诊断心境障碍的个体或医疗专业人员的其他症状的频次或严重性。因此,在一些实施方案中,本发明包括通过以有效消除或降低症状的频次或严重性的量向个体单独施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物),或者还联合施用文中所述的一种或多种其他活性物质,来治疗显示至少一种心境障碍症状的个体。在特定实施方案中,心境障碍是抑郁症。在其他实施方案中,可将本发明尤其描述为消除或降低上文所述的心境障碍的任何一种具体症状的频次或严重性。
在一具体实施方案中,所述方法包括消除或降低抑郁症具体症状的频次或严重性。在所述实施方案中,方法可包括向个体单独施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)或将它们与文中所述的一种或多种其他活性物质联合施用。所述方法的功效可通过分析受治疗的个体;通过受治疗个体的自我报告;或者通过评价受治疗的个体后,医疗专业人员提供的有效治疗的诊断而确定。
在其他实施方案中,本发明提供治疗焦虑性障碍的方法。具体地讲,本发明提供治疗任何归类为焦虑性障碍的病患(包括例如惊恐障碍、强迫性障碍、创伤后应激障碍、社会恐怖症、特异恐怖症和广泛性焦虑症)的方法。通常,本发明的方法包括将甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)单独施用或将它们与文中所述的一种或多种其他活性物质联合施用至患有焦虑性障碍的病患的个体。所述方法的功效可通过分析受治疗的个体;通过受治疗个体的自我报告;或者通过评价受治疗的个体后,医疗专业人员提供的有效治疗的诊断而确定。
在另外的实施方案中,本发明提供用于治疗注意缺陷障碍例如注意力缺陷伴多动症(ADHD)或自闭症的方法。对于心境障碍,当个体显示个体和/或医疗专业人员认定的所述障碍的一些症状时,可诊断为ADHD和自闭症。因此,根据本发明的ADHD和自闭症的治疗可包括消除或降低任何所述的症状或者依赖于诊断ADHD和自闭症方面的个体或医疗专业人员所确定的其他症状的频次或严重性。
因此,在一些实施方案中,本发明包括通过以有效消除或降低症状的频次或严重性的量向个体单独施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)或将它们与文中所述的一种或多种其他活性物质联合施用而治疗显示注意缺陷障碍的至少一种症状的个体。在其他实施方案中,本发明可具体描述为消除或降低ADHD或自闭症的任何一种具体症状的频次或严重性。在此类实施方案中,方法可包括单独施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)或将它们与文中所述的一种或多种其他活性物质联合施用。所述方法的功效可通过分析受治疗的个体;通过受治疗个体的自我报告;或者通过评价受治疗的个体后,医疗专业人员提供的有效治疗的诊断而确定。
还在另外的实施方案中,本发明提供用于治疗痴呆的方法。痴呆是神经变性疾病,通常表现为个体学习和认知能力的丧失,并且其一般伴随行为、心理和活动症状。痴呆的关键因素是短期和长期记忆的缺失,伴随有抽象思维困难、错误判断、个性变化和其他高级皮质功能的损害。这些损害通常是严重的,以至于个体不能保持正常的社会活动或关系。通常,痴呆的认知技能和记忆的丧失是缓慢的,伴随有历经数年的精神衰退。痴呆在老年人中是最常见的,并且随着发展中国家人口的老龄化,其正变得越来越普遍。
已将许多不同的痴呆进行了列举,包括例如皮质痴呆、额颞痴呆(fronto-temporal dementia)、阿尔茨海默病痴呆、lewy体痴呆、进行性痴呆、血管性痴呆、多发梗塞性痴呆、药物-或酒精-相关的痴呆和帕金森病相关的痴呆。痴呆还可以由头损伤、心搏聚停、与癌症治疗相关的放射疗法、获得性免疫缺陷综合征(AIDS)、皮克氏(Pick′s)病和克雅氏(Creutzfeldt-Jakob)病包括其变体引起。通常根据其病因学诊断痴呆,两个最常见病因学是阿尔茨海默病痴呆和血管性痴呆(例如中风引起的)。痴呆通常是进行性的且不可逆转的,除非病因本身是可治疗的。许多个体具有不止一种类型的痴呆。痴呆的诊断通常涉及排除重性抑郁障碍(major depressive disorders)或精神错乱。
在多数痴呆中,个体通常显示原发的(primary)认知症状,以及继发的行为症状。认知症状可包括下述情形,例如记忆丧失、方位知觉(orientation perception)丧失、语言能力丧失和受损的判断力。继发或行为症状可包括下述情况,如人格和行为的变化,其中个体是攻击性或言辞激动的。通常,用抗精神病药、苯二氮类、β-阻滞剂、选择性血清素再摄取抑制剂、抗抑郁药、抗惊厥药和膳食补充剂治疗痴呆。
因此,根据本发明的痴呆治疗可包括消除或降低任何所述症状或者依赖于进行痴呆诊断的个体或医疗专业人员的其他症状的频次或严重性。因此,在一些实施方案中,本发明包括通过以有效消除或降低所述症状的频次或严重性的量向个体单独施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)或者将它们与文中所述的一种或多种其他活性物质联合施用来治疗显示至少一种痴呆症状的个体。在其他实施方案中,可将本发明具体描述为消除或降低上文所提供的痴呆的任何一种具体症状的频次或严重性。
在其他实施方案中,本发明提供治疗应激的方法。具体地讲,本发明提供用于治疗与具有超负荷感且不能应付(unable to cope)感相关的精神状态的方法。本发明的方法通常包括向遭受应激的个体单独施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物),或者还联合施用文中所述的一种或多种其他活性物质。所述方法的功效可通过分析受治疗的个体;通过受治疗个体的自我报告;或者通过评价受治疗的个体后,医疗专业人员提供的有效治疗的诊断而确定。
在另一方面,本发明提供改善个体认知性能的方法,所述方法包括将治疗有效量的药物组合物施用至个体的步骤,所述药物组合物包含(a)甲磺酰基甲烷或其衍生物,(b)葡糖胺或其衍生物,(c)L-甘氨酸或其衍生物和(d)维生素B12或其衍生物。
如文中所用,“改善认知性能”包括提高和/或增强与一种或多种认知能力或技能例如问题解决、记忆、方位知觉、语言和判断力相关的质量或状况。
术语“个体”包括人个体和兽医对象(veterinary subjects)。例如,向个体施用可包括向人个体或兽医对象施用。优选地,个体是人。
“施用”意指通过选择的途径将组合物(例如药物组合物)引入到个体中。
术语“治疗有效量”描述足够在被所述物质治疗的个体中实现期望效果的指定物质的量。例如,其可以是治疗或预防不希望的身体或精神/情绪状态或者病理情况或者改善认知性能所必需的药物组合物的量,所述药物组合物包含甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)。在一些实施方案中,“治疗有效量”是足以减轻或消除由促炎症反应引起的非感染性疾病的症状的量和/或足以实现所期望的生物效应的量。
理想地,物质的治疗有效量是足以在个体中实现所期望的结果而不引起显著细胞毒作用的量。用于治疗或预防不希望的身体或精神/情绪状态或者病理情况的物质的有效量将取决于被治疗的个体、所述状态或情况的类型和严重性,以及治疗组合物的施用方式。
可通过细胞培养或试验动物中的标准药学方法,例如通过测定LD50(对50%种群致死的剂量)和/或ED50(在50%种群中有治疗效力的剂量),来测定治疗例如甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12的毒性和疗效。毒性作用和治疗作用间的剂量比是治疗指数,并其可表示为例如比率LD50/ED50。显示大的治疗指数的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)的组合是有用的。
