CN1809350A - Aboxadol for treating depression and other affective disorders - Google Patents
Aboxadol for treating depression and other affective disorders Download PDFInfo
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- CN1809350A CN1809350A CNA2004800175886A CN200480017588A CN1809350A CN 1809350 A CN1809350 A CN 1809350A CN A2004800175886 A CNA2004800175886 A CN A2004800175886A CN 200480017588 A CN200480017588 A CN 200480017588A CN 1809350 A CN1809350 A CN 1809350A
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- gaboxadol
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Abstract
The present invention relates to use of gaboxadol for preparing a pharmaceutical composition for treating depression. Moreover, it 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.
Description
Invention field
The present invention relates to gaboxadol (gaboxadol) and be used for the treatment of application in the medicine of depression in preparation.The invention still further relates to gaboxadol and 5-hydroxy tryptamine reuptake inhibitor (SRI), any other combination of compounds that maybe can cause extracellular 5-hydroxy tryptamine level to raise is used for the treatment of the application of depression and other affective disorder.
Background of invention
Gaboxadol (gaboxadol) (THIP) all has description in EP patent 0000338B1 and EP patent 0840601B1, it is showing very big potential aspect treatment sleep disorder.
In the treatment of some form of depression, anxiety and social phobia, selectivity 5-hydroxy tryptamine reuptake inhibitor (hereinafter being called SSRIs) becomes choice drug, this be because compare with traditional tricyclic antidepressants its effectively, have toleration and a good safety preferably.
But the clinical research of depression and anxiety disorder shows there be considerable non-replying in SSRJs, up to 30%.Usually unheeded another factor is to be obedient in the depression treatment, and it has very strong effect to the motivation that patient continues pharmacotherapy.
Summary of the invention
According to the present invention, provide a kind of pharmaceutical composition for the treatment of depression.
The general formula of gaboxadol is
And description in full in " gaboxadol " be meant any form that comprises described chemical compound, alkali (amphion) for example, pharmaceutically acceptable salt, for example, pharmaceutically-acceptable acid addition, the hydrate of alkali or salt or solvate, and dehydrate and amorphous or crystal form.
More specifically, the gaboxadol that the present invention relates to have following general formula is used for the treatment of application in the pharmaceutical composition of depression in preparation.
Further the aspect the present invention relates to a kind of method for the treatment of depression, and this method comprises its gaboxadol of the pharmaceutically acceptable amount of individual administration of needs.Described individuality preferably is people, for example sex, child, adult or old man.
According to the present invention, gaboxadol can alkali (amphion) or its pharmaceutically-acceptable acid addition or the dehydrate of this class salt or alkali or the form of hydrate use.The salt of the chemical compound that uses among the present invention is the salt form that forms with non-toxic organic or mineral acid.The example of this class organic salt is the salt that forms with following acid: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethane disulfonic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, the p-amino benzoic Acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and 8-halo theophylline, for example 8-bromo theophylline.The example of this class inorganic salt is: hydrochlorate, hydrobromate, sulfate, sulfamate, phosphate and nitrate.The all right amphion of gaboxadol, for example the form of its simple hydrate is used.
The preparation method of acid-addition salts of the present invention, can be included in and use the acid treatment gaboxadol in the atent solvent, with postprecipitation, separate and the optional known method recrystallization of employing, and as required can by wet or dry grinding method or other easily method crystallized product is carried out micronization, or prepare granule by the solvent emulsion process.Suitable method is recorded in the EP patent 0000338.
The precipitation of salt is typically at atent solvent, for example inert polar solvents for example ethanol (as, ethanol, 2-propanol and n-propanol) in carry out, but the mixture of water or water and atent solvent also can adopt.
In one embodiment, gaboxadol is with acid-addition salts, or the form of amphion hydrate or amphion dehydrate is used.In the specific embodiment further, gaboxadol uses with the form of pharmaceutically-acceptable acid addition, and described acid-addition salts is selected from: hydrochloric acid or hydrobromate, perhaps use with the form of amphion monohydrate.Most convenient, gaboxadol is crystal form.
According to the present invention, gaboxadol can administered in any suitable way, and is for example oral or parenteral, and it can be made into any suitable form that is used for this class administration, for example is tablet, capsule, powder, the form of syrup or solvent that is used to inject or dispersant.Preferably, according to goal of the invention of the present invention, gaboxadol is with the mode administration of solid pharmaceutical entity, and suitable can be tablet or capsule, or the suspension that is used to inject, the form of solution or dispersant.
The method for preparing solid pharmaceutical preparation is well known in the art.Therefore tablet can pass through active component and conventional adjuvant and/or mixing diluents, and compressed mixture prepares in suitable tablet machine subsequently.The example of adjuvant or diluent comprises: corn starch, lactose, Pulvis Talci, magnesium stearate, gelatin, lactose, natural gum etc.Any other adjuvant or additives that can be compatible with active component, for example toner, aromatic, antiseptic etc. all can use.
The appropriate formulations form of gaboxadol is recorded among the WO 02/094225 that the applying date is on May 17th, 2002.
Any aspect or the specific embodiment that should be appreciated that present patent application do not attempt to limit by any way the present invention, it be herein medicament or the suitable embodiment of pharmaceutical composition.
The administration of the typical through port oral dosage form of gaboxadol, for example solid oral dosage form is typically tablet or capsule, perhaps as the liquid oral dosage form administration.The gaboxadol most convenient be by the oral unit dosage form administration, for example tablet or capsule, the amount of its contained active component is from about 0.1 to about 150mg/ day, for example from about 0.1 to about 100mg/ day, typically from about 0.5 to about 50mg/ day, preferably from about 2.5 to about 20mg/ days, for example from about 5 to about 15mg/ days.The amount of gaboxadol adopts the form of free alkali to calculate.
