ZA200509356B - Gaboxadol for treating depression and other affective disorders - Google Patents
Gaboxadol for treating depression and other affective disorders Download PDFInfo
- Publication number
- ZA200509356B ZA200509356B ZA200509356A ZA200509356A ZA200509356B ZA 200509356 B ZA200509356 B ZA 200509356B ZA 200509356 A ZA200509356 A ZA 200509356A ZA 200509356 A ZA200509356 A ZA 200509356A ZA 200509356 B ZA200509356 B ZA 200509356B
- Authority
- ZA
- South Africa
- Prior art keywords
- gaboxadol
- pharmaceutical composition
- reuptake inhibitor
- serotonin reuptake
- serotonin
- Prior art date
Links
- ZXRVKCBLGJOCEE-UHFFFAOYSA-N Gaboxadol Chemical compound C1NCCC2=C1ONC2=O ZXRVKCBLGJOCEE-UHFFFAOYSA-N 0.000 title claims description 111
- 229950004346 gaboxadol Drugs 0.000 title claims description 111
- 208000019022 Mood disease Diseases 0.000 title claims description 10
- 239000003772 serotonin uptake inhibitor Substances 0.000 claims description 94
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 90
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 claims description 82
- 150000001875 compounds Chemical class 0.000 claims description 64
- 239000008194 pharmaceutical composition Substances 0.000 claims description 51
- 229940076279 serotonin Drugs 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 22
- 230000001225 therapeutic effect Effects 0.000 claims description 19
- 208000019901 Anxiety disease Diseases 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 239000002552 dosage form Substances 0.000 claims description 16
- -1 ion monohydrate Chemical class 0.000 claims description 15
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 15
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 15
- 239000002775 capsule Substances 0.000 claims description 13
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 claims description 13
- 229960004341 escitalopram Drugs 0.000 claims description 13
- 208000020401 Depressive disease Diseases 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 9
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical group C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 8
- 229960001653 citalopram Drugs 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 229960002464 fluoxetine Drugs 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 7
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 7
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 7
- 229960004038 fluvoxamine Drugs 0.000 claims description 7
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 229960002296 paroxetine Drugs 0.000 claims description 7
- 229960002073 sertraline Drugs 0.000 claims description 7
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 7
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 claims description 6
- 208000030814 Eating disease Diseases 0.000 claims description 6
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 230000003190 augmentative effect Effects 0.000 claims description 6
- 235000014632 disordered eating Nutrition 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229960002866 duloxetine Drugs 0.000 claims description 6
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 5
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 5
- 208000032841 Bulimia Diseases 0.000 claims description 5
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 5
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 claims description 5
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 claims description 5
- 206010013654 Drug abuse Diseases 0.000 claims description 5
- 208000030990 Impulse-control disease Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 5
- 208000022531 anorexia Diseases 0.000 claims description 5
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 5
- 229960004606 clomipramine Drugs 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 claims description 5
- 229960005217 dapoxetine Drugs 0.000 claims description 5
- 206010061428 decreased appetite Diseases 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 208000024732 dysthymic disease Diseases 0.000 claims description 5
- OJSFTALXCYKKFQ-YLJYHZDGSA-N femoxetine Chemical compound C1=CC(OC)=CC=C1OC[C@@H]1[C@@H](C=2C=CC=CC=2)CCN(C)C1 OJSFTALXCYKKFQ-YLJYHZDGSA-N 0.000 claims description 5
- 229950003930 femoxetine Drugs 0.000 claims description 5
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 claims description 5
- 229960001800 nefazodone Drugs 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 208000019899 phobic disease Diseases 0.000 claims description 5
- 208000011117 substance-related disease Diseases 0.000 claims description 5
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960004688 venlafaxine Drugs 0.000 claims description 5
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 17
- 230000000694 effects Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000003826 tablet Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 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 10
- 229930006000 Sucrose Natural products 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 230000035882 stress Effects 0.000 description 10
- 239000005720 sucrose Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 8
- 230000001430 anti-depressive effect Effects 0.000 description 7
- 239000000935 antidepressant agent Substances 0.000 description 7
- 229940005513 antidepressants Drugs 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 238000002648 combination therapy Methods 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 206010041250 Social phobia Diseases 0.000 description 5
- 230000036506 anxiety Effects 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 208000013200 Stress disease Diseases 0.000 description 4
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 4
- 208000026345 acute stress disease Diseases 0.000 description 4
- 230000003416 augmentation Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000012048 forced swim test Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000000697 serotonin reuptake Effects 0.000 description 3
- 208000019116 sleep disease Diseases 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- XFPJZGUGGRESHD-PHJLCXHGSA-N (6r,10br)-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline;hydrobromide Chemical compound Br.ClC1=CC=CC=C1[C@H]1C2=CC=CC=C2[C@H]2CCCN2C1 XFPJZGUGGRESHD-PHJLCXHGSA-N 0.000 description 2
- PBALTVQMQFVDBV-GRTNUQQKSA-N (6s,10br)-6-(4-methylsulfanylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline;perchloric acid Chemical compound OCl(=O)(=O)=O.C1=CC(SC)=CC=C1[C@H]1C2=CC=CC=C2[C@H]2CCCN2C1 PBALTVQMQFVDBV-GRTNUQQKSA-N 0.000 description 2