可将治疗有效量的包含甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)的药物组合物在一个疗程中,例如每天,以单一剂量或几个剂量施用。然而,施用的频次取决于所用的制剂、被治疗的个体、不希望的身体或精神/情绪状态或者病理情况的严重性和类型,以及治疗或组合物的施用方式。
术语“甲磺酰基甲烷”指具有式(CH3)2SO2的有机硫化合物。其还称作二甲基砜、DMSO2、二甲砜、甲磺酰基甲烷和磺酰基二甲烷(sulfonylbismethane)。
术语“葡糖胺”描述发现于健康软骨中的天然化合物。硫酸葡糖胺是软骨基质和滑液中的葡萄糖胺聚糖的正常组分。
术语“L-甘氨酸”常见于蛋白质中的20个氨基酸中最小的一个。其还称作甘氨酸、氨基乙烷酸和氨基乙酸。
术语“维生素B12”描述钴胺素或氰钴胺素,含有钴的维生素B复合物中的一员。
本发明还特别包括文中公开的作为活性物质的各种化合物的生物活性变体。此类变体应保持原化合物的一般生物活性;然而,其他活性的存在不必然限制其在本发明中的应用。可采用标准测试方法和本领域技术人员公认的通常可用于确定此类活性的生物学测定法来评价所述活性。
甲磺酰基甲烷、葡糖胺、L-甘氨酸或维生素B12的“衍生物”意指与其母体化合物的化学结构不同的分子,例如同系物(通过化学结构增量而不同,例如烷基链的长度不同)、分子片段、1个或多个官能团不同的结构或离子化的变化。借助例如Remington:The Scienceand Practice of Pharmacy,第19版,第28章,1995中公开的那些技术,利用定量构效关系(QSAR)通常可发现结构类似物。衍生物还可称作“类似物”。
例如,本发明包含的葡糖胺的类似物包括但不限于硫酸葡糖胺、N-乙酰基葡糖胺和季铵化氨基葡糖胺(quaternized amino glucosamine)。
维生素B12的形式可如本领域普通技术人员已知那样变化。例如钴铵素可以至少部分以甲基钴铵素或羟基钴铵素而存在。
此外,文中公开的作为活性物质的各种化合物中的一种或多种还可以以螯合形式存在。在一实施方案中,使用氨基酸螯合物。螯合形式有助于更有效的吸收和提高生物活性,以及提高贮存期限。
文中公开的作为活性物质的化合物还可以为酯、酰胺、盐、溶剂合物、前药或代谢物的形式,前提是它们保持本发明的药理学活性。本发明化合物的酯、酰胺、盐、溶剂合物、前药和其他衍生物可根据本领域普遍已知的方法例如J.March,Advanced OrganicChemistry:Reactions,Mechanisms and Structure,第4版,(纽约,Wiley-interscience,1992)(将其引入文中作为参考)中描述的那些方法制备。
根据本发明可用的化合物的药学上可接受的盐的示例包括酸加成盐。然而,非药学上可接受的酸的盐可用于例如化合物的制备和纯化。根据本发明的适当的酸加成盐包括有机酸和无机酸。优选的盐包括由盐酸、氢溴酸、硫酸、磷酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、琥珀酸、富马酸、马来酸、草酰乙酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸和羟乙磺酸形成的那些盐。其他可用的酸加成盐包括丙酸、羟乙酸、草酸、苹果酸、丙二酸、苯甲酸、肉桂酸、扁桃酸、水杨酸等。药学上可接受的盐的具体示例包括但不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、醋酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-l,4-二酸盐、己炔-l,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、酞酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
通过用适当的碱处理,可将酸加成盐转化为游离碱。可存在于根据本发明可用的化合物中的酸基团的碱性盐的制备可用类似的方式利用药学上可接受的碱例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙、三乙胺等来制备。
可通过可存在于化合物的分子结构内的羟基和/或羧基的官能化制备根据本发明的活性物质化合物的酯。还可利用本领域技术人员已知的技术制备酰胺和前药。例如,可利用适当的胺反应物,由酯制备酰胺,或者可通过与氨或低级烷基胺反应由酸酐或酰氯制备酰胺。并且,可通过与羰基化试剂(例如甲酸乙酯、乙酸酐、甲氧基乙酰氯、苯甲酰氯、异氰酸甲酯、氯甲酸乙酯、甲磺酰氯)和适当的碱(例如4-二甲氨基吡啶、吡啶、三乙胺、碳酸钾)在适当的有机溶剂(例如四氢呋喃、丙酮、甲醇、吡啶、N,N-二甲基甲酰胺)中于0°C-60°C的温度下反应,制备本发明化合物的酯和酰胺。通常,通过基团的共价连接制备前药,所述共价连接致使化合物无治疗活性,直至被个体代谢系统修饰。药学上可接受的溶剂合物的示例包含但不限于根据本发明的化合物以及水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸或乙醇胺。
对于固体组合物,应该理解:本发明方法所用的化合物可以以不同形式存在。例如,化合物可以以稳定的和相对稳定的晶体形式,以及各向同性形式和无定形形式存在,所有形式意欲包含于本发明的范围内。
如果根据本发明的可作为活性物质使用的化合物是碱,那么可通过本领域已知的任何适当方法制备期望的盐,所述方法包括用无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等或用有机酸例如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟乙酸、水杨酸、吡喃糖酸(pyranosidyl acids)例如葡糖醛酸和半乳糖醛酸、α-羟基酸例如柠檬酸和酒石酸、氨基酸例如天冬氨酸和谷氨酸、芳香酸例如苯甲酸和肉桂酸、磺酸例如对甲苯磺酸和乙磺酸等处理游离碱。
如果本文所述的作为活性物质的化合物是酸,那么可通过本领域已知的任何适当方法制备期望的盐,所述方法包括用无机碱或有机碱例如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等处理游离酸。适当的盐的说明性示例包括衍生自氨基酸例如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺、以及环状胺例如哌啶、吗啉和哌嗪的有机盐,和衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
本发明还包括文中所述的活性物质化合物的前药和活性代谢物。可将文中所述的任何化合物作为前药施用,以提高化合物的活性、生物利用度或稳定性或者以便在其他方面改变化合物的性质。前药的典型示例包括在活性化合物的官能团上具有生物学上不稳定保护基的化合物。前药包括可被氧化、还原、胺化、脱氨、羟基化、脱羟基、水解、脱水、烷基化、脱烷基化、酰化、脱酰基化、磷酸化和/脱磷酸化而产生活性化合物的化合物。在优选的实施方案中,本发明的化合物具有针对异常增殖细胞的抗增殖活性或者可代谢成显示所述活性的化合物。
许多前药配体是已知的。一般来讲,化合物的一个或多个杂原子例如游离胺或羧酸基的烷基化、酰基化或其他亲脂修饰降低极性并允许进入细胞。可替换游离胺和/或羧酸基团上的一个或多个氢原子的取代基的示例包括但不限于下述:芳基;甾类;碳水化合物类(包括糖类);1,2-二酰基甘油;醇;酰基(包括低级酰基);烷基(包括低级烷基);磺酸酯(包括烷基或芳基烷基磺酰基,例如甲磺酰基和苄基,其中苯基任选地被1个或多个文中给出的芳基定义中所提供的取代基取代);任选取代的芳基磺酰基;脂类(包括磷脂类);磷脂酰胆碱;磷酸胆碱;氨基酸残基或衍生物;氨基酸酰基残基或衍生物;肽类;胆固醇类;或其他药学上可接受的离去基团,当体内施用时,所述离去基团提供游离胺和/或羧酸基团。可将上述中的任一种与公开的活性物质联合使用,以获得期望的效果。