Gaboxadol can be used as single medicine treatment or with the mode administration of other drug therapeutic alliance.Especially, gaboxadol can be united with 5-hydroxy tryptamine reuptake inhibitor as described below.
The associating of gaboxadol and 5-hydroxy tryptamine reuptake inhibitor
In addition, gaboxadol can be used to strengthen and provide the therapeutic effect generation of 5-hydroxy tryptamine reuptake inhibitor, particularly citalopram (citalopram) and escitalopram (escitalopram) faster.
Wonderful discovery gaboxadol can be used to strengthen and provide the therapeutic effect generation of 5-hydroxy tryptamine reuptake inhibitor faster.
On the one hand, the present invention relates to gaboxadol is used for causing the chemical compound of extracellular 5-hydroxy tryptamine level rising to unite the application of the pharmaceutical composition of use with 5-hydroxy tryptamine reuptake inhibitor or any other in preparation.
On the other hand, the present invention relates to gaboxadol is used for strengthening and/or provides the pharmaceutical composition that 5-hydroxy tryptamine reuptake inhibitor faster or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise produce in preparation application.
Aspect further, the present invention relates to a kind of pharmaceutical composition or test kit, it comprises gaboxadol and a kind of chemical compound, described chemical compound can be 5-hydroxy tryptamine reuptake inhibitor or any other chemical compound that can cause extracellular 5-hydroxy tryptamine level to raise, and optional pharmaceutically acceptable carrier or diluent.
Aspect further, the present invention relates to chemical compound that a kind of treatment can cause extracellular 5-hydroxy tryptamine level to raise to 5-hydroxy tryptamine reuptake inhibitor or any other and produce the disease of replying or the method for obstacle (disorders), individual administration gaboxadol and 5-hydroxy tryptamine reuptake inhibitor that it comprises this treatment of needs, the chemical compound that perhaps can cause extracellular 5-hydroxy tryptamine level to raise.
Aspect further, the present invention relates to gaboxadol and a kind of chemical compound and be used for the treatment of application in the pharmaceutical composition that the therapeutic effect that can cause the chemical compound that extracellular 5-hydroxy tryptamine level raises to 5-hydroxy tryptamine reuptake inhibitor or any other produces the disease of replying or obstacle in preparation, described chemical compound is 5-hydroxy tryptamine reuptake inhibitor or any other chemical compound that can cause extracellular 5-hydroxy tryptamine level to raise.
Aspect further, the present invention relates to gaboxadol and be used for the treatment of those in preparation and prepare accept or accepting application in the pharmaceutical composition of individuality that 5-hydroxy tryptamine reuptake inhibitor or any other can cause the compounds for treating that extracellular 5-hydroxy tryptamine level raises, wherein said individuality suffers from 5-hydroxy tryptamine reuptake inhibitor or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise is produced the disease or the obstacle of replying.
Aspect further, the present invention relates to gaboxadol and a kind of chemical compound and be used for the treatment of application in the test kit that the compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise to 5-hydroxy tryptamine reuptake inhibitor or any other produces the disease of replying or obstacle in preparation, wherein said chemical compound is for being 5-hydroxy tryptamine reuptake inhibitor or any other chemical compound that can cause extracellular 5-hydroxy tryptamine level to raise.
Aspect further, a kind of method that is used to strengthen and/or provides 5-hydroxy tryptamine reuptake inhibitor faster or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise to produce is provided, comprises those are prepared to accept or accepting the individual administration gaboxadol that 5-hydroxy tryptamine reuptake inhibitor or any other can cause the compounds for treating that extracellular 5-hydroxy tryptamine level raises.This class is individual to be the people preferably, sex for example, child, adult or old man.
In one embodiment, the chemical compound that the 5-hydroxy tryptamine reuptake inhibitor maybe can cause extracellular 5-hydroxy tryptamine level to raise is used to treat depression, anxiety disorder and other affective disorder, eating disorder, polyphagia for example, apositia and obesity, phobia, dysthymia, premenstrual syndrome, cognitive disorder, impulse control disorder, attention-deficient superfunction disease and drug dependence, especially depression.
In embodiment further, the chemical compound that the 5-hydroxy tryptamine reuptake inhibitor maybe can cause extracellular 5-hydroxy tryptamine level to raise is used to treat anxiety disorder, it comprises generalized anxiety disorder, panic anxiety, obsession, acute stress disorder, posttraumatic stress disorder or social anxiety disorder.
In embodiment further, the 5-hydroxy tryptamine reuptake inhibitor is selected from: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), Sertraline (sertraline), paroxetine (paroxetine), fluvoxamine (fluvoxamine), venlafaxine (venlafaxine), duloxetine (duloxetine), dapoxetine, nefazodone (nefazodone), imipramine (imipramin), any pharmaceutically acceptable salt of Fa Mokexiting (femoxetine) and clomipramine (clomipramine) or these chemical compounds.Only this explanation, above-mentioned every kind of 5-hydroxy tryptamine reuptake inhibitor mentioning especially is as the discrete specific embodiment.Therefore, the prescription that any and its application in them can be independent is claimed.
In embodiment further, the 5-hydroxy tryptamine reuptake inhibitor is a selectivity 5-hydroxy tryptamine reuptake inhibitor (SSRI).
In embodiment further, the pharmaceutical composition of preparation or test kit are applicable to the active component of administration simultaneously.In one embodiment, described active component is included in the identical unit dosage forms.
In further embodiment, the pharmaceutical composition of preparation or test kit are applicable to sequenced administration active component.In one embodiment, described active component is included in the isolating unit dosage forms.