- 101000617964 Homo sapiens Sorcin Proteins 0.000 description 2
- 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 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000008503 anti depressant like effect Effects 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- XXPVSQRPGBUFKM-SAPNQHFASA-N clovoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(Cl)C=C1 XXPVSQRPGBUFKM-SAPNQHFASA-N 0.000 description 2
- 229950002663 clovoxamine Drugs 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 244000144993 groups of animals Species 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose 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
- FTKXWCQSVJPWPZ-VDWBQBBKSA-N org 6906 Chemical compound Cl.C1C2=CC=CC=C2[C@H]2C=C[C@@H](N)[C@@H]1C2 FTKXWCQSVJPWPZ-VDWBQBBKSA-N 0.000 description 2
- AVVSOBGTJTTZKQ-RXVWUEJASA-N org 6997 Chemical compound Cl.C1C2=CC(Cl)=CC=C2[C@H]2C=C[C@@H](N)[C@@H]1C2 AVVSOBGTJTTZKQ-RXVWUEJASA-N 0.000 description 2
- LWRJZIPAGMGXQJ-DIJVWCDGSA-N org-6582 Chemical compound Cl.C1C2=CC(Cl)=CC=C2[C@@H]2[C@@H](N)[C@H]1C=CC2 LWRJZIPAGMGXQJ-DIJVWCDGSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 description 1
- WIQRCHMSJFFONW-HNNXBMFYSA-N (3s)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound O([C@@H](CCN)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 WIQRCHMSJFFONW-HNNXBMFYSA-N 0.000 description 1
- STDYWHYUOSSCBO-UHFFFAOYSA-N 2,3-dimethyl-4-phenyl-4,5-dihydro-1,3-benzodiazepine Chemical compound C1C2=CC=CC=C2N=C(C)N(C)C1C1=CC=CC=C1 STDYWHYUOSSCBO-UHFFFAOYSA-N 0.000 description 1
- WETRBJOSGIDJHQ-UHFFFAOYSA-N 2-(3,4-dihydronaphthalen-2-ylmethyl)-4,5-dihydro-1h-imidazole Chemical compound C=1C2=CC=CC=C2CCC=1CC1=NCCN1 WETRBJOSGIDJHQ-UHFFFAOYSA-N 0.000 description 1
- FWYRGHMKHZXXQX-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)-2-(dimethylamino)-2-methylpropan-1-ol Chemical compound CN(C)C(C)(CO)CC1=CC=C(Cl)C(Cl)=C1 FWYRGHMKHZXXQX-UHFFFAOYSA-N 0.000 description 1
- ZDZDSZQYRBZPNN-UHFFFAOYSA-N 4,5,6,7-tetrahydro-[1,2]oxazolo[5,4-c]pyridin-6-ium-3-olate;hydrochloride Chemical compound Cl.C1NCCC2=C1ONC2=O ZDZDSZQYRBZPNN-UHFFFAOYSA-N 0.000 description 1
- UFGTZUKOBHLAAC-UHFFFAOYSA-N 4-(5,6-dimethyl-1-benzofuran-2-yl)piperidine Chemical compound O1C=2C=C(C)C(C)=CC=2C=C1C1CCNCC1 UFGTZUKOBHLAAC-UHFFFAOYSA-N 0.000 description 1
- JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 description 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- IWVRVEIKCBFZNF-UHFFFAOYSA-N LSM-1636 Chemical compound C1CNC2CCCC3=C2N1C1=CC=C(C)C=C13 IWVRVEIKCBFZNF-UHFFFAOYSA-N 0.000 description 1
- RGPDEAGGEXEMMM-UHFFFAOYSA-N Nefopam Chemical compound C12=CC=CC=C2CN(C)CCOC1C1=CC=CC=C1 RGPDEAGGEXEMMM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-O S-adenosyl-L-methionine Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H]([NH3+])C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-O 0.000 description 1
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 206010042008 Stereotypy Diseases 0.000 description 1
- 101710164184 Synaptic vesicular amine transporter Proteins 0.000 description 1
- 102100034333 Synaptic vesicular amine transporter Human genes 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Natural products O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- FZSPJBYOKQPKCD-VIFPVBQESA-N [1-(4-chlorophenyl)-2-methylpropan-2-yl] (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC(C)(C)CC1=CC=C(Cl)C=C1 FZSPJBYOKQPKCD-VIFPVBQESA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960003225 alaproclate Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960002980 amitriptyline oxide Drugs 0.000 description 1
- ZPMKQFOGINQDAM-UHFFFAOYSA-N amitriptylinoxide Chemical compound C1CC2=CC=CC=C2C(=CCC[N+](C)([O-])C)C2=CC=CC=C21 ZPMKQFOGINQDAM-UHFFFAOYSA-N 0.000 description 1
- 229960002519 amoxapine Drugs 0.000 description 1
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229950005683 bazinaprine Drugs 0.000 description 1
- KRNDIPHOJLIHRI-UHFFFAOYSA-N bazinaprine Chemical compound N#CC1=CC(C=2C=CC=CC=2)=NN=C1NCCN1CCOCC1 KRNDIPHOJLIHRI-UHFFFAOYSA-N 0.000 description 1
- SRIJFPBZWUFLFD-UHFFFAOYSA-N befuraline Chemical compound C=1C2=CC=CC=C2OC=1C(=O)N(CC1)CCN1CC1=CC=CC=C1 SRIJFPBZWUFLFD-UHFFFAOYSA-N 0.000 description 1
- 229950000159 befuraline Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229950000303 cericlamine Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000037326 chronic stress Effects 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 229950005551 dazepinil Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 229950007329 diclofensine Drugs 0.000 description 1
- ZJDCGVDEEHWEIG-UHFFFAOYSA-N diclofensine Chemical compound C1N(C)CC2=CC(OC)=CC=C2C1C1=CC=C(Cl)C(Cl)=C1 ZJDCGVDEEHWEIG-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229960001393 dosulepin Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000009837 dry grinding Methods 0.000 description 1
- 230000000517 effect on sleep Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- NELSQLPTEWCHQW-UHFFFAOYSA-N fezolamine Chemical compound N=1N(CCCN(C)C)C=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 NELSQLPTEWCHQW-UHFFFAOYSA-N 0.000 description 1
- 229950000761 fezolamine Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000004886 head movement Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229950006314 ifoxetine Drugs 0.000 description 1
- ZHFIAFNZGWCLHU-YPMHNXCESA-N ifoxetine Chemical compound CC1=CC=CC(O[C@@H]2[C@@H](CNCC2)O)=C1C ZHFIAFNZGWCLHU-YPMHNXCESA-N 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- QZIQORUGXBPDSU-UHFFFAOYSA-N imipramine oxide Chemical compound C1CC2=CC=CC=C2N(CCC[N+](C)([O-])C)C2=CC=CC=C21 QZIQORUGXBPDSU-UHFFFAOYSA-N 0.000 description 1
- 229960003441 imipramine oxide Drugs 0.000 description 1
- SVFXPTLYMIXFRX-BBRMVZONSA-N indatraline Chemical compound C1([C@@H]2C[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 SVFXPTLYMIXFRX-BBRMVZONSA-N 0.000 description 1
- 229950008889 indatraline Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- MJJDYOLPMGIWND-UHFFFAOYSA-N litoxetine Chemical compound C=1C=C2C=CC=CC2=CC=1COC1CCNCC1 MJJDYOLPMGIWND-UHFFFAOYSA-N 0.000 description 1
- 229950004138 litoxetine Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960000600 milnacipran Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- YYWKMPCKXDNMTJ-UHFFFAOYSA-N n-[[1-[(6-fluoronaphthalen-2-yl)methyl]piperidin-4-yl]carbamoyl]pyridine-3-carboxamide Chemical compound C1=CC2=CC(F)=CC=C2C=C1CN(CC1)CCC1NC(=O)NC(=O)C1=CC=CN=C1 YYWKMPCKXDNMTJ-UHFFFAOYSA-N 0.000 description 1