除了治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物),可将本领域技术人员已知的用于治疗和/或预防非感染性疾病和病患的一种或多种其他活性物质的各种组合施用至有其需要的个体。也就是说,除了治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)外,可将传统上用于治疗和/或预防精神疾病、心境障碍、焦虑性障碍、注意缺陷障碍、痴呆、成瘾行为及相关的戒断问题、应激、焦虑、脑瘫、贝尔麻痹、早老症、类风湿性关节炎、心脏病、帕金森病、1型和2型糖尿病、脱髓鞘疾病、纤维肌痛、炎性肠病、哮喘、变应性鼻炎、深静脉血栓形成和血小板聚集的一种或多种其他活性物质施用至个体。
例如,在一些实施方案中,可将去甲肾上腺素再摄取抑制剂、选择性血清素再摄取抑制剂、三环抗抑郁药和/或单胺氧化酶抑制剂与甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)一起施用,用于治疗和/或预防心境障碍、焦虑性障碍、注意缺陷障碍、痴呆或应激或者用于改善认知性能。
在一些实施方案中,一种或多种其他活性物质对甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12提供保存(conserving)作用。在另外的实施方案中,甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12对一种或多种其他活性物质提供保存作用。在其他实施方案中,一种或多种其他活性物质对于甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12的作用提供补充(complimentary)作用,优选消除或降低与非感染性疾病相关的一种或多种症状的频次或严重性。
在降低与非感染性疾病相关的一种或多种症状(包括具体(specific)症状)的频次或严重性中的“降低”意指减轻或缩短与非感染性疾病相关的症状、外观或特征,或者减少或缩短个体经历与非感染性疾病相关的症状、外观或特征的时长。应该理解:所述降低不必对患者是绝对有利的。
去甲肾上腺素再摄取抑制剂也称作正甲肾上腺素再摄取抑制剂,通常通过抑制去甲肾上腺素从突触间隙向突触前神经末端的再摄取而起升高中枢神经系统去甲肾上腺素水平的作用。去甲肾上腺素是起神经递质作用的儿茶酚胺和苯乙胺,并已知影响多种病患。术语“去甲肾上腺素再摄取抑制剂”包括通常认为抑制中枢神经系统去甲肾上腺素再摄取的任何化合物。根据本发明可用的去甲肾上腺素再摄取抑制剂的非限制性示例包括托莫西汀瑞波西汀 或维洛沙秦 或马普替林 或安非他酮或和雷达法辛。
根据本发明可使用的特异选择性血清素再摄取抑制剂的非限制性示例包括氟西汀帕罗西汀西酞普兰依他普仑氟伏沙明和舍曲林
三环抗抑郁药是一类抗抑郁化合物,其可用于描述包括显示抗抑郁活性并具有包含稠合三环结构的化学式的任何化合物。根据本发明可用的示例性三环抗抑郁药包括但不限于阿米替林阿莫沙平、布替林、氯米帕明地昔帕明二苯西平、度硫平、多塞平丙米嗪洛非帕明、去甲替林或普罗替林和曲米帕明
单胺氧化酶抑制剂包括理解为通过抑制单胺氧化酶(一种广泛见于大脑和肝脏的酶)活性而起作用的一类化合物,单胺氧化酶通常通过脱氨基而起裂解单胺化合物的作用。
有两种亚型的抑制单胺氧化酶的化合物MAO-A和MAO-B。MAO-A亚型优选使通常作为神经递质出现的单胺(例如血清素、褪黑激素、肾上腺素、去甲肾上腺素和多巴胺)脱氨基。因此,单胺氧化酶抑制剂历史上作为抗抑郁药使用,并用于社交障碍例如广场恐怖症和社交焦虑的治疗。MAO-B亚型优选使苯乙胺和微量胺脱氨基。两种亚型同样地使多巴胺脱氨基。单胺氧化酶抑制剂可以是可逆的或不可逆的,并且对特定亚型可以是选择性的。例如,已知单胺氧化酶抑制剂吗氯贝胺(还称作Manerix或Aurorix)对MAO-A的选择性大约比对MAO-B强三倍。
通常认为是单胺氧化酶抑制剂的任何化合物可根据本发明使用。可与用于制备根据本发明组合物的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)联合使用的单胺氧化酶抑制剂的非限制性示例包括下述:异卡波肼吗氯贝胺(Aurorix、Manerix或Moclodura)、苯乙肼反苯环丙胺司来吉兰 或1-地普雷尼尔)、拉扎贝胺、尼亚拉胺、异丙烟肼(异烟酰异丙肼、iprozid、异丙异烟肼、rivivol或propilniazida)、异丙氯肼、托洛沙酮、harmala、溴法罗明(Consonar)、苯莫辛(Neuralex),以及某些色胺类例如5-MeO-DMT(5-甲氧基-N,N-二甲色胺)或5-MeO-AMT(5-甲氧基-α-甲基色胺)。
在一些实施方案中,甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)与一种或多种其他活性物质的组合在非感染性疾病的治疗和/或预防中产生协同作用。因此,本发明还包括提高活性物质在治疗使用所述活性物质的任何病患中的疗效的方法。
在一实施方案中,将甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)在一种或多种其他活性物质施用之前施用。在另一实施方案中,将甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12在一种或多种其他活性物质施用之后施用。在另一实施方案中,将甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12与一种或多种其他活性物质同时施用。还在另一实施方案中,甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12的施用和一种或多种其他活性物质的施用(依次或同时)致使不希望的身体或精神/情绪状态或病理情况的改善,所述改善大于施用甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12或者施用一种或多种其他活性物质(而没有施用其他)所产生的改善。
可通过与药物组合物相关的任何可用的常规方法将本公开书的活性物质施用。可将本公开书的药物组合物单独施用,或者如果需要,可将本公开书的药物组合物与其他活性物质一起施用。
可将所述的药物组合物以药物制剂形式例如气雾剂、固体、半固体或液体形式使用,所述药物制剂含有作为活性成分公开的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)。此外,可将组合物以与适当的药学上可接受的载体混合在一起使用。所述药学上可接受的载体包括但不限于适合于药物应用的有机或无机载体、赋形剂或稀释剂。可将活性成分例如与用于片剂、丸剂、胶囊剂、吸入剂、栓剂、溶液剂、乳剂、混悬剂、气雾剂和任何其他适合使用形式的常规的无毒药学上可接受的载体、赋形剂或稀释剂混合。
用于药物组合物的药学上可接受的载体是本领域众所周知的,并描述例如于Remington:The Science and Practice of Pharmacy Pharmaceutical Sciences,Lippincott Williams and Wilkins(A.R.Gennaro编,第20版)中。在所用的剂量和浓度下,所述物质对受者来说是无毒的,并且包括但不限于水、滑石粉、阿拉伯树胶、明胶、三硅酸镁、角蛋白、胶体硅、尿素;缓冲剂例如磷酸盐、柠檬酸盐、乙酸盐和其他有机酸盐;抗氧化剂例如抗坏血酸;肽类;低分子量(少于大约10个残基)肽类例如但不限于聚精氨酸;蛋白质例如但不限于血清白蛋白、明胶或免疫球蛋白类;亲水聚合物例如但不限于聚乙烯吡咯烷酮;氨基酸类例如但不限于甘氨酸、谷氨酸、天冬氨酸或精氨酸;单糖类、二糖类和其他碳水化合物类,包括纤维素及其衍生物、乳糖、甘露醇、葡萄糖、甘露糖、糊精类、马铃薯或玉米淀粉或者淀粉糊;螯合剂例如但不限于EDTA;糖醇类例如甘露醇或山梨醇;抗衡离子例如但不限于钠;和非离子表面活性剂例如但不限于吐温、普流罗尼类(Pluronics)或聚乙二醇。此外,组合物可包辅助剂例如但不限于味道改善剂、稳定剂、增稠剂、着色剂等。