Further, the present invention relates to gaboxadol can cause the chemical compound of extracellular 5-hydroxy tryptamine level rising to unite application in the pharmaceutical composition of use at preparation and 5-hydroxy tryptamine reuptake inhibitor or any other.
Particularly, the present invention relates to gaboxadol is used for strengthening and/or provides the pharmaceutical composition that 5-hydroxy tryptamine reuptake inhibitor faster or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise produce in preparation application.
More particularly, the present invention relates to gaboxadol as indicated above and treating depression with 5-hydroxy tryptamine reuptake inhibitor or any other chemical compound that can cause extracellular 5-hydroxy tryptamine level to raise, anxiety disorder and other affective disorder, generalized anxiety disorder for example, panic anxiety, obsession, acute stress disorder, posttraumatic stress disorder and social anxiety disorder, eating disorder, for example polyphagia, apositia and obesity, phobia, dysthymia, premenstrual syndrome, cognitive disorder, impulse control disorder, the application in attention-deficient superfunction disease and drug dependence, the especially depression.
Above-mentioned anxiety disorder comprises generalized anxiety disorder, panic anxiety, obsession, acute stress disorder, posttraumatic stress disorder or social anxiety disorder.
As used herein, term strengthens (angmenting) and comprises and improve therapeutic effect and/or strengthen the therapeutic effect that SRI maybe can cause the chemical compound that extracellular 5-HT level raises.
In further embodiment, the present invention relates to gaboxadol and 5-hydroxy tryptamine reuptake inhibitor chemical compound, maybe can cause chemical compound that extracellular 5-hydroxy tryptamine level raises to be used for the treatment of application in the pharmaceutical composition that 5-hydroxy tryptamine reuptake inhibitor or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise is produced the disease of replying or disfunction in preparation.
In further embodiment, the present invention relates to gaboxadol and 5-hydroxy tryptamine reuptake inhibitor chemical compound, maybe can cause chemical compound that extracellular 5-hydroxy tryptamine level raises to be used for the treatment of application in the component test kit (kit-of-parts) (test kit) that 5-hydroxy tryptamine reuptake inhibitor or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise is produced the disease of replying or disfunction in preparation.
The 5-hydroxy tryptamine reuptake inhibitor is produced the disease of replying to be comprised: depression, anxiety disorder and other affective disorder, eating disorder, for example polyphagia, apositia and obesity, phobia, dysthymia, premenstrual syndrome, cognitive disorder, impulse control disorder, attention-deficient superfunction disease and drug dependence, especially depression.
The term anxiety disorder as hereinbefore defined.
In one embodiment, the present invention relates to the application of gaboxadol in preparation pharmaceutical composition as indicated above, it is applicable to the active component of administration simultaneously.Particularly, described pharmaceutical composition can contain active component in same unit dosage forms, for example in same tablet or capsule.This unit dosage forms can or contain active component with the form of homogeneous mixture in the partition that separates of unit dosage forms.
In another embodiment, the present invention relates to gaboxadol and preparing pharmaceutical composition as indicated above or the application in the test kit, it is applicable to the sequential administration active component.Particularly, this pharmaceutical composition can contain active component in isolating unit dosage forms, for example contains the independent tablet or the capsule of arbitrary active component respectively.The isolating unit dosage forms of this class can be comprised in same container or the packing, for example in the blister-pack.
As described herein, the term test kit is meant the pharmaceutical composition that contains every kind of active component, but in isolating unit dosage forms.
The invention still further relates to a kind of pharmaceutical composition or test kit, it comprises gaboxadol and 5-hydroxy tryptamine reuptake inhibitor chemical compound, or any other chemical compound that can cause extracellular 5-HT level to raise, and optional pharmaceutically acceptable carrier or diluent.
As indicated above, pharmaceutical composition of the present invention or test kit are applicable to while administration active component or be used for the sequential administration active component.
At last, the present invention relates to chemical compound that a kind of treatment can cause extracellular 5-hydroxy tryptamine level to raise to 5-hydroxy tryptamine reuptake inhibitor or any other and produce the disease of replying or the method for disfunction, comprise individual administration gaboxadol and 5-hydroxy tryptamine reuptake inhibitor, the chemical compound that maybe can cause extracellular 5-HT level to raise to the needs treatment.
Particularly, a kind of method that is used to strengthen and/or provides 5-hydroxy tryptamine reuptake inhibitor faster or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise to produce is provided, comprises preparing to accept or accepting the individual administration gaboxadol that 5-hydroxy tryptamine reuptake inhibitor or any other can cause the compounds for treating that extracellular 5-hydroxy tryptamine level raises.
The individuality that those are benefited in can therapeutic alliance from above may suffer from depression, anxiety disorder and other affective disorder, eating disorder, polyphagia for example, apositia and obesity, phobia, premenstrual syndrome, dysthymia, cognitive disorder, impulse control disorder, attention-deficient superfunction disease and drug dependence, especially depression.
As indicated above, anxiety disorder comprises generalized anxiety disorder, panic anxiety, obsession, acute stress disorder, posttraumatic stress disorder or social anxiety disorder.
As indicated above, the administration simultaneously of gaboxadol and 5-hydroxy tryptamine reuptake inhibitor.
Selectable, but described active component sequential administration is for example, as indicated above in two kinds of isolating unit dosage forms.
At present, compare with individually dosed 5-hydroxy tryptamine reuptake inhibitor, wonderful discovery gaboxadol and 5-hydroxy tryptamine reuptake inhibitor co-administered can be predicted animal model at antidepressant effect, produce replying of significantly increasing in the experiment of mice forced swimming.