- 229950000323 napamezole Drugs 0.000 description 1
- 229960000751 nefopam Drugs 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229950001527 nitroxazepine Drugs 0.000 description 1
- CGYWLLGTCBIGSR-UHFFFAOYSA-N nitroxazepine Chemical compound O=C1N(CCCN(C)C)C2=CC=CC=C2OC2=CC=C([N+]([O-])=O)C=C21 CGYWLLGTCBIGSR-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- AMJPIGOYWBNJLP-UHFFFAOYSA-N pirandamine Chemical compound C1C2=CC=CC=C2C2=C1C(CCN(C)C)(C)OCC2 AMJPIGOYWBNJLP-UHFFFAOYSA-N 0.000 description 1
- 229950007239 pirandamine Drugs 0.000 description 1
- 229950002220 pirlindole Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940124811 psychiatric drug Drugs 0.000 description 1
- 229960000279 quinupramine Drugs 0.000 description 1
- JCBQCKFFSPGEDY-UHFFFAOYSA-N quinupramine Chemical compound C12=CC=CC=C2CCC2=CC=CC=C2N1C(C1)C2CCN1CC2 JCBQCKFFSPGEDY-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229950000319 seproxetine Drugs 0.000 description 1
- FTKTZRKAVSDSRA-UHFFFAOYSA-N sercloremine Chemical compound C1CN(C)CCC1C1=CC2=CC(Cl)=CC=C2O1 FTKTZRKAVSDSRA-UHFFFAOYSA-N 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960005138 tianeptine Drugs 0.000 description 1
- 229950008817 tiflucarbine Drugs 0.000 description 1
- BNKIWXODDDABSJ-UHFFFAOYSA-N tiflucarbine Chemical compound N1C2=CC(F)=C3SC=C(C)C3=C2C2=C1CCN(CC)C2 BNKIWXODDDABSJ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 229960003740 vilazodone Drugs 0.000 description 1
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 description 1
- 229950006360 viqualine Drugs 0.000 description 1
- XFXANHWIBFMEOY-JKSUJKDBSA-N viqualine Chemical compound C12=CC(OC)=CC=C2N=CC=C1CCC[C@@H]1CCNC[C@@H]1C=C XFXANHWIBFMEOY-JKSUJKDBSA-N 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
TREATMENT OF DEPRESSION AND OTHER AFFECTIVE DISORDERS
The present invention relates to the use of gaboxadol for the preparation of medicaments s useful for the treatment of depression. The present invention also relates to the use of a combination of gaboxadol and a serotonin reuptake inhibitor (SRI), or any other compound, which causes an elevation in the level of extracellular serotonin, for the treatment of depression and other affective disorders.
Gaboxadol (THIP), described in EP patent 0000338 B1 and in EP Patent 0840601 Bl, have shown great potential in the treatment of sleep disorders.
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants. .
However, clinical studies on depression and anxiety disorders indicate that non-response to
SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient’s motivation to continue pharmacotherapy.
According to the present invention 2 pharmaceutical composition for the treatment of depression is provided.
Gaboxadol has the general formula
OH
0 ; and throughout the description “gaboxadol” is intended to include any form of the compound, such as the base (zwitter ion), pharmaceutically acceptable salts, e.g. pharmaceutically acceptable acid addition salts, hydrates or solvates of the base or salt, as 5s well as anhydrates, and also amorphous, or crystalline forms.
More specifically, the present invention relates to the use of gaboxadol having the general formula
OH
: for the preparation of a pharmaceutical composition for the treatment of depression.
In a further aspect, the present invention relates to a method for the treatment of depression comprising administering to an individual in need thereof a pharmaceutically acceptable amount of gaboxadol. Such individual is preferably a human, such as male or female human, child, adult or elderly.
According to the invention, gaboxadol may be used as the base (the zwitter ion) or as 2 pharmaceutically acceptable acid addition salt thereof or as an anhydrate or hydrate of such salt or base. The salts of the compound used in the invention are salts formed with non-toxic organic or inorganic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane- disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Gaboxadol may also be used as the zwitter ion, e.g. the mono hydrate thereof.
The acid addition salts according to the invention may be obtained by treatment of gaboxadol with the acid in an inert solvent followed by precipitation, isolation and optionally re-crystallisation by known methods and if desired micronisation of the crystalline product by wet or dry milling or another convenient process, or preparation of particles from a solvent-emulsification process. Suitable methods are described in EP patent 0000338.
Precipitation of the salt is typically carried out in an inert solvent, e.g. an inert polar solvent such as an alcohol (e.g. ethanol, 2-propanol and n-propanol), but water or mixtures of water and inert solvent may also be used.
In an embodiment, gaboxadol is used in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate. In a further embodiment, gaboxadol is used in the form of the pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate. Most conveniently, gaboxadol is in a crystalline form.
According to the invention, gaboxadol may be administered in any suitable way e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
Preferably, and in accordance with the purpose of the present invention, gaboxadol is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsuleor in the form of a suspension, solution or dispersion for injection.
Methods for the preparation of solid pharmaceutical preparations are well known in the art.
Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and ‘subsequently compressing the mixture in a convenient tabletting machine. Examples of adjuvants or diluents comprise: com starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colourings, aroma, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
A suitable formulation of gaboxadol is described in WO 02/094225 filed May 17, 2002.
Without limiting the invention in any way, it is intended that any one of the aspects or embodiments of this patent application is suitable embodiments of the medicament or pharmaceutical compositions herein.
Gaboxadol is typically administered as an oral dose form, such as a solid oral dose form, typically tablets or capsules, or as a liquid oral dose form. Gaboxadol is most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 0.1 to about 150 mg/day, such as from about 0.1 to about 100 mg/day, typically from about 0.5 to about 50 mg/day, preferably from about 25 to about 20 mg/day, e.g. from about 5 to about 15 mg/day. The amount of gaboxadol is calculated based on the free base form.