可通过将活性成分(各成分具有所需要的纯度)与生理学上可接受的载体、赋形剂、稳定剂、辅助剂等混合而制备药物组合物用于贮存或者施用,这在本领域是公知的。所述组合物可以以持续释放或延时释放制剂提供。
可将含有活性成分的药物组合物以固体剂型例如胶囊、片剂和散剂或者以液体剂型例如酏剂、糖浆剂和混悬剂口服施用。此外,可将含有活性成分的组合物以无菌液体剂型肠胃外施用,以固体、液体或气雾剂形式通过透粘膜递送施用,或者经贴剂机制或软膏剂透皮施用。各种类型的透粘膜施用包括呼吸道粘膜施用、鼻腔粘膜施用、口腔透粘膜(例如舌下和含服)施用和直肠透粘膜施用。
对于制备固体组合物例如但不限于片剂或胶囊,可将所述的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)与适当的药学上可接受的载体例如常规压片成分(例如乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、海藻酸、微晶纤维素、阿拉伯胶、明胶、树胶、胶体二氧化硅、交联羧甲纤维素钠、滑石粉、山梨醇、硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸和磷酸二钙)、其他赋形剂、着色剂、稀释剂、缓冲剂、崩解剂、润湿剂、防腐剂、调味剂和药学上可配伍的载体以及稀释剂(例如水、盐水或缓冲溶液)混合,以形成基本均匀的组合物。基本均匀的组合物意指成分均匀分散于组合物中,以致可容易地将组合物再分成等效的单位剂型例如片剂、丸剂和胶囊。
可将所述的固体组合物包衣或另外混合,以提供具有延长作用优点的剂型。例如,片剂或丸剂可包含内部剂量和外部剂量组分,后者是包封于前者上的形式。所述两种组分可通过肠衣层分开,所述肠衣层起防止胃中崩解并保证内部组分完整地通过胃或延迟释放的作用。可将各种材料用于所述肠衣层或包衣,所述材料包括许多聚合酸和聚合酸与例如虫胶、鲸蜡醇和醋酸纤维素的物质的混合物。
还可将活性成分配制成直肠组合物例如栓剂或保留灌肠剂,其诸如含有常规栓剂基质如可可脂或其他甘油酯。固体组合物还可包括胶囊,例如硬-或软-壳明胶型胶囊,其含有例如表面活性剂、润滑剂和惰性填料如乳糖、蔗糖、磷酸钙和玉米淀粉。
对于鼻内施用、肺内施用或通过其他吸入方式的施用,可将药物组合物以溶液或混悬液的形式从泵喷雾容器递送或者作为气雾剂喷洒形式利用适当的抛射剂(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氮、丙烷、二氧化碳或其他适当的气体)或以干粉从加压容器或喷雾器递送。对于气雾剂或干粉形式,递送的组合物的量(剂量)可通过配备计量递送的阀来确定。
液体形式可经口服、肠胃外施用或者经粘膜施用。用于液体施用的适当形式包括水溶液剂、适当矫味的糖浆剂、水性或油性混悬剂和矫味的乳剂,其含有可食用油例如棉籽油、芝麻油、椰子油或花生油,以及酏剂和类似的药物溶媒。用于水性混悬剂的适当的分散剂或助混悬剂包括合成的天然树胶诸如黄蓍胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮和明胶。可通过常规方式,用药学上可接受的添加剂例如助悬剂(诸如山梨醇糖浆、甲基纤维素或氢化可食用脂肪)、乳化剂(诸如卵磷脂或阿拉伯胶)、非水溶媒(诸如杏仁油、油性酯类或乙醇)、防腐剂(诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或者山梨酸)和人工或天然的着色剂和/或甜味剂制备所述液体制剂。
液体制剂可包含稀释剂例如水和醇类(诸如乙醇、苄醇、丙二醇、甘油和聚乙二醇),添加或者不添加药学上可接受的表面活性剂、助悬剂或乳化剂。
对于含服或舌下施用,药物组合物可采用以常规方式制成的片剂或锭剂形式。锭剂形式可含有在矫味剂通常是蔗糖和阿拉伯胶或黄蓍胶中的活性成分,以及软锭剂,其含有在惰性基质例如明胶和甘油或者蔗糖和acadia中的活性成分,乳剂和凝胶剂,除了活性成分,其含有本领域已知的载体。
可配制用于肠胃外施用的药物组合物。肠胃外施用包括但不限于静脉施用、皮下施用、肌内施用、皮内施用、鞘内施用、关节内施用、心内施用、眼球后施用和经植入物例如缓释植入物施用。
药物组合物可存在于单位剂量或多剂量密封容器例如安瓿和小瓶中,并可在冻干(冷冻干燥)条件下贮存,仅需要使用前立即加入无菌液体赋形剂例如注射用水。可由无菌粉末、颗粒剂和片剂制备即时注射溶液剂和混悬剂。对于注射用组合物而言,有效的药学上可接受的载体的要求是本领域众所周知的。
治疗可包括预防或治疗不希望的身体或精神/情绪状态或病理情况或者改善认知性能所必需的治疗有效量的甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)。理想地,物质的治疗有效量是足够在个体中实现所需要的结果而不引起显著细胞毒作用的量。用于预防或治疗不希望的身体或精神/情绪状态或病理情况或者用于改善认知性能的物质的有效量将取决于要治疗的个体、状态或病患的严重性,以及疗效组合物的施用方式。可通过标准临床技术测定有效量。
例如,当施用含有甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12(或其任何一种的衍生物)的药物组合物时,制剂中要使用的精确剂量将取决于施用途径,并应根据卫生保健医生和各个体的情况决定。局部用组合物(例如软膏剂、乳膏剂、凝胶剂或洗剂)中的活性成分(例如甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12)的浓度通常是大约0.2%-大约1%(相对于局部用组合物总重量的重量含量);例如大约0.3%-大约0.9%、大约0.4%-大约0.8%和大约0.5%-大约0.7%。在所述范围内,当以较低的量或用较少的频次施用洗剂、软膏剂、凝胶剂或乳膏剂时,较高的浓度保证要达到的适当剂量。
在其它实施方案中,对于单一剂量或分剂量中的各活性物质而言,含有甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12的药物组合物的非局部施用(例如口服施用或静脉或腹膜内注射)的剂量范围是大约0.1mg/kg体重-大约200mg/kg体重;例如大约1mg/kg-大约100mg/kg、大约2mg/kg-大约50mg/kg、大约3mg/kg-大约25mg/kg或大约5mg/kg-大约10mg/kg。
本发明药物组合物的活性成分(即甲磺酰基甲烷、葡糖胺、L-甘氨酸和维生素B12)的可接受日剂量包括500mg-6,000mg甲磺酰基甲烷(例如800mg、1,000mg、1,500mg、2,000mg、2,500mg、3,000mg、3,500mg、4,000mg、4,500mg、5,000mg和5,500mg);500mg-6,000mg葡糖胺(例如800mg、1,000mg、1,500mg、2,000mg、2,500mg、3,000mg、3,500mg、4,000mg、4,500mg、5,000mg和5,500mg);500mg-2,000mg L-甘氨酸(例如800mg、1,000mg和1,500mg);和0.02mg-2.0mg维生素B12(例如0.02mg、0.04mg、0.06mg、0.08mg、0.2mg、0.4mg、0.6mg、0.8mg、l.0mg、1.2mg和1.5mg)。
可将本公开书的药物组合物在整个治疗期以大约相同的剂量、以升高的剂量方案(escalating dose regimen)、负荷剂量方案(loading-dose regimen)(例如负荷剂量是维持剂量的大约2-5倍)施用。在一些实施方案中,根据被治疗个体的情况、偏头痛的严重度、对治疗的明显反应和/或本领域普通技术人员所判断的其他因素而在治疗期间改变剂量。在一些实施方案中,考虑用所公开的药物组合物长期治疗。