As indicated above, the effect that the 5-hydroxy tryptamine reuptake inhibitor shows postponement produces.Even in the SSRIs respondent, also need the treatment in several weeks could realize sx.Gaboxadol can realize that 5-hydroxy tryptamine reuptake inhibitor therapeutic effect produces faster.
Gaboxadol and 5-hydroxy tryptamine reuptake inhibitor are united the amount that use can significantly reduce the required 5-hydroxy tryptamine reuptake inhibitor of treatment depression and other affective disorder, therefore can reduce the side effect that the 5-hydroxy tryptamine reuptake inhibitor brings.Particularly, the associating of the SRI of reduction and gaboxadol can reduce sexual disorder that SSRI causes and sleep disordered risk.
Gaboxadol and 5-hydroxy tryptamine reuptake inhibitor administration altogether also can be used for treating refractory depression disease, and promptly those are through the individually dosed depression that can't appropriately treat of 5-hydroxy tryptamine reuptake inhibitor.Typically, gaboxadol is used among the patient that can't realize 40-60% sx at least in those initial 6 weeks of adopting the SRI treatment and strengthens the enhancing treatment (add-on therapy) that SRIs is replied.
Typically, gaboxadol can acid-addition salts, or amphion hydrate or amphion dehydrate form are used.In embodiment further, gaboxadol uses with the pharmaceutically-acceptable acid addition form, and described salt is selected from hydrochlorate or hydrobromate, or uses with amphion monohydrate form.Most convenient, gaboxadol uses with crystal form.
Many have the 5-hydroxy tryptamine reuptake to suppress the antidepressant of effect on the books in the literature.Fetch the potentiation that any pharmacologically active chemical compounds main or its therapeutic effect of performance partly all can have benefited from gaboxadol by the 5-hydroxy tryptamine rephotography that suppresses central nervous system (CNS).
Many 5-hydroxy tryptamine reuptake inhibitors that have benefited from the potentiation of gaboxadol have been comprised in listing down: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), R-fluoxetine (R-fluoxetine), Sertraline (sertraline), paroxetine (paroxetine), fluvoxamine (fluvoxamine), venlafaxine (venlafaxine), duloxetine (duloxetine), dapoxetine, nefazodone (nefazodone), imipramine (imipramin), imipramine N oxide (imipramin N-oxide), desipramine (desipramine), pirandamine (pirandamine), HRP-543 (dazepinil), nefopam (nefopam), befuraline (befuraline), fezolamine (fezolamine), Fa Mokexiting (femoxetine), clomipramine (clomipramine), cianoimipramine, litoxetine, cericlamine (cericlamine), seproxetine, WY 27587, WY 27866, imeldine, ifoxetine (ifoxetine), tiflucarbine (tiflucarbine), viqualine (viqualine), midalcipran (milnacipran), bazinaprine (bazinaprine), YM 922, S 33005, F 98214-TA, OPC 14523, alaproclate (alaproclate), cyanodothepine, trimeprimine (trimipramine), quinupramine (quinupramine), dosulepin (dothiepin), amoxapine (amoxapine), nitroxazepine, McN 5652, and McN 5707, O177, Org 6582, Org 6997, and Org 6906, amitriptyline (amitriptyline), amitriptyline N oxide (amitriptyline N-oxide), nortriptyline (nortriptyline), CL 255.663, pirlindole (pirlindole), indatraline (indatraline), LY 113.821, and LY 214.281, CGP 6085 A, RU 25.591, napamezole (napamezole), dinitrogen is put forth energy emerging (diclofensine), trazodone (trazodone), EMD 68.843, BMY 42.569, and NS 2389, Sercloremine (sercloremine), nitroquipazine, ademetionine (ademethionine), sibutramine (sibutramine), clovoxamine (clovoxamine), desmethylsubitramine, didesmethylsubitramine, clovoxamine vilazodone (clovoxamine vilazodone)
N-[(1-[(6-fluoro-2-naphthalene) methyl]-the 4-piperidyl] amino] carbonyl]-3-pyridine carbonyl amide, [trans-6-(2-chlorphenyl)-1,2,3,5,6,10b-hexahydro pyrrolo--(2,1-a) different Kui quinoline] (McN 5707),
(outside racemization-4--amino-8-chloro-benzo-(b)-bicyclo-[3.3.1] nine-2-6 α (10 α)-diene hydrochlorate) (Org 6997),
(racemization)-(5 α, 8 α, 9 α)-5,8,9,10-tetrahydrochysene-5,9-methylene benzo cyclo-octene-8-amine hydrochlorate (Org 6906),
-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1 (2H)-pyridine radicals] ethyl]-3-isopropyl-6-(sulfonyloxy methyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558), [4-(5,6-dimethyl-2-benzofuranyl)-piperidines] (CGP 6085)
Dimethyl-[5-(4-nitro-phenoxy group)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-7-yl]-amine (RU 25.591),
Above-claimed cpd can alkali or pharmaceutically acceptable salt, and for example the form of its acid-addition salts is used.Every kind of above-mentioned 5-hydroxy tryptamine reuptake inhibitor is independent embodiment.Therefore, its each with its purposes all can be independent prescription claimed.
Other can have benefited from the gaboxadol potentiation therapeutic compound, be not the 5-hydroxy tryptamine reuptake inhibitor though comprise those, the chemical compound that can cause 5-hydroxy tryptamine level in extracellular in the synaptic cleft to raise.One of this compounds is a Tianeptine.
Above-mentioned 5-hydroxy tryptamine reuptake inhibitor and other can cause the tabulation of the chemical compound of extracellular 5-hydroxy tryptamine level rising cannot be interpreted as restrictive.