Gaboxadol may be administered as monotherapy or as combination therapy with other drugs. In a particular aspect, gaboxadol may be combined with a serotonin reuptake inhibitor as described below.
The combination of gaboxadol with a serotonin reuptake inhibitor
In addition, gaboxadol may be used to augment and provide faster onset of the therapeutic effect of serotonin reuptake inhibitors, in particular citalopram and escitalopram.
It has now surprisingly been found that gaboxadol may be used to augment and provide faster onset of the therapeutic effect of serotonin reuptake inhibitors.
In one aspect, the invention relates to use of gaboxadol for the preparation ofa pharmaceutical composition to be used in combination with a serotonin reuptake inhibitor or any other compound, which causes an elevation in the level of extracellular serotonin.
In another aspect, the invention relates to use of gaboxadol for the preparation ofa pharmaceutical composition useful for augmenting and/or providing faster onset of the therapeutic effect of a serotonin reuptake inhibitor or any other compound, which causes an elevation in the level of extracellular serotonin. 5
In a further aspect, the invention relates to a pharmaceutical composition or kit comprising gaboxadol and a compound, which is a serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, and optionally pharmaceutically acceptable carriers or diluents.
In a further aspect, the invention relates to a method for the treatment of diseases or disorders responsive to a serotonin reuptake inhibitor or any other compound which causes an elevation in the level of extracellular serotonin, comprising administering gaboxadol and a serotonin reuptake inhibitor, or a compound which causes an elevation in the level extracellular serotonin, to an individual in need thereof.
In a further aspect, the invention relates to use of gaboxadol and a compound, which is a serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, for the preparation of a pharmaceutical composition for the treatment of diseases or disorders responsive to the therapeutic effect of a serotonin reuptake inhibitor or any other compound causing an elevation in the level of extracellular serotonin.
In a further aspect, the invention relates to use of gaboxadol for the preparation of a pharmaceutical composition for the treatment of an individual to be treated with or undergoing treatment with the serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, wherein said individual suffers from diseases or disorders responsive to the therapeutic effect of a serotonin reuptake inhibitor or any other compound causing an elevation in the level of extracellular serotonin.
In a further aspect, the invention relates to use of gaboxadol and a compound, which is a serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, for the preparation of 2 kit for the treatment of diseases or disorders responsive to the therapeutic effect of a serotonin reuptake inhibitor or any other compound causing an elevation in the level of extracellular serotonin.
In a further aspect, the invention relates to a method for augmenting and/or providing faster onset of the therapeutic effect of a serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, comprising administering gaboxadol to an individual to be treated with or undergoing treatment with the serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin. Such individual is preferably a human, such as male or female human, child, adult or elderly.
In an embodiment, the serotonin reuptake inhibitor or the compound which causes an elevation in the level of extracellular serotonin is used in the treatment of depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.
In a further embodiment, the serotonin reuptake inhibitor or the compound which causes an elevation in the level of extracellular serotonin is used in the treatment of anxiety disorders including general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder or social anxiety disorder.
In a further embodiment, the serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramin, femoxetine and clomipramine or a pharmaceutically acceptable salt of any of these compounds. Just to clarify, each of the serotonin reuptake inhibitors specified above is intended to be an individual embodiment. Accordingly, each of them and the use thereof may be claimed individually.
In a further embodiment, the serotonin reuptake inhibitor is a selective serotonin reuptake inhibitor (SSRI).
In a further embodiment, the pharmaceutical composition or kit prepared is adapted for simultaneous administration of the active ingredients. In an embodiment, the active ingredients are contained in the same unit dosage form. :
In a further embodiment, the pharmaceutical composition or kit prepared is adapted for sequential administration of the active ingredients. In an embodiment, the active ingredients are contained in discrete unit dosage forms.
In a further aspect, the present invention relates to the use of gaboxadol for the preparation of a pharmaceutical composition to be used in combination with a serotonin reuptake inhibitor or any other compound which causes an elevation in the level of extracellular serotonin.
In particular, the present invention relates to the use of gaboxadol for the preparation of a pharmaceutical composition useful for augmenting and/or providing faster onset of the therapeutic effect of a serotonin reuptake inhibitor or any other compound which causes an elevation in the level of extracellular serotonin.
More particularly, the present invention relates to the use as above, of gaboxadol, for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder and social anxiety disorder eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression with a serotonin reuptake inhibitor or any other compound which causes an elevation in the level of extracellular serotonin.
The anxiety disorders mentioned above include general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder or social anxiety disorder.
As used herein, the term augmenting covers improving the therapeutic effect and/or potentiating the therapeutic effect of an SRI or a compound which causes an elevation in the level of extracellular 5-HT. s In a further embodiment, the invention relates to the use of gaboxadol and a compound, which is a serotonin reuptake inhibitor, or a compound, which causes an elevation in the level of extracellular serotonin, for the preparation of a pharmaceutical composition for the treatment of diseases or disorders responsive to the therapeutic effect of a serotonin reuptake inhibitor, or any other compound, which causes an elevation in the level of extracellular serotonin.
In a further embodiment, the invention relates to the use of gaboxadol and a compound, which is a serotonin reuptake inhibitor, or a compound, which causes an elevation in the level of extracellular serotonin, for the preparation of a kit-of-parts (kit) for the treatment of diseases or disorders responsive to the therapeutic effect of a serotonin reuptake inhibitor, or any other compound, which causes an elevation in the level of extracellular serotonin.
The diseases responsive to a serotonin reuptake inhibitor include depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.
The term anxiety disorders is as defined above.
In one embodiment, the present invention relates to the use of gaboxadol for the preparation of a pharmaceutical composition as above, which is adapted for simultaneous administration of the active ingredients. In particular, such pharmaceutical compositions may contain the active ingredients within the same unit dosage form, e.g. in the same tablet or capsule. Such unit dosage forms may contain the active ingredients as a homogenous mixture or in separate compartments of the unit dosage form.
In another embodiment, the present invention relates to the use of gaboxadol for the preparation of a pharmaceutical composition or kit as above, which is adapted for sequential administration of the active ingredients. In particular, such pharmaceutical compositions may contain the active ingredients in discrete unit dosage forms, e.g. discrete tablets or capsules containing either of the active ingredients. These discrete unit dosage forms may be contained in the same container or package, e.g. a blister pack.
As used herein the term kit means a pharmaceutical composition containing each of the active ingredients, but in discrete unit dosage forms.