还在另一方面,本发明提供甲磺酰基甲烷或其衍生物、葡糖胺或其衍生物、L-甘氨酸或其衍生物和维生素B12或其衍生物在制备用于治疗个体的非感染性疾病的药物中的用途。
在另一方面,本发明提供用于治疗或预防非感染性疾病或用于改善认知性能的药物组合物,其包含甲磺酰基甲烷或其衍生物、葡糖胺或其衍生物、L-甘氨酸或其衍生物和维生素B12或其衍生物,以及药学上可接受的载体、稀释剂或赋形剂。
在一实施方案中,药物组合物包含500mg-6,000mg甲磺酰基甲烷(例如800mg、1,000mg、1,500mg、2,000mg、2,500mg、3,000mg、3,500mg、4,000mg、4,500mg、5,000mg和5,500mg);500mg-6,000mg葡糖胺(例如800mg、1,000mg、1,500mg、2,000mg、2,500mg、3,000mg、3,500mg、4,000mg、4,500mg、5,000mg和5,500mg);500mg-2,000mg L-甘氨酸(例如800mg、1,000mg和1,500mg);和0.02mg-2.0mg维生素B12(例如0.02mg、0.04mg、0.06mg、0.08mg、0.2mg、0.4mg、0.6mg、0.8mg、l.0mg、1.2mg和1.5mg)。
本领域技术人员参照下述非限制性实施例,以便可更容易理解本发明,并将其投入实际应用中。
实施例
实施例l:初期研究
因为对于与本研究相关的大多数潜在的非感染性疾病需要复杂的监控,认为利用GMGB1改善抑郁症的评价将是简单的起点。尽管本研究受限于大小和仅收集定性数据的事实,但是在该阶段的良好反应将是令人鼓舞的。将利用评价抑郁程度的标准工具Beck抑郁指数(BDI)的定量数据回顾地用于参与者。
BDI评分指示四种程度的抑郁:(i)0-9分表示最低程度的抑郁或者无抑郁迹象;10-16分表示轻度抑郁的迹象;(iii)17-29分表示中度抑郁;和(iv)30-63表示重度抑郁。
本研究的目的是评价精神疾病是否是由大量促炎细胞因子(主要是TNF)的存在引起的。通过评价用GMGBl治疗是否可在参与者的表现中产生积极改变来实现所述目的。本研究仅包含几个人(n=9),但是是有价值的,因为其显示了指明更详细研究是有益的趋向。参与者都欣然同意参与本研究,并表示知情同意。
GMGBl中所有的成分是小分子量的,因此,生物利用度是非常好的,并由此,它们可进出所有组织。半衰期表明我们能以一天一次施用化合物进行治疗,其将改善顺应性。基于分子量的比率,用于研究的配方是1200mg葡糖胺类似物或400mg季铵化氨基葡糖胺、400mgL-甘氨酸、500mg甲磺酰基甲烷和250μg维生素B12。
结果
患者1:初始报告说她是难过的、心情沉重且事事受挫;不能做决定、生气、消极地看待每件事情,且不能继续生活。大约10天治疗后,她是更高兴的、更无忧无虑的、更不容易烦乱、更平静、放松的,并发现问题不再是如此重要、更不担忧的、有能力继续前行。开始后,结果仍持续了8周。
患者2:是双相患者,其没有使用双相障碍药物,但使用抗抑郁药。双相治疗的典型问题是他们使你“乏味”,感觉不好也不坏。他评价用所述方案,他没有他所习惯的心境不稳,但是没有“乏味”感;他感到正常。
患者3:患有贝尔麻痹的女士,自从开始治疗后,她每天有改善。
患者4:一位使用抑郁症药物但仍然抑郁的抑郁男性。自从开始方案,他已长期以来第一次感觉正常。
患者5:一个抑郁的人,应激、焦虑,且每天哭,并看不见未来。治疗后,现在稳定了,并有积极的生活观。
患者6:一个遭受应激并易于抑郁的非常忙的人。他报告治疗对他的情绪和精神正常起有益的作用,并且他更少应激,且能应付其忙碌的时间安排。
患者7:一个怀疑的临床医生开始所述方案,并且一周后,报告其心情已显著改善。
从对患有重性抑郁的志愿患者用GMGB1的初步研究的初步结果表明所述治疗有积极结果。利用Beck抑郁指数作为测量工具,在开始治疗方案之前,所有患者评分为20-45。这表明中度至严重抑郁范围。用GMGB1治疗两周后,所有患者相应将其得分降低至小于5,表明他们不再抑郁。
除三个患者外所述所有患者先前已用精神药物,且先前从未经历所述程度的益处。最常见的评论是思维清晰,并提高了认知能力。即使在用选择性血清素再摄取抑制剂药物的那些患者已显著改善,并且“发呆”的头脑消失了。另一个常见的评论是稳定,即使在以前会让他们感到抑郁的触因存在下,他们也没有像先前一样在燥狂和抑郁之间循环。
如此,从初始研究部分的患者得到的初始结果是令人鼓舞的。与抑郁症一致,患者遭受了多年表现为脱髓鞘疾病的特征在于高反射性自反性和两只脚的爪状趾的疾病。对与纤维肌痛相关的爪状趾的治疗是选择性血清素再摄取抑制剂药物治疗。这个人已用选择性血清素再摄取抑制剂治疗了超过8年,未解决问题。然而,自从用GMGB1,两只脚的问题已解决,表明所述化合物在常见的神经肌肉疾病和纤维肌痛中的可能用途。
研究中的人已用选择性血清素再摄取抑制剂和地西泮治疗多年的,地西泮治疗降低了他们对所述药物的突然摄取。正常地,因为令人担忧的戒断效应,停止所述药物治疗应需要几个月的时间来停止。在停止时服用GMGB1能够使人停止所述药物治疗,且无任何副作用,表明其在相似药物或药物滥用戒断中的有益作用。
实施例2:GMGB1在患有某些抑郁症和焦虑性障碍的个体中作为情绪稳定剂的效力
由于GMGB1初始小量试验令人鼓舞的结果,计划进行更大的和更严密的研究。本研究在全科医师诊所进行,并依据“所表现(as presenting)”的选择患者。最初计划在第一方案中,应有安慰剂组。然而,由于潜在参与者到全科医师诊所是为了治疗,感到不提供潜在有益的治疗是不道德的做法。
所有参与者表明根据方案他们适合进入本项研究,他们被告知研究的各个方面并完成了知情同意书。每个参与者占用唯一的号,这将用于鉴别结果和保持保密性。
39个参与者参加本研究。其中,四个没有反应,并且两个退出研究。
主要利用Beck抑郁指数监测疗效。在研究的第一天、第14天以及第28天,评价从最初评分的变化。利用患者的日志和效果记录表评价效力。到研究结束,注意到参与者许多不同的效果。将所有效果汇总在检查表中,并且除其日志外,参与者完成检查表。
结果
在第一天,BDI数据分析显示24.6的平均值,具有9.6的标准偏差。在第14天,平均值是8.3,具有6.3的标准偏差,并且在第28天,平均值是5.8,具有4.4的标准偏差(图1)。第1天和第28天间的差异的统计学分析得到<0.001的p值。
在研究开始,24%的参与者是严重抑郁的,71%是中度抑郁的,5%是轻度抑郁的,并且无人在非抑郁范畴(图2)。
图3和图4分别说明在第14天和第28天所看到的变化,并且可以发现参与者组终止于73%为“无”或最小抑郁迹象,没有人严重受抑郁的影响。
研究期间,要求参与者记录治疗可能表明GMGB1疗效的任何效果(积极的或消极的)。有许多表明进一步研究领域的出乎意料的效果(图5;表I)。
所述结果表明研究的28天内,抑郁症强度的急剧变化。所述数据表明参与本研究的参与者具有68%的BDI结果改善。这是显著的个体改善,正如所认为的,任何超过50%的改善是显著的临床改善。
参与者报告的那些效果表明GMGB1在改善情绪和使参与者头脑清醒方面是非常有用的。表明在与年龄相关的痴呆中的作用。一个参与者(超过80岁)具有明显改善的注意力和清晰思维。超过60%的参与者报告改善的注意力、更少的焦虑、改善的清晰思维和改善的情绪,使其成为跨越年龄和性别的重要治疗。
完成28天研究后,12个个体选择继续试验,持续至少6个月。在这段时间内,个体维持其BDI水平,并报道提高的处理变化的能力,这些变化在过去使他们陷入深度焦虑或抑郁。
28天临床试验后,其他决定停止治疗(由于各种原因)的研究个体报道仅中断治疗几天后,他们受到的益处终止。一个参与者(一位患有双相抑郁的女士)陈述一旦停止GMGB1,5天内,她的抑郁和纤维肌痛重现。终止药物治疗14天后,另一个参与者(其以严重抑郁症开始,且14天后,记录无抑郁)变回患有严重抑郁症。