In one embodiment, SRIs is selected from: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), Sertraline (sertraline), paroxetine (paroxetine), fluvoxamine (fluvoxamine), duloxetine (duloxetine), venlafaxine (venlafaxine), duloxetine (duloxetine), dapoxetine, nefazodone (nefazodone), imipramine (imipramin), femoxetine and clomipramine (clomipramine).Only this explanation, every kind of SRIs all constitutes independent embodiment, and can be used as the protection theme of indivedual claim.
Selection of terms 5-hydroxy tryptamine reuptake inhibitor (SSRI) is meant the inhibitor of monoamine transporter, and with dopamine and noradrenaline transporter bulk phase ratio, it has stronger inhibitory action to the 5-hydroxy tryptamine transporter.
Selectivity 5-hydroxy tryptamine reuptake inhibitor (SSRIs) is a member in the used most preferred 5-hydroxy tryptamine reuptake inhibitor of the present invention.Therefore, in further embodiment, described SRI is selected among the SSRIs, for example: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), fluvoxamine (fluvoxamine), Sertraline (sertraline), or paroxetine (paroxetine).
Active component of the present invention, for example can the dissociate form of base or the form of its pharmaceutically-acceptable acid addition of gaboxadol and the SRI chemical compound that maybe can cause the outer 5-hydroxy tryptamine level of born of the same parents to raise used, and the latter prepares by alkali form and suitable acid reaction.
Citalopram (citalopram) preferably uses with the form of hydrobromate or alkali, escitalopram (escitalopram) uses with the form of oxalates, fluoxetine (fluoxetine), Sertraline (sertraline) and paroxetine (paroxetine) use with the form of hydrochlorate, and fluvoxamine (fluvoxamine) uses with the form of maleate.
As indicated above, the associating of gaboxadol and 5-hydroxy tryptamine reuptake inhibitor shows the synergism to CNS unexpectedly.Consequently, gaboxadol is with more the therapeutic alliance of the 5-hydroxy tryptamine reuptake inhibitor of low dosage can be very effective than conventional use amount in the single therapy, and the side effect that the more substantial 5-hydroxy tryptamine reuptake inhibitor of use causes in the single medicine treatment simultaneously can alleviate or prevent fully.
In addition, the therapeutic alliance of gaboxadol and the 5-hydroxy tryptamine reuptake inhibitor that adopts routine dose has at the conventional single medicine of those usually a large amount of employing SSRIs and treats the advantage that can obtain effective CNS effect among the unresponsive patient.
The amount of the gaboxadol that uses in therapeutic alliance can be in about 0.1 to about 150mg/ day scope, for example from about 0.1 to about 100mg/ day, and from about 0.5 to about 50mg/ day, from about 5 to about 50mg/ days, or from about 1 to about 5mg/ day scope.The gaboxadol and the 5-hydroxy tryptamine reuptake inhibitor that sleep disorder are not had the low dosage of remarkable result, for example escitalopram (escitalopram) therapeutic alliance demonstrates clear and definite and significant effect.Low dosage typically is selected from about 0.1 to about 2.5mg/ day, and for example from about 0.1 to about 2.0mg/ day, and more high dose typically is selected from about 2.5 to about 150mg/ days.
The 5-hydroxy tryptamine reuptake inhibitor comprises the above-mentioned SSRIs that mentions especially, its molecular weight and active aspect all there are differences.Thereby the amount of the 5-hydroxy tryptamine reuptake inhibitor that uses in therapeutic alliance is decided on the characteristic of described 5-hydroxy tryptamine reuptake inhibitor.In a specific embodiments of the present invention, the 5-hydroxy tryptamine reuptake inhibitor maybe can cause the chemical compound of extracellular 5-HT level rising to be lower than the amount administration that described chemical compound uses required dosage separately.In another embodiment, described 5-hydroxy tryptamine reuptake inhibitor maybe can cause the chemical compound of extracellular 5-HT level rising with the routine dose administration.
In order to prepare pharmaceutical composition of the present invention, the active component and the pharmaceutically acceptable carrier that are the appropriate amount of salt form or alkali form are mixed into immixture, and it can take various forms according to the difference of the required dosage form of administration.These pharmaceutical compositions can be suitable for oral, rectum, through skin or through the ideal unit dosage forms of non-intestinal drug administration by injection.For example, be in the compositions of oral dosage form in preparation, the drug media of any routine all can adopt, and for example, for instance at oral liquid, for example can adopt water, ethylene glycol, oil, ethanol etc. in suspension, syrup, elixir and the solution; Perhaps in powder, pill, capsule and tablet, can adopt solid carrier for example starch, sugar, Kaolin, lubricant, binding agent, disintegrating agent etc.Because its easy administration, tablet and capsule are represented best oral dosage unit form, obviously adopt solid pharmaceutical carriers in this case.
Aforementioned pharmaceutical compositions is useful especially to be easy to that the administration unit dosage forms consistent with dosage prepare.As employed in description and the claim, unit dosage forms (unit dosageform) is meant the physically discrete unit that is suitable as unit dose, contain the active component that can produce the scheduled volume of ideal therapeutic effect as calculated in the per unit, it mixes mutually with required pharmaceutical carrier.The example of this dosage unit form is that amount of tablet (comprising indentation or overlay film tablet), capsule, pill, powder bag, disk, Injectable solution or suspension, teaspoonful, a soupspoon etc. and its are repeatedly isolating.
Gaboxadol can be before the administration of 5-hydroxy tryptamine reuptake inhibitor, in the process, or administration afterwards, prerequisite is that gaboxadol administration and 5-hydroxy tryptamine reuptake inhibitor time of administration allow composition that CNS is produced synergism at interval.When while administration gaboxadol and 5-hydroxy tryptamine reuptake inhibitor, a kind of compositions that contains 5-hydroxy tryptamine reuptake inhibitor and gaboxadol may be convenient especially.Selectable, the composition forms that gaboxadol and 5-hydroxy tryptamine reuptake inhibitor can be suitable administration respectively.Described compositions can prepare according to mentioned above.