The invention also relates to a pharmaceutical composition or kit comprising gaboxadol and a compound, which is a serotonin reuptake inhibitor, or any other compound which causes an elevation in extracellular 5-HT, and optionally pharmaceutically acceptable carriers or diluents.
The pharmaceutical composition or Kit of the invention may be adapted for simultaneous administration of the active ingredients or for sequential administration of the active ingredients, as described above.
Finally, the present invention relates to a method for the treatment of diseases or disorders responsive to a serotonin reuptake inhibitor or any other compound which causes an elevation in the level of extracellular serotonin, comprising administering gaboxadol and a serotonin reuptake inhibitor, or a compound which causes an elevation in the level extracellular serotonin, to an individual in need thereof.
In particular, the present invention relates to a method for augmenting and/or providing faster onset of the therapeutic effect of a serotonin reuptake inhibitor or any other compound which causes an elevation in the level extracellular serotonin, comprising administering gaboxadol to an individual to be treated with or undergoing treatment with the serotonin reuptake inhibitor or any other compound which causes an elevation in the level of extracellular serotonin.
The individuals, which may benefit from treatment with a combination as above, may suffer from depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, premenstrual syndrome, dysthymia, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.
As mentioned above, anxiety disorder includes general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post trauma stress disorder or social anxiety disorder.
Gaboxadol and the serotonin reuptake inhibitor may be administered simultaneously as described above.
Alternatively, the active ingredients may be administered sequentially, e.g. in two discrete unit dosage forms as described above.
Tt has now, surprisingly, been found that co-administration of gaboxadol and a serotonin reuptake inhibitor produces a significant increased response in an animal model predictive of antidepressant effect, the mouse forced swim test, compared to the administration of the serotonin reuptake inhibitor alone.
As mentioned above, serotonin reuptake inhibitors show delayed onset of action. Even in responders to SSRIs, several weeks of treatment are necessary to achieve a relief in symptoms.
Gaboxadol may provide fast onset of therapeutic effect of serotonin reuptake inhibitors.
The use of a combination of gaboxadol and a serotonin reuptake inhibitor may greatly reduce the amount of serotonin reuptake inhibitor necessary to treat depression and other affective disorders and may thus reduce the side effects caused by the serotonin reuptake inhibitor. In particular, the combination of a reduced amount of SRI and gaboxadol may reduce the risk of SSRI-induced sexual dysfunction and sleep disturbances.
Co-administration of gaboxadol and a serotonin reuptake inhibitor may also be useful for the treatment of refractory depression, i.e. depression, which cannot be treated appropriately by administration of a serotonin reuptake inhibitor alone. Typically, gaboxadol may be used as add-on therapy for the augmentation of the response to SRIs in patients where at least 40-60% s reduction in symptoms has not been achieved during the first 6 weeks of treatment with an
SRL
Typically, gaboxadol is used in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate. In a further embodiment, gaboxadol is used in the form of the pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate. Most conveniently, gaboxadol is in a crystalline form.
Many antidepressants with serotonin reuptake inhibiting effect have been described in the literature. Any pharmacologically active compound, which primarily or partly exert its therapeutic effect via inhibition of serotonin reuptake in the central nervous system (CNS), may benefit from augmentation with gaboxadol.
The following list contains a number of serotonin reuptake inhibitors which may benefit from augmentation with gaboxadol: citalopram, escitalopram, fluoxetine, R-fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, imipramine N-oxide, desipramine, pirandamine, dazepinil, nefopam, befuraline, fezolamine, femoxetine, clomipramine, cianoimipramine, litoxetine, cericlamine, seproxetine, WY 27587, WY 27866, imeldine, ifoxetine, tiflucarbine, viqualine, milnacipran, bazinaprine, YM 922, S 33005, F 98214-TA, OPC 14523, alaproclate, cyanodothepine, trimipramine, quinupramine, dothiepin, amoxapine, nitroxazepine, McN 5652, McN 5707, Ol 77, Org 6582, Org 6997, Org 6906, amitriptyline, amitriptyline N- oxide, nortriptyline, CL 255.663, pirlindole, indatraline, L'Y 113.821, LY 214.281, CGP 6085 A, RU 25.591, napamezole, diclofensine, trazodone, EMD 68.843, BMY 42.569, NS 2389, sercloremine, nitroquipazine, ademethionine, sibutramine, clovoxamine, desmethylsubitramine, didesmethylsubitramine, clovoxamine vilazodone,
N-[( 1-{(6-Fluoro-2-naphthalenyl)methyl]- 4-piperidinyl]amino]carbonyl]-3-pyridine carboxamide, [trans-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo- 2,1- a)isoquinoline] (McN 5707), (d1-4-exo0-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6 alpha(10 alpha)-diene hydrochloride)(Org 6997), (d)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-8-amine hydrochloride (Org 6906), -[2-[4-(6-fluoro-1H-indol-3-y1)-3 6-dihydro-1(2H)-pyridinyl]ethyl}-3-isopropyl-6- (methylsulphonyl)-3 A-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558), [4- (5,6-dimethyl-2-benzofuranyl)-piperidine] (CGP 6085), dimethyl-[5-(4-nitro-phenoxy)-6,7 8,9-tetrahydro-SH-benzocyclohepten-7-yl]-amine RU 25.591), ~° (A 80426), i 0 o
IA
AX fo ~~ (EMD 86006), ~~ or
Ci
Ne
LJ ad : ,0 - (OPC 14523), x
NA (
HO o ve (McN 5652), wih ¢ J]
LZ
CH
F (YM 35992),
a
Z
Cl (Org 6582).
The compounds mentioned above may be used in the form of the base or a pharmaceutically acceptable salt, such as acid addition salt, thereof. Each of the serotonin reuptake inhibitors specified above is intended to be an individual embodiment. Accordingly, each of them and the use thereof may be claimed individually.
Other therapeutic compounds, which may benefit from augmentation with gaboxadol, include compounds which causes an elevation in the extracellular level of 5-HT in the synaptic cleft, although they are not serotonin reuptake inhibitors. One such compound is tianeptine.
The above list of serotonin reuptake inhibitors and other compounds which causes an increase in the extracellular level of serotonin, may not be construed as limiting.
In an embodiment, the SR1s is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, duloxetine, venlafaxine, duloxetine, dapoxetine, nefazodone, jmipramin, femoxetine and clomipramine. Just to clarify, each of these SRIs constitute individual embodiments, and may be the subject of individual claims.