一些志愿参加研究以评价改善应激行为能力的情感正常个体报告当服用GMGB1时,有显著且连续的益处,持续至多12个月的一段时间。停止服用GMGB1后2-3天,所述益处消失,并且个体历经情绪波动的复发,所述个体再次下决心继续服用GMGB1。
几种报道的作用仅是与经历首次被缓解的问题的那些个体相关。例如,不是所有的参与者患有皮肤病患,但是所有那些参与者确实因使用GMGB1而得到缓解。一些参与者报告有过度酒精使用和其他成瘾行为。例如,一位报告每晚需要2-3杯酒并持续多年的女性参与者陈述她不再对酒精感兴趣。显示降低与这些成瘾行为相关的渴望。报告性欲增加的参与者确认所述增加不是小量的而是非常显著增加的事实。所有报道的作用与下述一致:GMGB1对各种不同表现(presentations)的一些促成因素(contributing factors)具有显著的影响。
讨论
根据用于评价抗抑郁药的EU指南,如果具有良好反应的参与者百分数超过50%,认为新药是有效的,并具有良好的效力。将效力反应定义为基线和治疗后的症状学评分的差异,但是还应表示为响应者的比率。在重性抑郁中,50%的通常评定量表(usual ratingscale)改善被认为临床相关的反应。
在所述39个人的研究中,相对于无响应者,89%的患者实现了临床改善。尽管如BDI评分改善所示,抑郁症有改善,并且焦虑水平降低,但是主要的改善是情绪稳定。即使在情感正常的个体中,他们报告试验期间(多于6个月),他们没有爆发愤怒或情绪负面内化的事实是非常显著的。
GMGB1几乎没有副作用(体重增加是合理正常的,且少数人报告头痛),因此,是良好耐受的。这种耐受使得其能够伦理学上可用于经历与在应激环境生活相关的较小的情绪波动的个体,并且GMGB1可长期使用,甚至预防使用。尽管在研究中在抑郁患者中见到BDI评分显著降低,但是这可能主要由于他们处理日常应激源的能力的改善。所述化合物在降低焦虑患者的应激源影响方面起有效作用的能力使得所述药物从其他情绪稳定剂中脱颖而出,所述情绪稳定剂仅与躁狂状态的抑郁患者相关。
整个说明书中,目标是描述本发明的优选实施方案,而不是将本发明限制于任何一个实施方案中或者特征的具体集合中。可对文中所述和说明的实施方案进行各种变化和修改,而不背离本发明的广阔精神和范围。
将本说明书中提及的所有计算机程序、算法、专利和科学文献以其全部内容引入文中作为参考。
表1.GMGB1试验的积极作用
ID:身份编号
%:BDI所指示的症状改善
Dur:指示如果患者应用GMGB1稳定>6个月
Quest:指示如果患者完成了定性改善调查表
BP:指示血压降低>25mm HG
Conc:指示认知和清晰思维的改善报告
应激:指示应激水平降低的报告
情绪:指示情绪稳定的报告
Anx:指示更不焦虑的报告
睡眠:指示改进的睡眠模式的报告
皮肤:指示皮肤、头发和指甲状况方面的改善的报告
病态(sick):指示感冒/流感期间症状(疾病行为)减轻的报告
作用:指示体重增加之外的副作用的报告
参考文献
Anderson等人,Glucosamine effects in humans:a review of effects onGlucose metabolism,side effects,safety considerations and efficacy.Food andChemical Toxicology43:187-201(2005).
Baud和Karin,Signal transduction by tumour necrosis factor and itsrelatives.Trends Cell Biol.11:372-77(2001).
Bonizzi和Karin,The two NFκB activation pathways and their role ininnate and adaptive immunity.Trends Immunol.25:280-88(2004).
Burstein和Duckett,Dying for NFκB?Control of cell death bytranscriptional regulation of the apoptotic machinery.Curr.Opin.Cell Biol.15:732-37(2003).
Clark等人.,The roles of TNF in brain dysfunction anddisease.Pharmacol Ther.128:519-48(2010).
D′Acquisto等人.,Inhibition of nuclear factor kappa B(NFκB):anemerging theme in anti-inflammatory therapies.Molecular Interventions2:22-35(2002).
Dejardin等人.,The lymphotoxinβreceptor induces different patterns ofgene expression via two NFκB pathways.Immunity17:525-35(2002).
Ghosh等人.,NFκB and Rel proteins:evolutionarily conserved mediatorsof immune responses.Annu.Rev.Immunol.16:225-60(1998).
Ghosh和Karin,Missing pieces in the NFκB puzzle.Cell109(Suppl.):S81-96(2002).
Greten等人.,ΙΚΚβlinks inflammation and tumorigenesis in a mousemodel of colitis associated cancer.Cell118:285-96(2004).
Horváth等人.,Toxicity of methylsulfonylmethane in rats.FoodChem.Toxicol.40:1459-62(2002).
Lawrence等人.,IKKαlimits macrophage NFκB activation and contributesto the resolution of inflammation.Nature434:1138-43(2005).
Lin等人,NFκB functions as both a pro-apoptotic and anti-apoptoticregulatory factor within a single cell type.Cell Death Differ.6:570-82(1999).
Playfair和Chain,Immunology at a glance,seventh addition,BlackwellsPublishing(2001).
Raison等人,Cytokines sing the blues:inflammation and the pathogenesisof depression.Trends.Immunol.27:24-31(2006).
Xiao等人,NFκB inducing kinase regulates the processing of NFκB2p100.Mol.Cell7:401-09(2001).
Claims (7)
1.药物组合物在制备用于治疗非感染性疾病的药物中的用途,其中所述药物组合物中的活性物质由(a)、(b)、(c)和(d)组成:
(a)甲磺酰基甲烷或其药学上可接受的盐或溶剂合物;
(b)葡糖胺、葡糖胺衍生物或其药学上可接受的盐或溶剂合物,其中葡糖胺衍生物选自硫酸葡糖胺、N-乙酰基葡糖胺和季铵化氨基葡糖胺;
(c)L-甘氨酸或其药学上可接受的盐或溶剂合物;