The present invention also comprises the product that contains gaboxadol and 5-hydroxy tryptamine reuptake inhibitor, and it is used for simultaneously, independent or sequenced is applied to the treatment of psychosis medicine as combination formulations.This product can comprise, for example, comprises independent unit dosage forms that contains gaboxadol and the test kit that contains the independent unit dosage forms of 5-hydroxy tryptamine reuptake inhibitor, and it all is included in identical container or packing, for example in the blister-pack.
The above-mentioned preparation of mentioning that is used for while or sequential administration can not contain the 5-hydroxy tryptamine reuptake inhibitor and contain the chemical compound that other can cause extracellular 5-HT level to raise.
The pharmacological evaluation of gaboxadol depression effect
(Chronic mild stress, CMS) model has the very forecasting accuracy of high level (Willner (1997), Psychopharmacol 134:319-329) for antidepressant activity to the rat chronic moderate pressure of depression.In addition, this method is the appropriate model (Behavioural Pharmacology 14:465-470,2003, S á nchez, C. etc.) that antidepressant activity tells in zoologizeing.The principle of this model is based on the dependency between pressure and the affective disorder.The sensitivity that the rat that suffers from chronic pressure shows rewarding (for example, good to eat sucrose solution) reduces.
The experimental technique of chronic moderate pressure
On-test the first two months (Gorzkowska Warsaw) brings laboratory into male Wistar rat.Described animal is raised separately one by one, and water and food are freely taken in, and except hereinafter described, keeps 12h light/dark cycle, 22 ± 2 ℃ of temperature.
At first animal training consumes 1% sucrose solution; Training is made of 8 1h baseline experiments, the sucrose of in experimentation, feeding in the mouse cage, and following does not provide water and food by 14h; By when experiment finishes, those sucrose solution bottles that fill of having weighed in advance of weighing are measured intake.Subsequently, under similar condition, the sugar consumption amount in the monitoring whole experiment.Sucrose intake according in its baseline experiment in the end is divided into two coupling groups with animal.One treated animal carries out chronic moderate pressure process, continues 8 continuous weeks.Pressure scheme weekly is made of following: the not fed food or the water in 2 cycles, mouse cage 45 degree tilt, intermittent illumination (every 2h turns on light and turns off the light once), the cage (in the sawdust batts, spilling 250ml water) of making dirty, with two no pressure that place a cage and low intensive stroboscopic illumination (150 dodge/minute) and 2 cycles.All stressor all continue 10-14h and independent and successive application night and day.Other treated animals, no pressure contrast is raised in other room, and is not contacted with the animal that is stressed.Before each sucrose experiment, animal is fed food and water 14h not, and still food and water can freely be taken in cage in addition.Behind experience 3 all pressure, take in score according to its sucrose, pressure and control animal are divided into the coupling subgroup, and it accepts the peritoneum medicine injection (about 10.00 and 17.00) of twice every day in 5 weeks subsequently.10 of mornings on weekly basis are carried out (Tuesday) in sucrose experiment.Not animal (n=8) administration excipient (1ml/kg every day) on the same group or experiment medicine.Before experimental session, medicine administration when about 10.00h, and carry out the sucrose experiment of 24h after the medicine injection formerly.In whole treatment cycle, continue to keep-up pressure.And body weight is evaluated a baseline at the Drug therapy end.
Chronic moderate pressure result
The gaboxadol experiment shows that this chemical compound has remarkable depression sample effect in the rat chronic moderate pressure model.In this model, the dosage of 2.5mg/kg every day has clear and definite and significant effect.
Gaboxadol and escitalopram (escitalopram) unite use
Activity for the system that regulates and control to be responsible for antidepressant activity, we suppress behavior model at the 5-hydroxy tryptamine reuptake, mice 5-HTP strengthens experiment, model with the prediction antidepressant activity, the interaction of research gaboxadol and escitalopram (a kind of SSRI) in the mice forced swimming experiment (referring to C.S á nchez etc., Psychopharmacology (2003), 167:353-362).
Experimental procedure
Select male NMRI/BOM mice (18-25g for use; Bomholtgaard, Denmark).Mice is raised in plastics cage (35 * 30 * 12cm), 10 in every cage makes it be familiar with animal facility in experiment at least the last week.Room temperature (21 ± 2 ℃), relative humidity (55 ± 5%), and auto-control air exchange (per hour 16 times).Animal can freely be taken in commercial food particle and tap water before experiment.
5-HTP-induces the reinforcement of behavior
In the document that is recorded in Hyttel etc. that the experimental procedure of mice study is detailed (1992).Briefly, after the experimental compound s.c. administration 30 minutes, to mice administration 5-HTP (100mg/kg, i.v.).Estimate the stereotypy (movement outside) of animal in the cage subsequently in the 15-min observation period, vibration and hind leg abduction.A kind of symptom occurs and then give one fen.Each dosage adopts 8-16 mice altogether.
The inhibition of the not kinestate that forced swimming causes
The mice that is compelled to swim in the container of a limited space will show typically not athletic posture.Adopt antidepressant to treat in advance and will offset this effect.According to S á nchez and Meier document (Psychopharmacol 129:197-205; 1997) write up in experimentizes.Briefly, adopt one to have the full-automatic experimental system of 6 swimming unit (fill the 2000ml glass jar of 1200ml addle (23-25 ℃), wherein mouse is put in advance).Estimate not kinestate by image analysis.Medicine or excipient treatment mice is after 30 minutes, puts it in the glass jar and allows mice keep in water 6 minutes altogether.Measured the not exercise duration of accumulative total in the end 3 minutes.Each dosage amounts to 9-18 mice.