The term selective serotonin reuptake inhibitor (SSRI) means an inhibitor of the monoamine transporters which has stronger inhibitory effect at the serotonin transporter than the dopamine and the noradrenaline transporters.
Selective serotonin reuptake inhibitors (SSRIs) are among the most preferred serotonin reuptake inhibitors used according to the present invention. Thus, in a further embodiment the SRI is selected from SSRIs, such as citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline or paroxetine.
The active ingredients according to the invention, i.e. gaboxadol and the SRI or a compound causing an increase in extracellular serotonin levels, may be used in the free base form or in the form of a pharmaceutically acceptable acid addition salt thereof, the latter being obtainable by reaction of the base form with an appropriate acid.
Citalopram is preferably used in the form of the hydrobromide or as the base, escitalopram in the form of the oxalate, fluoxetine, sertraline and paroxetine in the form of the hydrochloride and fluvoxamine in the form of the maleate.
As mentioned above, the combination of gaboxadol with a serotonin reuptake inhibitor unexpectedly shows a synergistic effect on the CNS. As a consequence, combination therapy using gaboxadol and lower doses of the serotonin reuptake inhibitor than normally used in monotherapy, may be effective, and side-effects associated with the larger amounts of serotonin reuptake inhibitor used in monotherapy may be reduced or prevented altogether.
Additionally, combination therapy with gaboxadol using a normal dose of serotonin reuptake inhibitor has the advantage that an effective CNS effect may be obtained in the often large number of patients who do not respond to conventional monotherapy with
SSRIs.
The amount of gaboxadol used in combination therapy may range from about 0.1 to about 150 mg/day, such as from about 0.1 to about 100 mg/day, from about 0.5 to about 50 mg/day, from about 5 to about 50 mg/day, or from about 1 to about 5 mg/day. Low amounts of gaboxadol having no significant effect on sleep disorders have shown clear and significant effect in combination therapy with a serotonin reuptake inhibitor, such as escitalopram. Low amounts are typically selected from about 0.1 to about 2.5 mg/day, such as from about 0.1 to about 2.0 mg/day, whereas higher amounts are typically selected from about 2.5 to about 150 mg/day.
Serotonin reuptake inhibitors, including the SSRIs specifically mentioned hereinabove, differ both in molecular weight and in activity. As a consequence, the amount of serotonin reuptake inhibitor used in combination therapy depends on the nature of said serotonin reuptake inhibitor. In one embodiment of the invention, the serotonin reuptake inhibitor or the compound causing an increase in the level of extracellular 5-HT, is administered at lower doses than required when the compound is used alone. In another embodiment, the serotonin reuptake inhibitor or the compound causing an increase in the level of extracellular 5-HT, is administered in normal doses.
To prepare the pharmaceutical compositions of this invention, an appropriate amount of the active ingredient(s), in salt form or base form, is combined in an intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable for administration orally, rectally, percutaneously ot by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, . glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, Syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. As used in the specification and claims, unit dosage form refers to physically discrete units suitable as unitary dosages, cach unit containing a predetermined quantity of active ingredient(s) calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Gaboxadol may be administered before, during or after the administration of the serotonin reuptake inhibitor provided that the time between the administration of gaboxadol and the / administration of the serotonin reuptake inhibitor is such that ingredients are allowed to act synergistically on the CNS. When simultaneous administration of gaboxadol and a serotonin reuptake inhibitor is envisaged, a composition containing both a serotonin reuptake inhibitor and gaboxadol may be particularly convenient. Alternatively, gaboxadol and the serotonin reuptake inhibitor may be administered separately in the form of suitable compositions. The compositions may be prepared as described hereinabove.
The present invention also comprises products containing gaboxadol and a serotonin reuptake inhibitor as a combination preparation for simultaneous, separate or sequential use in psychiatric drug therapy. Such products may comprise, for example, a kit comprising discrete unit dosage forms containing gaboxadol and discrete unit dosage forms containing a serotonin reuptake inhibitor, all contained in the same container or pack, ¢.g. 2 blister pack.
The above mentioned preparations for simultaneous or sequential administration may 90 instead of a serotonin reuptake inhibitor contain another compound causing an elevation in the level of extracellular 5-HT.
Pharmacological Test of antidepressant effect of gaboxadol
The rat chronic mild stress (CMS) model of depression has a high degree of preditive validity for antidepressant activity (Willner (1997), Psychopharmacol 134:3 19-329).
Furthermore the procedure is an appropriate model to study onset of antidepressant action in animals. (Behavioural Pharmacology 14:465-470, 2003, Sanchez, C. et al). The principle of the model is based on the relation between stress and affective disorders. Rats exposed to chronic stress will show a reduced sensitivity to rewards (e.g. a palatable sucrose solution).
Experimental Procedure chronic mild stress
Male Wistar rats (Gorzkowska, Warsaw) were brought into the laboratory two months before the start of the experiment. The animals were singly housed with food and water freely available, and maintained on a 12-h light/dark cycle at a temperature of 22 + 2 °C, except as described below.
The animals were first trained to consume a 1% sucrose solution; training consisted of eight 1h baseline tests in which sucrose was presented, in the home cage, following 14h food and water deprivation; intake was measured by weighing pre-weighed bottles containing the sucrose solution, at the end of the test. Subsequently, sucrose consumption was monitored, under similar conditions, throughout the whole experiment. On the basis of their sucrose intakes in the final baseline test, the animals were divided into two matched groups. One group of animals was subjected to a chronic mild stress procedure for a period of 8 consecutive weeks. The weekly stress regime consisted of 2 periods of food or water deprivation, 45 degree cage tilt, intermittent illumination (lights on and off every 2 h), soiled cage (250 ml water in sawdust bedding), paired housing and low intensity stroboscopic illumination (150 flashes/min), and 2 periods of no stress. All stressors Were 10 - 14 h of duration and were applied individually and continuously, day and night. The other groups of animals, the unstressed controls, were housed in separate rooms and had no contact with the stressed animals. The rats were deprived of food and water for the 14 h preceding each sucrose test, but otherwise food and water were freely available in the home cage. On the basis of their sucrose intake scores following 3 weeks of stress, both stressed and control animals were divided into matched subgroups, and for the subsequent five weeks they 55 received twice daily intraperitoneal drug injections (at approximately 10.00 and 17.00).