(d)维生素B12、其衍生物或其药学上可接受的盐或溶剂合物,其中维生素B12衍生物选自钴铵素、甲基钴铵素、羟基钴铵素及其混合物;
其中所述非感染性疾病选自心境障碍、焦虑性障碍、注意缺陷障碍和痴呆。
2.根据权利要求1所述的药物组合物在制备用于治疗非感染性疾病的药物中的用途,其中所述活性物质由(a)、(b)、(c)和(d)组成:
(a)甲磺酰基甲烷;
(b)葡糖胺;
(c)L-甘氨酸;
(d)维生素B12。
3.根据权利要求1-2任何一项所述的药物组合物的用途,其中所述药物组合物还包含药学上可接受的载体、稀释剂或赋形剂。
4.根据权利要求3所述的药物组合物的用途,其中所述活性物质由以下组成:500mg-6000mg甲磺酰基甲烷;500mg-6000mg葡糖胺;500mg-2000mg L-甘氨酸;和0.02mg-2.0mg维生素B12。
5.根据权利要求1所述的药物组合物的用途,其中所述心境障碍是抑郁症;所述焦虑性障碍选自惊恐障碍、强迫性障碍、创伤后应激障碍、社会恐怖症、特异恐怖症和广泛性焦虑症;以及所述注意缺陷障碍是ADHD。
6.根据权利要求1-2和4-5任何一项所述的药物组合物的用途,其中非感染性疾病的治疗导致个体认知性能改善。
7.根据权利要求3所述的药物组合物的用途,其中非感染性疾病的治疗导致个体认知性能改善。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2010904479 | 2010-10-07 | ||
AU2010904479A AU2010904479A0 (en) | 2010-10-07 | The use of a novel compound GMGB1 in the treatment of depression and other non-infectious diseases | |
PCT/AU2011/001275 WO2012045118A1 (en) | 2010-10-07 | 2011-10-05 | Combination therapy for the treatment of depression and other non-infectious diseases |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103249407A CN103249407A (zh) | 2013-08-14 |
CN103249407B true CN103249407B (zh) | 2017-05-17 |
Family
ID=45927130
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201180058704.9A Active CN103249407B (zh) | 2010-10-07 | 2011-10-05 | 用于治疗抑郁症和其他非感染性疾病的联合疗法 |
Country Status (6)
Country | Link |
---|---|
US (2) | US20130281401A1 (zh) |
EP (1) | EP2624821B1 (zh) |
CN (1) | CN103249407B (zh) |
AU (1) | AU2011313814B2 (zh) |
CA (1) | CA2816595C (zh) |
WO (1) | WO2012045118A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6188784B2 (ja) | 2012-04-02 | 2017-08-30 | イーグルファーマ ピーティーワイ エルティーディEaglepharma Pty Ltd | 炎症性および免疫性疾患の治療のための組成物 |
WO2017085437A1 (en) * | 2015-11-19 | 2017-05-26 | The Wwk Trust | Combinations for the treatment of dementia, and the enhancement of cognitive function |
GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
WO2020212952A1 (en) | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Treatment of depression and other various disorders with psilocybin |
CN110237062A (zh) * | 2019-07-10 | 2019-09-17 | 吉林农业大学 | 一种以葡萄糖胺为调节剂的能够增强注意力的制剂 |
AU2021276656A1 (en) | 2020-05-19 | 2022-11-24 | Cybin Irl Limited | Deuterated tryptamine derivatives and methods of use |
WO2021250435A1 (en) * | 2020-06-12 | 2021-12-16 | Beckley Psytech Limited | Pharmaceutical composition comprising 5-methoxy-n,n-dimethyltryptamine |
WO2024099883A1 (en) * | 2022-11-07 | 2024-05-16 | Société des Produits Nestlé S.A. | Compositions and methods using glycine to reduce biological age of an adult animal |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1882602A (zh) * | 2003-10-10 | 2006-12-20 | 梅迪泰克研究有限公司 | 在疾病治疗中乙酰透明质酸合成的调节和降解 |
CN101317684A (zh) * | 2007-06-08 | 2008-12-10 | 张文彪 | 一种固体饮料及制作方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4616039A (en) * | 1979-08-30 | 1986-10-07 | Herschler R J | Methylsulfonylmethane in dietary products |
US20040005304A1 (en) * | 2002-07-08 | 2004-01-08 | Mak Wood, Inc. | Novel compositions and methods for treating neurological disorders and associated gastrointestinal conditions |
US20060281822A1 (en) * | 2005-04-20 | 2006-12-14 | Cardinal Associates, Inc. | Treatment and prevention of elevated homocysteine |
US20090110674A1 (en) * | 2007-10-24 | 2009-04-30 | Loizou Nicos C | Health supplement |
US20100168053A1 (en) * | 2008-03-17 | 2010-07-01 | Revitapop | Oral delivery system for methylcobalamin to treat disorders |