The result
Strengthen in the experiment at 5-HTP, the intensive acute effect that strengthens escitalopram (escitalopram) (0.5 to 0.025mg/kg) of gaboxadol (2.5mg/kg), and the gaboxadol dosage (2.5mg/kg) that itself not have to act in forced swimming experiment has significantly strengthened the antidepressant sample effect of escitalopram (escitalopram) (2.5 and 5mg/kg).
Claims (46)
1. a method for the treatment of depression comprises the gaboxadol to the pharmaceutically acceptable amount of individual administration of needs treatment.
2. the method for claim 1, wherein gaboxadol is acid-addition salts, or the form of amphion hydrate or amphion dehydrate.
3. any described method among the claim 1-2, wherein gaboxadol is the pharmaceutically-acceptable acid addition form that is selected from hydrochlorate or hydrobromate, or is the form of amphion monohydrate.
4. any described method among the claim 1-3, wherein said pharmaceutically acceptable amount be at 2.5mg to 20mg, for example in the scope of 5mg to 15mg gaboxadol every day.
5. any described method among the claim 1-4, wherein gaboxadol is with the peroral dosage form administration.
6. any described method among the claim 1-5, wherein gaboxadol is solid oral dosage form, for example tablet or capsule, or liquid oral dosage form.
7. any described method among the claim 1-6, wherein said gaboxadol is crystallization.
8. any described method among the claim 1-7, wherein said individuality is the people.
9. gaboxadol is used for the treatment of application in the pharmaceutical composition of depression in preparation.
10. the described application of claim 9, wherein gaboxadol is acid-addition salts, or the form of amphion hydrate or amphion dehydrate.
11. any described application among the claim 9-10, wherein gaboxadol is the pharmaceutically-acceptable acid addition form that is selected from hydrochlorate or hydrobromate, or is the form of amphion monohydrate.
12. any described application among the claim 9-11, wherein said pharmaceutical composition comprises 2.5mg to 20mg, for example the gaboxadol of 5mg to 15mg.
13. any described application among the claim 9-12, wherein gaboxadol is peroral dosage form.
14. any described application among the claim 9-13, wherein gaboxadol is solid oral dosage form, for example tablet or capsule, or liquid oral dosage form.
15. any described application among the claim 9-14, wherein said gaboxadol is crystallization.
16. any described application among the claim 9-15, wherein said pharmaceutical composition is used for the treatment of the people who suffers from depression.
17. gaboxadol is used for causing the chemical compound of extracellular 5-hydroxy tryptamine level rising to unite the application of the pharmaceutical composition of use with 5-hydroxy tryptamine reuptake inhibitor or any other in preparation.
18. gaboxadol is used for strengthening and/or provides the application of the pharmaceutical composition that 5-hydroxy tryptamine reuptake inhibitor faster or any other compounds for treating effect that can cause extracellular 5-hydroxy tryptamine level to raise produce in preparation.
19. gaboxadol is used for the treatment of the application of prepare accepting or accepting in the pharmaceutical composition of individuality that 5-hydroxy tryptamine reuptake inhibitor or any other can cause the compounds for treating that extracellular 5-hydroxy tryptamine level raises in preparation, wherein said individuality suffers from and can cause the therapeutic effect of the chemical compound that extracellular 5-hydroxy tryptamine level raises to produce the disease or the obstacle of replying to 5-hydroxy tryptamine reuptake inhibitor or any other.
20. any described application among the claim 17-19, wherein the 5-hydroxy tryptamine reuptake inhibitor maybe can cause the chemical compound of extracellular 5-hydroxy tryptamine level rising to be used to treat depression, anxiety disorder and other affective disorder, eating disorder, polyphagia for example, apositia and obesity, phobia, dysthymia, premenstrual syndrome, cognitive disorder, impulse control disorder, attention-deficient superfunction disease and drug dependence.
21. the described application of claim 20, wherein the 5-hydroxy tryptamine reuptake inhibitor maybe can cause the chemical compound of extracellular 5-hydroxy tryptamine level rising to be used to the treatment of depression.
22. any described application in the claim 17 to 21, wherein said 5-hydroxy tryptamine reuptake inhibitor is selected from: citalopram, escitalopram, fluoxetine, Sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, any pharmaceutically acceptable salt in Fa Mokexiting and clomipramine or these chemical compounds.
23. any described application in the claim 17 to 22, wherein said 5-hydroxy tryptamine reuptake inhibitor is a selectivity 5-hydroxy tryptamine reuptake inhibitor.
24. any described application in the claim 17 to 23, wherein gaboxadol is acid-addition salts, or the form of amphion hydrate or amphion dehydrate.
25. any described application in the claim 17 to 24, wherein gaboxadol is the pharmaceutically-acceptable acid addition form that is selected from hydrochlorate or hydrobromate, or is the form of amphion monohydrate.
26. any described application among the claim 17-25, wherein said pharmaceutical composition comprise the gaboxadol of measuring between about 0.1 to about 2.5mg.
27. any described application among the claim 17-25, wherein said pharmaceutical composition comprise from about 2.5mg to the gaboxadol of measuring between about 20mg.
28. any described application among the claim 17-27, wherein gaboxadol is a peroral dosage form.
29. any described application among the claim 17-28, wherein the 5-hydroxy tryptamine reuptake inhibitor chemical compound that maybe can cause extracellular 5-hydroxy tryptamine level to raise is a peroral dosage form.
30. the described application of claim 28, wherein gaboxadol is solid oral dosage form, for example tablet or capsule, or liquid oral dosage form.
31. the chemical compound that the described application of claim 29, wherein said 5-hydroxy tryptamine reuptake inhibitor maybe can cause extracellular 5-hydroxy tryptamine level to raise is solid oral dosage form, for example tablet or capsule, or liquid oral dosage form.
32. any described application among the claim 17-31, wherein gaboxadol is crystallization.
33. any described application among the claim 17-32, wherein said pharmaceutical composition are suitable for gaboxadol and the administration simultaneously of 5-hydroxy tryptamine reuptake inhibitor.
34. any described application among the claim 17-33, wherein gaboxadol and 5-hydroxy tryptamine reuptake inhibitor are comprised in the same unit dosage forms.
35. any described application among the claim 17-34, wherein said pharmaceutical composition is suitable for gaboxadol and 5-hydroxy tryptamine reuptake inhibitor sequential administration.
36. a pharmaceutical composition, it comprises gaboxadol and 5-hydroxy tryptamine reuptake inhibitor chemical compound, or any other chemical compound that can cause extracellular 5-hydroxy tryptamine level to raise, and optional pharmaceutically acceptable carrier or diluent.
37. the described pharmaceutical composition of claim 36 is characterized in that described 5-hydroxy tryptamine reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, Sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, any pharmaceutically acceptable salt in Fa Mokexiting and clomipramine or these chemical compounds.
38. any described pharmaceutical composition among the claim 36-37, it is suitable for administration gaboxadol and 5-hydroxy tryptamine reuptake inhibitor simultaneously.
39. any described pharmaceutical composition among the claim 36-38, wherein gaboxadol and 5-hydroxy tryptamine reuptake inhibitor are comprised in the same unit dosage forms.
40. any described pharmaceutical composition among the claim 36-39, wherein gaboxadol is acid-addition salts, or the form of amphion hydrate or amphion dehydrate.
41. any described pharmaceutical composition among the claim 36-40, wherein gaboxadol is the pharmaceutically-acceptable acid addition form that is selected from hydrochlorate or hydrobromate, or is the form of amphion monohydrate.
42. any described pharmaceutical composition among the claim 36-41, wherein the amount of gaboxadol is to about 2.5mg from about 0.1.
43. any described pharmaceutical composition among the claim 36-41, wherein the amount of gaboxadol is to about 20mg from about 2.5.
44. any described pharmaceutical composition among the claim 36-43, wherein gaboxadol is a peroral dosage form, solid oral dosage form for example, for example tablet or capsule, or liquid oral dosage form.
45. any described pharmaceutical composition among the claim 36-44, wherein said 5-hydroxy tryptamine reuptake inhibitor is a peroral dosage form, solid oral dosage form for example, for example tablet or capsule, or liquid oral dosage form.
46. any described pharmaceutical composition among the claim 36-45, wherein gaboxadol is crystallization.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200300956 | 2003-06-25 | ||
| DKPA200300956 | 2003-06-25 | ||
| DKPA200400016 | 2004-01-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101801789A Division CN101156850A (en) | 2003-06-25 | 2004-06-25 | Treatment of depression and other affective disorders |
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| Publication Number | Publication Date |
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| CN1809350A true CN1809350A (en) | 2006-07-26 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800175886A Pending CN1809350A (en) | 2003-06-25 | 2004-06-25 | Aboxadol for treating depression and other affective disorders |
| CNA2007101801789A Pending CN101156850A (en) | 2003-06-25 | 2004-06-25 | Treatment of depression and other affective disorders |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2007101801789A Pending CN101156850A (en) | 2003-06-25 | 2004-06-25 | Treatment of depression and other affective disorders |
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| CN (2) | CN1809350A (en) |
| CL (1) | CL2004001603A1 (en) |
| UA (1) | UA90656C2 (en) |
| ZA (1) | ZA200509356B (en) |
Cited By (3)
| 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 |
| CN110996910A (en) * | 2017-05-24 | 2020-04-10 | 奥维德医疗公司 | Treatment of depressive disorders |
| CN113395962A (en) * | 2018-11-21 | 2021-09-14 | Certego治疗公司 | Gaboxadol for reducing suicidal risk and rapidly relieving depression |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190321341A1 (en) * | 2018-04-06 | 2019-10-24 | Ovid Therapeutics, Inc. | Use of gaboxadol in the treatment of substance use disorders |
| EP4153549A2 (en) | 2020-05-20 | 2023-03-29 | Certego Therapeutics Inc. | Ring deuterated gaboxadol and its use for the treatment of psychiatric disorders |
-
2004
- 2004-06-24 CL CL200401603A patent/CL2004001603A1/en unknown
- 2004-06-25 ZA ZA200509356A patent/ZA200509356B/en unknown
- 2004-06-25 CN CNA2004800175886A patent/CN1809350A/en active Pending
- 2004-06-25 UA UAA200600374A patent/UA90656C2/en unknown
- 2004-06-25 CN CNA2007101801789A patent/CN101156850A/en active Pending
Cited By (3)
| 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 |
| CN110996910A (en) * | 2017-05-24 | 2020-04-10 | 奥维德医疗公司 | Treatment of depressive disorders |
| CN113395962A (en) * | 2018-11-21 | 2021-09-14 | Certego治疗公司 | Gaboxadol for reducing suicidal risk and rapidly relieving depression |
Also Published As
| Publication number | Publication date |
|---|---|
| UA90656C2 (en) | 2010-05-25 |
| CL2004001603A1 (en) | 2005-05-27 |
| ZA200509356B (en) | 2007-03-28 |
| CN101156850A (en) | 2008-04-09 |
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