Sucrose tests were performed at 10 am. on a weekly basis (Tuesdays). Different groups of animals (n = 8) were administered vehicle (1 ml/kg per day) or test drug. Before test sessions drugs were administered at approximately 10.00h and the sucrose tests were carried out 24h following the previous drug injection. Stress was continued throughout the entire treatment period. Body weights were assessed a baseline and by the end of drug treatment.
Results chronic mild stress
The testing of gaboxadol in the rat chronic mild stress model showed that the compound had a significant anti-depressant-like effect. The dose of 2.5 mg/kg per day had a clear and s significant effect in this model.
Gaboxadol in combination with escitalopram
In order to modulate the activity of systems, responsible for antidepressants activity, we have characterized the interaction between gaboxadol and escitalopram (an SSRN ina behavioural model of serotonin reuptake inhibition, the mouse 5-HTP potentiation test, and a model that is predictive of antidepressant activity, the mouse forced swim test (cf. C.
Sanchez et al, Psychopharmacology (2003), 167:353-362).
Experimental Procedures
Male NMRUBOM mice (18-25 g; Bomholtgaard, Denmark) were used. The mice were housed in plastic cages (35x30x12 cm), 10 in each and habituated to the animal facilities for at least a week before test. The room temperature (21 + 2°C), relative humidity (55 5%), and air exchange (16 times per h) were automatically controlled. The animals had free access to commercial food pellets and tap water before test.
Potentiation of 5_HTP-induced behaviour.
The test procedure for studies in mice is described in detail by Hyttel et al (1992). Briefly, 30 min after s.c. administration of test compound mice were given 5-HTP (100 mg/kg, i.v.).
Thereafter the animals were evaluated in their home cage during a 15-min observation period with respect to stereotypy (lateral head movements), tremor, and hind limb abduction. One point was given for each symptom being present. A total of 8-16 mice were used per dose.
Inhibition of forced swimming-induced immobility.
A mouse that is forced to swim in a spatially constrained container will exert a characteristic immobile posture. Pretreatment with an antidepressant will counteract this effect. The test was conducted as described in detail by Sanchez and Meier (Psychopharmacol 129:197-205; 1997). Briefly, a fully automated test system with 6 swim units (2000 ml glass jars filled with 1200 ml soiled water (23 - 25°C) in which a mouse had been placed previously) was used. The assessment of immobility was performed by image analysis. Thirty minutes after drug or vehicle treatment the mouse was placed into the glass jar and left in the water for a total of 6 min. The accumulated duration of immobility was measured during the last 3 min.
A total of 9-18 mice were tested per dose.
Results
Gaboxadol (2.5 mg/kg) strongly potentiated the acute effects of escitalopram ( 0.5 to 0.025 mg/kg) in the 5-HTP potentiation test and a gaboxadol dose (2.5 mg/kg) that was not active by itself in the forced swim test potentiated the antidepressant-like effect of escitalopram (2.5and 5 mg/kg) significantly.
Claims (49)
1. Use of gaboxadol for preparing a pharmaceutical composition for treating depression.
2. The use of claim 1 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.
3. The use of any one of claims 1-2 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.
4, The use of any one of claims 1-3 wherein the pharmaceutical composition comprises from about 0.1 to about 150 mg/day of gaboxadol.
5. The use of any one of claims 1-4 wherein the pharmaceutical composition comprises from about 0.1 to about 100 mg/day of gaboxadol.
6. The use of any one of claims 1-5 wherein the pharmaceutical composition comprises from about 0.5 to about 50 mg/day of gaboxadol.
7. The use of any one of claims 1-6 wherein the pharmaceutical composition comprises from about 2.5 to about 20 mg/day of gaboxadol.
8. The use of any one of claims 1-7 wherein the pharmaceutical composition comprises from about 5 to about 15 mg/day of gaboxadol.
9. The use of any one of claims 1-8 wherein gaboxadol is in an oral dose form.
10. The use of any one of claims 1-9 wherein gaboxadol is in a solid oral dose form.
11. The use of any one of claims 1-10 wherein gaboxadol is in the form of tablets or capsules, or a liquid oral dose form. Amended sheet 12/01/2007
12. The use of any one of claims 1-11 wherein said gaboxadol is crystalline.
13. The use of any one of claims 1-12 wherein said pharmaceutical composition is for treating a human having a depression.
14. The use of gaboxadol for the preparation of a pharmaceutical composition to be used in combination with a serotonin reuptake inhibitor or any other compound, which causes an elevation in the level of extracellular serotonin.
15. Use of gaboxadol for the preparation of a pharmaceutical composition useful for augmenting and/or providing faster onset of the therapeutic effect of a serotonin reuptake inhibitor or any other compound, which causes an elevation in the level of extracellular serotonin.
16. Use of gaboxadol for the preparation of a pharmaceutical composition for the treatment of an individual to be treated with or undergoing treatment with a serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, wherein said individual suffers from diseases or disorders responsive to the therapeutic effect of a serotonin reuptake inhibitor or any other compound causing an elevation in the level of extracellular serotonin.
17. The use of any one of claims 14-16 wherein the serotonin reuptake inhibitor or the compound which causes an elevation in the level of extracellular serotonin is used in the treatment of depression, anxiety disorders and other affective disorders, eating disorders, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse.
18. The use of claim 17 wherein the eating disorder is bulimia, anorexia or obesity.
19. The use of any one of claims 17-18 wherein the serotonin reuptake inhibitor or the compound which causes an elevation in the level of extracellular serotonin is used in the treatment of depression. Amended sheet 12/01/2007
20. The use of any one of claims 14 to 19 wherein the serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramin, femoxetine and clomipramine or a pharmaceutically acceptable salt of any of these compounds.
21. The use of any one of claims 14 to 20 wherein the serotonin reuptake inhibitor is a selective serotonin reuptake inhibitor.
22. The use of any one of claims 14 to 21 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.
23. The use of any one of claims 14 to 22 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.
24. The use of any one of claims 14-23 wherein the pharmaceutical composition comprises gaboxadol in an amount ranging from about 0.1 to about 2.5 mg.
25. The use of any one of claims 14-23 wherein the pharmaceutical composition comprises gaboxadol in an amount ranging from about 2.5 mg to about 20 mg.
26. The use of any one of claims 14-25 wherein gaboxadol is in an oral dose form.
27. The use of any one of claims 14-26 wherein the serotonin reuptake inhibitor or the compound which causes an elevation in the level of extracellular serotonin is in an oral dose form.
28. The use of claim 27 wherein gaboxadol is in a solid oral dose form.
29. The use of any one of claims 27-28 wherein gaboxadol is in the form of tablets or capsules, or a liquid oral dose form.
30. The use of claim 27 wherein the serotonin reuptake inhibitor or the compound which causes Amended sheet 12/01/2007 an elevation in the level of extracellular serotonin is in a solid oral dose form.
31. The use of any one of claims 27 and 30 wherein the serotonin reuptake inhibitor or the compound which causes an elevation in the level of extracellular serotonin is in the form of tablets or capsules, or a liquid oral dose form.
32. The use of any one of claims 14-31 wherein gaboxadol is crystalline.
33. The use of any one of claims 14-32 wherein the pharmaceutical composition prepared is adapted for simultaneous administration of gaboxadol and the serotonin reuptake inhibitor.
34. The use of any one of claims 14-33 wherein gaboxadol and the serotonin reuptake inhibitor are contained in the same unit dosage form.
35S. The use of any one of claims 14-34 wherein the pharmaceutical composition prepared is adapted for sequential administration of gaboxadol and the serotonin reuptake inhibitor.
36. A pharmaceutical composition comprising gaboxadol and a compound, which is a serotonin reuptake inhibitor, or any other compound which causes an elevation in the level of extracellular serotonin, and optionally pharmaceutically acceptable carriers or diluents.
37. The pharmaceutical composition of claim 36 for use in treating depression.
38. The pharmaceutical composition of any one of claims 36-37 characterised in that the serotonin uptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramin, femoxetine and clomipramine or a pharmaceutically acceptable salt of any of these compounds.
39. The pharmaceutical composition of any one of claims 36-38 which is adapted for simultaneous administration of gaboxadol and the serotonin reuptake inhibitor.
40. The pharmaceutical composition of any one of claims 36-39 wherein gaboxadol and the Amended sheet 12/01/2007 serotonin reuptake inhibitor are contained in the same unit dosage form.
41. The pharmaceutical composition of any one of claims 36-40 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.
42. The pharmaceutical composition of any one of claims 36-41 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.
43. The pharmaceutical composition of any one of claims 36-42 wherein gaboxadol is present in an amount ranging from about 0.1 to about 2.5 mg.
44. The pharmaceutical composition of any one of claims 36-42 wherein gaboxadol is present in an amount ranging from about 2.5 mg to about 20 mg.
45. The pharmaceutical composition of any one of claims 36-44 wherein gaboxadol is in an oral dose form.
46. The pharmaceutical composition of any of claims 36-45 wherein gaboxadol is in the form of tablets or capsules, or a liquid oral dose form.
47. The pharmaceutical composition of any one of claims 36-46 wherein the serotonin reuptake inhibitor is in an oral dose form.
48. The pharmaceutical composition of any one of claims 36-47 wherein the serotonin reuptake inhibitor is in the form of tablets or capsules, or a liquid oral dose form.
49. The pharmaceutical composition of any one of claims 36-48 wherein gaboxadol is crystalline. Amended sheet 12/01/2007
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200300956 | 2003-06-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200509356B true ZA200509356B (en) | 2007-03-28 |
Family
ID=36701616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200509356A ZA200509356B (en) | 2003-06-25 | 2004-06-25 | Gaboxadol for treating depression and other affective disorders |
Country Status (4)
| Country | Link |
|---|---|
| CN (2) | CN101156850A (en) |
| CL (1) | CL2004001603A1 (en) |
| UA (1) | UA90656C2 (en) |
| ZA (1) | ZA200509356B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105816457A (en) * | 2016-05-30 | 2016-08-03 | 杨强 | Pharmaceutical composition containing paroxetine hydrochloride and application of pharmaceutical composition |
| US20180338959A1 (en) * | 2017-05-24 | 2018-11-29 | Ovid Therapeutics Inc. | Treatment of depressive disorders |
| KR20210039324A (en) * | 2018-04-06 | 2021-04-09 | 오비드 테라퓨틱스 인크. | The use of gaboxadol in the treatment of substance use disorders |
| CN113395962A (en) * | 2018-11-21 | 2021-09-14 | Certego治疗公司 | Gaboxadol for reducing suicidal risk and rapidly relieving depression |
| CN116267014A (en) | 2020-05-20 | 2023-06-20 | Certego治疗公司 | Cyclic deuterated gaboxadol and its use for treating psychotic disorders |
-
2004
- 2004-06-24 CL CL200401603A patent/CL2004001603A1/en unknown
- 2004-06-25 CN CNA2007101801789A patent/CN101156850A/en active Pending
- 2004-06-25 CN CNA2004800175886A patent/CN1809350A/en active Pending
- 2004-06-25 ZA ZA200509356A patent/ZA200509356B/en unknown
- 2004-06-25 UA UAA200600374A patent/UA90656C2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| UA90656C2 (en) | 2010-05-25 |
| CN1809350A (en) | 2006-07-26 |
| CN101156850A (en) | 2008-04-09 |
| CL2004001603A1 (en) | 2005-05-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20090203731A1 (en) | Treatment of depression and other affective disorders | |
| EP1641456A2 (en) | Gaboxadol for treating depression and other affective disorders | |
| US10632116B2 (en) | Combinations of serotonin receptor agonists for treatment of movement disorders | |
| MX2008014840A (en) | Treatment for depressive disorders. | |
| US20100267772A1 (en) | Combination of a Serotonin Reuptake Inhibitor and Agomelatine | |
| US20140221385A1 (en) | Combinations of serotonin receptor agonists for treatment of movement disorders | |
| ZA200509356B (en) | Gaboxadol for treating depression and other affective disorders | |
| AU2004269858A1 (en) | The combination of a serotonin reuptake inhibitor and Loxapine | |
| CA2692334A1 (en) | Gaboxadol for treating depression and other affective disorders | |
| US20070042014A1 (en) | Combination of a serotonin reuptake inhibitor and loxapine | |
| AU2004266057A1 (en) | The combination of a serotonin reuptake inhibitor and a glycine transporter type 1 inhibitor for the treatment of depression | |
| AU2004269857A1 (en) | The combination of a serotonin reuptake inhibitor and Amoxapine | |
| CA2537757A1 (en) | The combination of a serotonin reuptake inhibitor and amoxapine | |
| ZA200509588B (en) | The combination of a serotonin reuptake inhibitors and agomelatine |