US20130018059A1 (en) * | 2010-03-31 | 2013-01-17 | Abela Pharmaceuticals, Inc. | Dimethyl sulfoxide (dmso) formulations for treating autism |
-
2011
- 2011-10-05 AU AU2011313814A patent/AU2011313814B2/en active Active
- 2011-10-05 US US13/882,706 patent/US20130281401A1/en not_active Abandoned
- 2011-10-05 EP EP11830119.1A patent/EP2624821B1/en active Active
- 2011-10-05 CN CN201180058704.9A patent/CN103249407B/zh active Active
- 2011-10-05 CA CA2816595A patent/CA2816595C/en active Active
- 2011-10-05 WO PCT/AU2011/001275 patent/WO2012045118A1/en active Application Filing
-
2017
- 2017-07-11 US US15/647,198 patent/US20170304351A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1882602A (zh) * | 2003-10-10 | 2006-12-20 | 梅迪泰克研究有限公司 | 在疾病治疗中乙酰透明质酸合成的调节和降解 |
CN101317684A (zh) * | 2007-06-08 | 2008-12-10 | 张文彪 | 一种固体饮料及制作方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2816595A1 (en) | 2012-04-12 |
EP2624821B1 (en) | 2018-06-27 |
EP2624821A1 (en) | 2013-08-14 |
EP2624821A4 (en) | 2014-02-26 |
AU2011313814A1 (en) | 2013-05-02 |
AU2011313814B2 (en) | 2015-12-24 |
US20130281401A1 (en) | 2013-10-24 |
WO2012045118A9 (en) | 2017-04-13 |
WO2012045118A1 (en) | 2012-04-12 |
US20170304351A1 (en) | 2017-10-26 |
CN103249407A (zh) | 2013-08-14 |
CA2816595C (en) | 2018-11-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103249407B (zh) | 用于治疗抑郁症和其他非感染性疾病的联合疗法 | |
US11738035B2 (en) | Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin | |
JP2021001222A (ja) | 神経障害および精神障害の行動症状を治療する方法 | |
Phillips | Pharmacologic treatment of body dysmorphic disorder: review of the evidence and a recommended treatment approach | |
US8461148B2 (en) | Use of memantine (namenda) to treat autism, compulsivity and impulsivity | |
ES2511772T3 (es) | Formulaciones de ácidos grasos omega-3 | |
US20170042878A1 (en) | Compositions comprising scopolamine and ketamine in the treatment of depression | |
CN105163731B (zh) | 内服组合物 | |
NO333614B1 (no) | Farmasoytiske preparater av modafinil | |
US11147781B2 (en) | Methods for alleviating statin myopathy | |
CN110072555A (zh) | 用于治疗中枢神经系统疾病的包含苯甲酸盐化合物和单宁酸的组合物 | |
Wu et al. | Acetoacetate improves memory in alzheimer’s mice via promoting Brain-Derived neurotrophic factor and inhibiting inflammation | |
CA3197966A1 (en) | Use of cannabidiol for the treatment of psychological distress | |
JP6940631B2 (ja) | 安息香酸塩で自閉症スペクトラム障害を予防または治療するための方法 | |
Phunikhom et al. | A Randomized, Double Blind Clinical Study to Assess the Effects of a Gamma-oryzanol-enriched Rice Bran Oil on Lipid Profile in the Hypercholesterolemic Patients. | |
Ha et al. | Psychopharmacology in dermatology: Five common disorders | |
Mulley | Depression in physically ill older patients | |
US20220143156A1 (en) | Lysozyme hydrolysate for proactive inhibitory control and control of impulsivity | |
WO2023272335A1 (en) | Cannabidiol formulation comprising a matrix pellet forming excipient | |
Burkey et al. | Antipsychotic-induced psychotic-like syndrome and pathological smiling in an adolescent | |
Nichols et al. | Amarin Sponsors Three Scientific Presentations Scheduled for American Diabetes Association Scientific Sessions | |
Wyeth | PrEFFEXOR® XR | |
Capsules et al. | Pr EFFEXOR® XR Capsules | |
WO2022251912A1 (en) | Use of cannabinoid combination for the treatment of irritable bowel syndrome-related psychological distress | |
Schilling | Writing A Medical Book |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |