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    • 专利摘要:
    Pharmaceutical composition comprising selective inhibitors of the reuptake of serotonin and galanin (1-15). The present invention relates to the use of galanin (1-15) or a pharmaceutically acceptable salt thereof for use in combination with a serotonin reuptake inhibitor or any other compound that causes a significant increase in the synthesis of postsynaptic 5HT1A receptors. in terminal areas. In particular, the present invention relates to the use of GAL (1-15) or a pharmaceutically acceptable salt thereof useful to increase and/or provide a more rapid onset of the therapeutic effect of a serotonin reuptake inhibitor or any other compound that a significant increase in the synthesis of postsynaptic 5HT1A receptors in terminal areas. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2659092A1
    申请号:ES201730214
    申请日:2017-02-20
    公开日:2018-03-13
    发明作者:Antonio FLORES BURGESS；Carmelo MILLÓN PEÑUELA；Belén GAGO CALDERÓN；Manuel Alejandro NARVÁEZ PELÁEZ；José Ángel NARVÁEZ BUENO；Luis Javier SANTÍN NÚÑEZ；Zaida DÍAZ CABIALE
    申请人:Universidad de Malaga；
    IPC主号:
    专利说明:

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    Pharmaceutical composition comprising selective serotonin reuptake inhibitors and
    galanina (1-15)
    Field of the Invention
    The present invention is framed in the medical field, in particular to a therapeutic use of the combination of selective serotonin and galanin reuptake inhibitors (1-15) for the treatment of depression and related disorders.
    Background of the invention
    Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become the main choice in the treatment of depression, certain forms of anxiety and social phobias, due to their effectiveness, good tolerance since they have a favorable safety profile compared to classic tricyclic antidepressants.
    However, clinical studies on depression and anxiety disorders indicate a substantial non-response of SSRIs of up to 30%. One factor to consider, often neglected, in treatment with antidepressants is compliance with it, which has a profound effect on the patient's motivation to continue pharmacotherapy.
    First, there is a delay in the therapeutic effect of SSRIs. Sometimes the symptoms get worse even during the first weeks of treatment. Second, sexual dysfunction is a common side effect of all SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely.
    In order to cope with the lack of response, psychiatrists sometimes make use of potentiation strategies. The potentiation of antidepressant therapy can be achieved by co-administration of mood stabilizers such as lithium carbonate or triiodothyronine or by the use of electric shock.
    In 1993, Artigas and collaborators described a potentiation strategy with pindolol in Trends Pharmacol. Sci. 1993, 14, p 262-263. The idea of Artigas is based on experiments of intracerebral microdialysis in animals. In fact, subsequent neurochemical studies based on the desensitization hypothesis of Blier et al. Indicated that the delay in the therapeutic effect of antidepressants is related to a gradual desensitization of 5-HT autoreceptors (Blier et al. J. Psycipharmacol. 1987. 7 suppl. 6, 24S-35S). A key point in his hypothesis is that the effects of SSRIs on release-controlling somatodendritic autoreceptors (5-HT1A) limit the release of 5-HT in
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    the terminal areas and, therefore, the effect of inhibition of 5-HT uptake in those regions. This is supported by microdialysis experiments in rats, showing that the increase in extracellular 5-HT caused by a single dose of an SSRI is increased by co-administration of a 5-HT1A self-receptor antagonist (Invernizzi et al. Brain Res, 1992, 584, p 322-324 and Hjorth, S., J. Neurochem, 1993, 60, p 776-779).
    The effect of the combined administration of a compound that inhibits the reuptake of serotonin and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis, RB et al. Eur. J. Pharmacol. 1987, 143, p. 1095- 204 and Gartside, SE, Br. J. Pharmacol, 1995, 115, p 1064-1070, Blier, P. et al. Trends in Pharmacol. Science 1994, 15, 220). In these studies it was found that 5-HT1A receptor antagonists would suppress the initial brake on 5-HT neurotransmission induced by serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a rapid onset of therapeutic action
    Several patent applications covering the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression have been registered (see for example EP-A2-687472 and EP-A2-714663 ).
    Another approach to increase the 5-HT terminal would be by blocking the 5-HT1B autoreceptor. Microdialysis experiments in rats have shown, in fact, that the increase in 5-HT in the hippocampus induced by citalopram is enhanced by GMC 2-29, an experimental 5-HT1B receptor antagonist.
    Several patent applications covering the combination of an SSRI and a 5-HT1B antagonist or partial agonist have also been registered (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).
    It has now been discovered that, surprisingly, a fragment of galanin (GAL), in particular GAL (1-15), which has the general formula Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu- Leu-Gly-Pro-His-Ala or GWTLNSAGYLLGPHA, or a pharmaceutically acceptable salt thereof, is capable of increasing and providing a faster onset of the therapeutic effect of serotonin reuptake inhibitors, in particular fluoxetine (FLX) .
    Brief Description of the Invention
    The present invention relates to the use of GAL (1-15) or a pharmaceutically acceptable salt thereof, in combination with a serotonin reuptake inhibitor or any other compound that causes an increase in the level of extracellular serotonin.
    In particular, the present invention relates to the use of GAL (1-15), or of a pharmaceutically acceptable salt of said fragment, useful for increasing and / or providing a faster onset of the effect.
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    therapeutic of a serotonin reuptake inhibitor or any other compound that causes an increase in the level of extracellular serotonin.
    More particularly, the present invention relates to the aforementioned use of GAL (1-15), or a pharmaceutically acceptable salt of said fragment, for the treatment of depression, anxiety disorders and other affective disorders, of eating disorders such such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, particularly depression, with a serotonin reuptake inhibitor or any other compound that causes an increase in the level of extracellular serotonin.
    Brief description of the figures
    Fig. 1. Behavioral effects of co-administration of an ineffective dose of FLX (2.5mg / Kg) and a subthreshold dose of GAL (1-15) (Inmol) in the forced swim test (in English, forced-swimming test or FST). FLX was administered subcutaneously (sc) 23, 5 and 1 hour before the test and GAL (1-15) was injected intracerebroventricularly (icv) 15 minutes before the test. The data are represented as the mean ± SEM of the immobility, climbing and swimming time in the FST during the 5 min of the test period (n = 8-9 rats per group). * p <0.05 compared to the other groups, a = p <0.05 compared to the control group and GAL (1-15) (1 mol) according to a one-way ANOVA test followed by the Newman multiple comparisons test. Keuls
    Fig. 2. Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and GAL (1-15) (1nmol) or GAL (1nmol) in the FST. FLX was administered sc 23, 5 and 1 hour before the test. Artificial cerebrospinal fluid (CSF), GAL (1-15) and GAL were administered icv 15 minutes before the test. The data are represented as the mean ± SEM of the immobility, climbing and swimming time in the FST during the 5 min of the test period (n = 7-8 rats per group). * p <0.05, ** p <0.01 compared to other groups; #p <0.05 compared to the control group according to a one-way ANOVA test followed by the Newman-Keuls multiple comparisons test.
    Fig. 3A. Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and subthreshold doses of GAL (1-15) (1nmol) in Sprague-Dawley rats to which M871 (3nmol) was also administered, antagonist of GALR2. The FLX or the vehicle (carrier) were administered sc 23, 5 and 1 hour before the test. The CSF, LAG (1-15) and LAG (1-15) + M871 were administered icv 15 min before the test. Data are represented as the mean ± SEM of immobility, climbing and swimming time in the FST during
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    the 5 min of the trial period (n = 7-9 rats per group). #p <0.05, ## p <0.01 compared to FLX10mg (sc) + CSF (icv) and FLX10mg (sc) + GAL (1-15) 1mol + M871 3mol (icv); * p <0.05, ** p <0.01 compared to the control group according to a one-way ANOVA test followed by the Newman-Keuls multiple comparisons test.
    Fig. 3B. Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and subthreshold doses of GAL (1-15) (Inmol) in GALR2 knockdown rats (siGalR2). The FLX or carrier were administered sc 23, 5 and 1 hour before the test. The CSF and LAG (1-15) were administered icv 15 min before the test. The data are represented as the mean ± SEM of the immobility, climbing and swimming time in the FST during the 5 min of the test period (n = 7-9 rats per group). #p <0.05, ## p <0.01 compared to FLX10mg (sc) + CSF (icv) and with FLX10mg (sc) + GAL (1-15) Inmol (icv); * p <0.05, ** p <0.01 versus the control group according to a one-way ANOVA test followed by the Newman-Keuls multiple comparisons test.
    Fig. 4. (a) GALR1 protein expression eight days after a single injection of the GALR1 siRNA (siRNA) or carrier vehicle in the rat's brain. The data are represented as mean ± SEM of the percentages with respect to the control value (100 &) of the optical density (D.O) * p <0.05 according to the t-Student test. (b) Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and the sub-threshold dose of GAL (1-15) (Inmol) in Knocdown GALR1 (siGalRl) rats. The FLX or carrier were administered sc 23, 5 and 1 hour before the test. The CSF and LAG (1-15) were administered icv 15 min before the test. The data are represented as the mean ± SEM of the immobility, climbing and swimming time in the FST during the 5 min of the test period (n = 7-9 rats per group) * p <0.05 according to t-Student test.
    Fig. 5. Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and Way100635 (6nmol), 5-HT1A antagonist, and co-administration of the effective dose of FLX (10mg / Kg) with GAL (1-15) (1nmol) and Way100635 (6nmol) in the FST. The FLX or carrier was administered sc 23, 5 and 1 hour before the test. GAL (1-15), Way100635 and GAL (1-15) + Way100635 was administered icv 15 min before the test. The data are represented as the mean ± SEM of the immobility, climbing and swimming time in the FST during the 5 min of the test period (n = 5-10 rats per group). * p <0.05, ** p <0.01 compared to the control group according to a one-way ANOVA test followed by the Newman-Keuls multiple comparisons test.
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    Fig. 6A. Effects of the co-administration of FLX (10mg / Kg) and GAL (1-15) (Inmol) on mRNA levels of 5- HT1AR in the dorsal hippocampus (CA1 region and dentate gyrus -DG-). FLX was administered 23, 5 and 1.25 hours before sacrifice and GAL (1-15) was injected 30 min before sacrifice. The optical density (D.O) values, mean ± SEM, are expressed as a percentage of the control value (100%). * p <0.05 compared to other groups. (B) Representative autoradiograms of the dorsal hippocampus showing mRNA levels of 5-HT1AR determined by in situ hybridization in the analyzed areas.
    Fig. 6B. Representative autoradiograms of the dorsal hippocampus showing mRNA levels of 5- HT1AR determined by in situ hybridization in the analyzed areas.
    Fig. 7A. Effects on the binding characteristics of [3H] -8-OH-DPAT, 5-HT1AR agonist, in the dentate gyrus of the hippocampus (GD) after co-administration of FLX ((10mg / Kg) and LCRa or GAL (1 -15) (1nmol).
    FLX was administered 23, 5 and 1.25 hours before sacrifice and GAL (1-15) was injected 30 min before sacrifice. Saturation experiments were performed with 10 concentrations of [3H] -8-OH-DPAT (0.26-10nM) in coronal sections of the hippocampus. Non-specific binding was defined in the presence of 10 ^ M serotonin. The values of Kd and Bmax are shown as mean ± SEM (n = 6 rats per group), the value of Kd (nM) for the FLX group is 1.2 ± 0.1 and that of Bmax (fmol / mg prot) is of 545 ± 37. * p <0.05; ** p <0.01 compared to the control group according to t-Student test.
    Fig. 7B. Representative autoradiograms of rat hippocampus sections with a radioligand concentration similar to Kd (1nM) showing the affinity increase of the 5-HT1AR agonist.
    Detailed description of the invention
    In the present invention it is described for the first time how GAL (1-15) improves FLX-induced antidepressant effects in FST. These effects are specific since GAL has no effect. Indications were also obtained of the involvement of the GALR1 / GALR2 complex in the actions mediated by GAL (1-15) based on the use M871, specific antagonist of GALR2, and icv injections of the GALR1 tRNA or the GALR2 tRNA producing a reduction of GALR1 or GALR2, respectively.
    It is important to highlight the participation of 5HT1AR in the GAL (1-15) / FLX interactions since WAY100635, 5HT1AR antagonist, blocked the effects induced by the co-administration of GAL (1-15) and FLX. In addition, the mechanism of GAL (1-15) / FLX interactions involved changes in 5HT1AR at the plasma membrane level with changes also at the transcriptional level. Therefore, GAL interactions (1-
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    15) / FLX affected binding characteristics, as well as 5-HT1AR mRNA levels specifically in the dorsal hippocampus.
    FST is used as a behavioral test to predict the efficacy of antidepressant treatments. The FST is an attractive behavioral test for the search for antidepressant drugs because it is quick to run, reliable between laboratories, and sensitive to the effects of all major classes of antidepressant medications. In this test, the main indication of an antidepressant effect of a given compound is a decrease in immobility behavior. The recording of active behaviors: swimming and climbing provide additional information on the mechanism of action that mediates the antidepressant effect. In fact, selective serotonin reuptake inhibitors decrease immobility and increase swimming behavior.
    In the present invention, injection of FLX10mg 23, 5 and 1 hour before the 5 min test significantly reduces immobility and increases swimming time in the FST. The results obtained coincide with previous studies and validate the behavioral model used (Estrada-Camarena, E., Fernandez-Guasti, A., Lopez-Rubalcava, C., 2003. Neuropsychopharmacology 28, 830-838). In addition, FLX at the dose of 2.5mg produced no effect, again corroborating previous results from other authors (Detke, M. J., Wieland, S., Lucki, I., 1995b. Psychopharmacology (Berl) 119, 47-54)
    In this invention, however, it has been shown that GAL (1-15) significantly improves the antidepressant effects of FLX on FST. A decrease in immobility and an increase in swimming were observed after co-administration of the subthreshold dose of GAL (1-15) and FLX. When administered separately, none of these treatments affected the behaviors analyzed in the trial, indicating that GAL (1-15) and FLX interact to elicit antidepressant responses.
    Since GAL (1-15) at an effective dose induces a pro-depressive effect (Millon, C., Flores-Burgess, A., Narváez, M., Borroto-Escuela, DO, Santin, L., Parrado, C ., Narvaez, JA, Fuxe, K., Diaz-Cabiale, Z., 2015. Int J Neuropsychopharmacol 18), the antidepressant effect can only be due to the improvement of the FLX action. In addition, the strong enhancement induced by GAL (1-15) on the antidepressant action of FLX was validated using an effective dose of FLX. GAL (1-15) has been shown to involve GALR1-GALR2 receptors to improve the antidepressant effect of FLX in FST. GALR2 participates in the effects of GAL (1-15) since M871, antagonist GALR2, blocked the potentiation of the antidepressant effects of FLX induced by GAL (1-15). The behavioral effects of GAL (1-15) on FLX in GALR1 and GALR2 knockdown rats were also blocked, confirming that the effects of GAL (1-15) depend on the existence of GALR1-GALR2.
    On the other hand, in the GALR1 and GALR2 knockdown rats, FLX only reduced immobility and swimming time in the FST, confirming that the effect of FLX is not affected by the reduction of GALR1 or GALR2 levels.
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    In addition, the results with respect to the present invention confirm that the effects of GAL (1-15) through heteroreceptor GALR1-GALR2 complexes could be a key mechanism in depression.
    In addition, the effects of GAL (1-15) on FLX-mediated actions in the FST are specific, since GAL does not induce effects. The fact that the improvement of the FLX antidepressant action by GAL (1-15) is blocked by WAY100365, 5-HT1AR antagonist, also indicates that 5-HT1AR has a significant participation in this interaction.
    According to several authors, the administration of WAY100635 together with an effective dose of FLX, induces the inhibition of the action of this SSRI (Serres et al., 2000, Estrada-Camarena et al., 2006). However, if the antagonist is administered at a different time, as in the present study, the activity of FLX antidepressant type is maintained in the FST (Serres et al., 2000, Estrada-Camarena et al., 2006). This injection pattern in which WAY100365 could not cancel the antidepressant activity shown by FLX alone in the FST, supports the idea that GAL (1-15), through GALR1 / GALR2, can interact with 5-HT1AR to facilitate the action of the FLX.
    In conclusion, the results indicate that GAL (1-15) increases FLX-induced antidepressant effects probably acting on the 5-HT1AR-GALR1-GALR2 heteoreceptor complex. The results open the possibility of using GAL (1-15) in combination with FLX as a novel strategy for the treatment of depression.
    The present invention thus provides:
    The present invention relates to the use of GAL (1-15) or a pharmaceutically acceptable salt thereof to be used in combination with a serotonin reuptake inhibitor or any other compound that causes an increase in the level of extracellular serotonin.
    In particular, the present invention relates to the use of GAL (1-15), or a useful pharmaceutically acceptable salt, to increase and / or provide a faster onset of the therapeutic effect of a serotonin reuptake inhibitor or any other compound that causes an increase in extracellular serotonin levels.
    More particularly, the present invention relates to the aforementioned use of GAL (1-15), or a pharmaceutically acceptable salt thereof, for 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, with a serotonin reuptake inhibitor or any other compound that causes elevation of the extracellular serotonin level. More particularly, the pharmaceutically acceptable salt of GAL (1-15) is a trifluoroacetate salt.
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    The anxiety disorders mentioned above include general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder or social anxiety disorder.
    As used herein, the term "increase" means to improve the therapeutic effect and / or enhance the therapeutic effect of an IRS or a compound that causes an elevation in the extracellular level of 5-HT.
    In a further embodiment, the invention relates to the use of GAL (1-15), or a pharmaceutically acceptable salt thereof, and a compound that is a serotonin reuptake inhibitor, or a compound that causes a level elevation. of extracellular serotonin, for the preparation of a pharmaceutical composition for the treatment of diseases or disorders that respond to the therapeutic effect of a serotonin reuptake inhibitor, or any other compound that causes an increase in the level of extracellular serotonin.
    Diseases that respond 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, in particular depression
    The term "anxiety disorders" has been defined above.
    In one embodiment of the invention, this refers to the use of GAL (1-15), or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition as indicated above, adapted for simultaneous administration of the active ingredients. In particular, said pharmaceutical compositions may contain the active ingredients within the same unit dosage form, for example in the same capsule or tablet. Said unit dosage forms may contain the active ingredients as a homogeneous mixture or in separate compartments of the unit dosage form.
    In another embodiment, the present invention relates to the use of GAL (1-15) or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition such as the one above, adapted for the sequential administration of the active ingredients. In particular, said pharmaceutical compositions may contain the active ingredients in individual unit dosage forms (pharmaceutical kit), for example individual tablets or capsules containing any of the active ingredients. These individual unit dosage forms may be contained in the same container or package, for example a blister pack.
    The term "pharmaceutical kit" used in the document means a pharmaceutical composition containing each of the active ingredients, but in individual unit dosage forms, and said active ingredients being able to be packaged together, for example in a blister pack, or not,
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    in which case the composition results from the combined use of said active ingredients, "combined use" being understood as the administration of the active ingredients associated with each other but not necessarily simultaneously.
    The invention also relates to a pharmaceutical composition that includes GAL (1-15), or a pharmaceutically acceptable salt thereof, and a compound that is a serotonin reuptake inhibitor, or any other compound that causes an elevation in 5 -HT extracellular, and optionally pharmaceutically acceptable carriers or diluents.
    The pharmaceutical composition of the invention may be adapted for the simultaneous administration of the active ingredients or for the sequential administration of the active ingredients, as described above, preferably for the sequential administration of the active ingredients as illustrated in the examples provided in the present specification, in particular by the administration of a serotonin reuptake inhibitor, such as FLX, subcutaneously at a different time from the administration of GAL (1-15), which is preferably administered parenterally, such as an intraarterial or intravenous route.
    Finally, the present invention relates to a method for the treatment of diseases or disorders that respond to a serotonin reuptake inhibitor, or to any other compound that causes an increase in the level of extracellular serotonin, which comprises administering to an individual. that needs it, GAL (1-15), or a pharmaceutically acceptable salt, and a serotonin reuptake inhibitor, or a compound that causes an increase in the level of extracellular serotonin.
    In particular, the present invention relates to a method for increasing and / or providing a faster onset of the therapeutic effect of a serotonin reuptake inhibitor, or any other compound that causes an increase in the level of extracellular serotonin, said method involving administering GAL (1-15), or a pharmaceutically acceptable salt thereof, to an individual to be treated, or under treatment, with a serotonin reuptake inhibitor or any other compound that causes an elevation of the level of extracellular serotonin. Individuals susceptible to benefit from treatment with a combination like the previous one, may suffer from depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, premenstrual syndrome, dysthymia, cognitive disorders, deficit disorder of attention with hyperactivity, and drug abuse; in particular depression.
    As mentioned earlier, anxiety disorders include general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder or social anxiety disorder.
    GAL (1-15) and the serotonin reuptake inhibitor can be administered simultaneously as described above.
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    Alternatively, the active ingredients can be administered sequentially, for example in two individual unit dosage forms, as described above.
    GAL (1-15) and its pharmaceutically acceptable salts have the general formula Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His-Ala or GWTLNSAGYLLGPHA.
    Surprisingly, it has been found that co-administration of GAL (1-15) and a serotonin reuptake inhibitor produces a significant increase in the synthesis of postsynaptic 5HT1A receptors in terminal areas ((with effects equivalent to those expected in case of an increase of the extracellular serotonin levels) compared to the administration of the serotonin reuptake inhibitor alone, the administration alone of an effective dose of GAL (1-15) causes a prodepressant effect.
    As mentioned above, serotonin reuptake inhibitors show a delay in the onset of action. Even in the response to SSRIs, several weeks of treatment are necessary to achieve relief in symptoms. GAL (1-15) can provide a rapid onset of the therapeutic effect of serotonin reuptake inhibitors.
    The use of a combination of GAL (1-15) and a serotonin reuptake inhibitor can greatly reduce the amount of serotonin reuptake inhibitor needed to treat depression and other affective disorders, and can thus reduce the effects side effects caused by the serotonin reuptake inhibitor. In particular, the combination of a reduced amount of SRI and LAG (1-15) may reduce the risk of sexual dysfunction induced by SSRIs and sleep disorders.
    The co-administration of GAL (1-15) and a serotonin reuptake inhibitor may also be useful for the treatment of refractory depression, that is, depression that cannot be properly treated using only the administration of a reuptake inhibitor of serotonin Typically, LAG (1-15) can be used as a complementary therapy to increase the response to SSRIs in patients in whom at least a 40-60% reduction in symptoms has not been achieved during the first 6 weeks of treatment with an SSRI.
    Many antidepressants with a serotonin reuptake inhibitory effect have been described in the literature. Any pharmacologically active compound that primarily or partially exerts its therapeutic effect through the inhibition of serotonin reuptake in the central nervous system (CNS), can benefit from the increase with GAL (1-15).
    The following list contains a series of serotonin reuptake inhibitors that may benefit from potentiation with GAL (1-15): Citalopram, escitalopram, FLX, R-FLX, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone , imipramine, imipramine N-oxide, desipramine, pyrandamine, dazepinyl, nefopam, befuralin, phezolamine, femoxetine, clomipramine, cyanoimipramine, lithoxyetine, cericlamine, seproxetine, WY 27587, WY 27866, imeldina, ifeldina, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine, ifeldine
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    viqualine, milnacipran, bazinaprine, YM 922, S 33005, F 98214-TA, OPC 14523, alaproclate, cyanodotepine, trimipramine, quinupramine, dotiepine, amoxapine, nitroxazepine, McN 5652, McN 5707, O1 69, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582, Org 6582 6906, amitriptyline, amitriptyline N-oxide, nortriptyline, CL 255.663, pirlindole, indatraline, LY 113.821, LY 214.281, CGP 6085 A, RU 25.591, napamezole, diclofensine, trazodone, EMD 68.843, BMY 42.569, NS 2389, serchlore, 2323, nitrochine ademethionine, sibutramine and clovoxamine. The compounds mentioned above can be used in basic form or of a pharmaceutically acceptable acid addition salt thereof. Especially preferred are FLX or a pharmaceutically acceptable acid salt thereof.
    The above list of serotonin reuptake inhibitors and other compounds, which cause an increase in the extracellular level of serotonin, cannot be interpreted as limiting.
    SSRIs that are particularly preferred according to the present invention include citalopram, escitalopram, FLX, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, nefazodone, imipramine, femoxetine and clomipramine. In particular, again, FLX or a pharmaceutically acceptable acid addition salt thereof is preferred.
    The term "selective serotonin reuptake inhibitor (SSRI)" means an inhibitor of monoamine transporters that has a stronger inhibitory effect on the serotonin transporter than dopamine and norepinephrine transporters.
    Selective serotonin reuptake inhibitors (SSRIs) are among the most preferred serotonin reuptake inhibitors used in accordance with the present invention. Particularly preferred SSRIs according to the invention are citalopram, escitalopram, FLX, fluvoxamine, sertraline or paroxetine.
    The active ingredients according to the invention, that is, GAL (1-15) and the SSRI or a compound that causes an increase in extracellular serotonin levels, can be used in the free basic form or in the form of a salt of pharmaceutically acceptable acid addition thereof, the latter being obtainable by reacting the basic form with an appropriate acid.
    Citalopram is preferably used in the form of hydrobromide or as a base; escitalopram, in the form of oxalate; FLX, sertraline and paroxetine, in the form of hydrochloride; and fluvoxamine, in the form of maleate.
    As mentioned above, the combination of GAL (1-15) with a serotonin reuptake inhibitor unexpectedly shows a synergistic effect on the CNS. As a consequence, combination therapy using GAL (1-15) and a lower dose of the serotonin reuptake inhibitor than those normally used alone can be effective, and the side effects associated with larger amounts of serotonin reuptake inhibitor used alone or prevent them completely.
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    In addition, combination therapy with GAL (1-15) using a normal dose of serotonin reuptake inhibitor has the advantage that an effective CNS effect can be obtained in a number of patients, often large, who do not respond to conventional monotherapy with SSRIs.
    Serotonin reuptake inhibitors, including the SSRIs specifically mentioned above, differ in both molecular weight and 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 that causes an increase in the level of extracellular 5-HT is administered at lower doses than those required when the compound is used alone. In another embodiment, the serotonin reuptake inhibitor or the compound that causes 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 or ingredients, in salt or base form, is combined, the mixing is carried out with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the desired form of preparation for administration. These pharmaceutical compositions are ideally in unit dosage form suitable for oral, rectal, percutaneous or parenteral injection administration. For example, when preparing the compositions in oral dosage form, any of the usual pharmaceutical means can 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. Due to their ease of 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 pharmaceutical compositions mentioned above in the form of a dosage unit for ease of administration and uniformity of dosage. As used in the specification and in the claims, the unit dosage form refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with The required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, packets of powder, wafers, injectable solutions or suspensions, teaspoons, tablespoons and the like, and multiple segregates thereof.
    GAL (1-15) may be administered before, during or after administration of the serotonin reuptake inhibitor, preferably after administration of the serotonin reuptake inhibitor, provided the time between administration of GAL (1 -15) and the administration of the
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    Serotonin reuptake inhibitor is such that the ingredients are allowed to act synergistically in the CNS. When simultaneous administration of GAL (1-15) and a serotonin reuptake inhibitor is envisaged, a composition containing both a serotonin reuptake inhibitor and GAL (1-15) may be particularly convenient. OR GAL (1-15) and the serotonin reuptake inhibitor can be administered separately in the form of suitable compositions. The compositions can be prepared as described above.
    The present invention also comprises products containing GAL (1-15) and a serotonin reuptake inhibitor as a combination preparation for simultaneous, separate or sequential use in psychiatric pharmacological therapy. Such products may comprise, for example, a pharmaceutical kit comprising discrete unit dosage forms containing GAL (1-15) and discrete unit dosage forms containing a serotonin reuptake inhibitor, all contained in the same package, e.g. a blister
    The aforementioned invention is further detailed in the following non-limiting and merely illustrative examples.
    Examples
    material and methods
    Animals
    Male Sprague-Dawley rats obtained from CRIFFA, Barcelona (200-250gr), were kept under a 12h light / dark cycle under controlled conditions of temperature and humidity (22 ± 2 ° C, 55-60%). The animals had free access to food pellets and tap water. Behavioral tests were performed during the light phase of the daily cycle. All experimental procedures were approved by the Institutional Animal Ethics Committee of the University of Malaga, Spain.
    Knockdown Rats GALR1 and GALR2.
    To generate knockdown rats, a procedure already described was used (Millon et al., 2015). In summary, during stereotactic surgery once the cannula is fixed, the animals received an icv injection of 5 ^ g (0.35 nmol) of Accell Smart pool siRNA (Dharmacon) for galanin receptor 2 (GALR2) or for its receiver 1 (GALR1). The animals had a recovery period of 8 days before the behavioral test, which is the time required to reduce the levels of GAL receptors as already described (Millon et al., 2015).
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    Behavioral assessment
    The groups of rats were evaluated in the FST. The doses, patterns and modes of administration of the substances were chosen based on previous work (Estrada-Camarena et al., 2003, Kuteeva et al., 2006, Zhang et al., 2004, Yoshiyama et al., 2003).
    In the first set of experiments, a dose-response curve of the FLX was performed. The groups of rats received three sc injections of FLX at doses of 10 mg / kg or 2.5 mg / kg, or carrier at 23, 5 and 1 hour before testing, in addition to an icv injection of CSF 15 min before the proof.
    It has been shown that this injection pattern produces FLX effects in the FST similar to those for which it produces effects after chronic treatments and to those that produces its clinical effects in humans (Detke et al., 1997). This injection pattern was used in all experiments related to this invention.
    In the second group of experiments, to evaluate the interactions of FLX with GAL (1-15) in the FST, the groups of rats received three sc injections of FLX (2.5 mg / kg) or FLX (10 mg / kg) and one Single ICV injection of GAL (1-15) (1 mol) 15 minutes before the test. The effects between the co-administration of FLX (10mg / Kg) and GAL (1-15) (1nmol) or GAL (1nmol) in the FST were also compared.
    In the third set of experiments, the participation of GALR1 and GALR2 in mediating the effect of GAL (1-15) on FLX was determined. The groups of rats received three sc injections of FLX (10mg / kg), a single icv injection of GAL (1-15) (1nmol) and M871 (3nmol), GALR2 antagonist, alone or in combination. In addition, FLX (10mg / Kg) and GAL (1-15) (1mol) were co-administered in ARNpi-knockdown GALR1 or GALR2 rats in order to analyze the participation of GALR1 and GALR2 receptors in the GAL-mediated effect (1- fifteen).
    To study whether the effects of GAL (1-15) on the action of FLX were mediated by the 5HT1AR receptor, groups of rats received three sc injections of FLX (10mg / kg), a single icv injection of GAL (1-15) (1nmol) and WAY100635 (6nmol), 5HT1AR antagonist, alone or in combination.
    Autoradiography and hybridization in situ
    The procedure for performing autoradiography of the recipient and in situ hybridization is described (Razani et al., 2000, Razani et al., 2001). Rats (n = 6 per group) received the three sc injections of FLX or carrier, and a single icv injection of GAL (1-15) or CSF and were sacrificed 30 min later. Coronal sections were obtained at the level of the dorsal hippocampus and dorsal raphe (DR).
    To how qualitative uraradiography
    Saturation experiments were performed using [3H] -8-OH-DPAT. Sections were pre-incubated for 30 minutes at room temperature in 50mM Tris-HCl buffer (pH 7.6), containing 4mM of
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    CaCl2, 0.01% ascorbic acid and 10mM pargiline. Sections were incubated for 60 minutes at room temperature with [3H] -8-OH-DPAT in the same solution as above. The exposure time of the film for the sections was 6 weeks.
    In situ hybridization:
    After prehybridization, the hybridization was performed in a humid chamber with the prehybridization buffer for 2h at 37 ° C, the sections were hybridized under coverslips with RNA probes at 1x106 cpm / 100 µl of the hybridization mixture for 16h at 55 ° C After hybridization, the sections were rinsed 4 times for 20min in 1xSSC at 55 ° C. Finally, the sections were rinsed in sterile water for 10 seconds, dehydrated in alcohol and air dried. The exposure time of the film for the sections was 2 weeks
    Image analysis
    The measurements were made in the Dentate Turn (DG) and in the CA1 region of the hippocampus (0.15mm2 square). The ventral part of the midline area of the DR was analyzed using a square as the sample field (0.09mm2).
    Statistic analysis
    Data are presented as means ± SEM and the number of samples (n) is indicated in the legends of the figures. All data were analyzed using GraphPad PRISM 4.0 (GraphPad Software, La Jolla, CA). To compare two experimental conditions, the statistical analysis of the unpaired t-Student test or, otherwise, ANOVA was followed by the Newman-Keuls multiple comparisons test after the test. The differences were considered significant at P <0.05 (* P <0.05, ** P <0.01, *** P <0.001). Data from saturation experiments were analyzed by nonlinear regression analysis for the determination of the dissociation constant (Kd) and the total number of agonist binding sites (Bmax) using GraphPad PRISM 4.0.
    Example 1. Dose-response of FLX
    As described above, three sc injections of FLX 10mg / Kg induced effects similar to antidepressants in FST in rats (Table 1). Total one-way ANOVA showed a significant effect between treatments on immobility (F220 = 4.628, p <0.05) and swimming (F220 = 7.044, p <0.01), while no significant difference in climbing was observed (F220 = 2,569, p = 0.102). FLX (10mg / Kg) reduced immobility (post hoc, p <0.05) and swimming time (post hoc, p <0.01) compared to controls and FLX (2.5mg / Kg). The three injections of sc FLX (2.5mg / Kg) were considered subthresholds in this test since
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    they produced no antidepressant effects compared to controls (Table 1).
     Immobility Time Swim Time Climbing Time
     Control  130 ± 4 84.9 ± 9 66.818
     FLX 2.5mg / Kg  122.6 ± 10 101.9 ± 10 56.819
     FLX 10mg / kg  91 ± 14 * 135.6110a 41.317
    Table 1. Effects on the behavior of the administration of FLX at doses of 2.5 or 10mg / Kg or of CSF in the FST. The FLX or carrier were administered sc 23, 5 and 1 hour before the test. The CSF was injected icv 15 min before the test in all groups. The data represent the mean ± SEM of the immobility, climbing and swimming time in the FST during the 5 min test period (n = 6-9 rats per group). * p <0.05 compared to the rest of the groups; ap <0.05 compared to FLX (2.5mg / Kg) and p <0.01 compared to controls according to a one-way ANOVA followed by the Newman-Keuls multiple comparisons test.
    Example 2. GAL (1-15) but not GAL enhances the antidepressant effects of FLX on the FST
    Co-administration of the three sc injections of the subthreshold dose of FLX (2.5mg / Kg) and a single icv injection of GAL (1-15) (Inmol) (Figure 1) induced antidepressant effects, with a significant decrease in immobility ( F327 = 3,973, p <0.05) compared to the rest of the groups (Figure 1, post hoc, p <0.05). In addition, an increase in swimming was observed (F328 = 4,137, p <0.05) compared to GAL (1-15) and controls (Figure 1, post hoc, p <0.05).
    The potent improvement of GAL (1-15) in FLX-mediated antidepressant effects was validated with an effective dose of FLX (10mg / kg). The subumbral dose of GAL (1-15) (1mol) improved the effects of antidepressant type mediated by the three sc injections of FLX (10mg / kg), according to a one-way ANOVA, in immobility (F328 = 10.96, p <0.001) and swimming (F328 = 16.46, p <0.001) without affecting climbing (F327 = 0.7554, p = 0.5289) (Fig. 1). The LAG (1-15) via icv significantly decreased the immobility behavior induced by the three injections of the effective dose of FLX (10mg / kg) by 50% in the FST (Figure 2, post hoc, p <0.05 ). In addition, there was also an increase in swimming behavior of around 40% compared to the FLX group (10mg / kg) (p <0.01).
    The co-administration of three sc injections of FLX (10mg / Kg) and a single icv injection of GAL (1mol) had no effect on the immobility and behavior of swimming compared to FLX (10mg / kg) in the FST (Figure 2) .
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    Example 3. GAL receptors involved in the GAL (1-15) -FLX interaction
    The participation of GALR2 in the GAL (1-15) -FLX (10mgkg) interaction with the GALR2 M871 selective antagonist and with an in vivo model of GALR2 knockdown rats has been tested.
    GALR2 participates in this interaction since M871 (3nmol), a GALR2 antagonist, significantly blocked immobility (F328 = 10.20, p <0.001, post hoc, p <0.05) and swimming (F329 = 15.75, p <0.001; post hoc, p <0.01) induced by the co-administration of a single icv injection of GAL (1-15) and the three sc injections of FLX (10mg / kg) in the FST (Figure 3A).
    M871, antagonist of GALR2, injected alone, at the dose of 3nmol, lacked effects with respect to immobility (141 ± 12 sec) and swimming (68.7 ± 10 sec) in the FST.
    Consequently, GALR2 knockdown rats were used to confirm the participation of GALR2 in the interaction between GAL (1-15) (1mol) and FLX (10mg / kg) (Figure 3B). According to the one-way ANOVA, significant effects of the treatment used in immobility are observed (F2, i7 = 5.932, p <0.05) and swimming behavior ^^ = 5.932, p <0.01). The three sc injections of FLX (10mg / kg) produced antidepressant effects in GALR2 knockdown animals with a decrease in immobility time (Figure 3B, post hoc, p <0.05) and an increase in swimming time (Figure 3B, post hoc, p <0.01) compared to the GALR2 knockdown rat control group. On the other hand, co-administration of the three sc injections of FLX (10mg / kg) and a single icv injection of GAL (1-15) in knockdown animals GALR2 did not produce any effect on immobility and swimming time compared to FLX ( Figure 3B).
    GAL (1-15) (1nmol) injected alone has no effect on FST in GALR2 knockdown animals compared to the control group on immobility (14.7 ± 3s), swimming (81.7 ± 3s) or climbing (60 ± 4s).
    GALR1 knockdown rats were also used to determine the participation of GALR1 in the GAL-induced effect (1-15) in FLX in the FST. In this model, a 30% reduction in GALR1 expression was confirmed by immunochemical assay in the CA1 region of the dorsal hippocampus (Figure 4-A, ti4 = 2.317, p <0.05) and and in the DG (Figure 4- A, t14 = 2,359, p <0.05).
    In the FST of GALR1 knockdown rats, the three sc injections of FLX (10mg / Kg) produced antidepressant effects with a decrease in immobility time (Table 2, t16 = 2,778, p <0.05) and an increase in swimming time (Table 2; t16 = 2,041, p <0.05) compared to the control group of knockdown rat GALR1.
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     Immobility Time Swimming Time Climbing Time
     (siRNA GALR1) (siRNA GALR1) (siRNA GALR1)
     Control  101.5 ± 7 88.8 ± 8 93.2 ± 11
     FLX (10 mg / kg)  70.9 ± 8 * 107.8 ± 5.8 * 92.3 ± 14
    Table 2 Effects on the behavior of the effective dose of FLX (10mg / Kg) in GALR1 knockdown rats (siGalRl). The FLX and carrier were administered sc 23, 5 and 1 hour before the test. The CSF and LAG (1-15) were injected icv 15 min before the test. Data are represented as the mean ± SEM of immobility, climbing and swimming time in the FST during the 5min test period (n = 7-9 rats per group) * p <0.05 according to the test t-Student
    In addition, in other experiments, co-administration of the three sc injections of FLX (10mg / kg) and a single icv injection of GAL (1-15) (Inmol) in knockdown animals GALR1 did not produce statistically significant differences compared to FLX (10mg / kg) at the time of immobility (Figure 4-B, ti5 = 0.121) or at the time of swimming (Figure 4-B; t14 = 0.319).
    Example 4. Involvement of 5HT1AR in the GAL (1-15) -FLX interaction
    To determine the role of 5HT1AR in the interaction between GAL (1-15) and FLX, WAY100635, 5HT1AR antagonist (Figure 5) was used.
    5HT1AR participates in this interaction since WAY100635 (6nmol), 5HT1AR antagonist, significantly blocked immobility (F330 = 4,243, p <0.05, post hoc, p <0.05) and swimming (F329 = 16.83, p <0.001; post hoc, p <0.01) induced by coadministration of icv GAL (1-15) and the three injections of sc FLX (10mg / kg) in the FST (Figure 5).
    WAY100635 (6nmol), 5HT1AR antagonist, injected only modified the immobility time (101 ± 12sec) (t13 = 2,617, p <0.01) and the climbing time (95 ± 9sec) (t13 = 2,200, p <0 , 05) in the FST. However, co-administration of three sc injections of FLX and a single icv injection of WAY100635 (6nmol) did not induce any difference compared to the effect of FLX alone (Figure 5).
    Example 5. GAL (1-15) + FLX modifies mRNA levels and binding characteristics of 5-HT1AR in the dorsal hippocampus
    Co-administration of the three sc injections of FLX (10mg / kg) and a single icv injection of GAL (1-15)
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    (Inmol) produced an increase in mRNA levels of 5HT1AR in the CA1 region (Figure 6A, F3i8 = 8.803, p <0.001, post hoc, p <0.05) and DG (Figure 6A, F3i7 = 5.033, p < 0.05, post hoc, p <0.05) of the dorsal hippocampus compared to the rest of the treatments. This effect was not observed in the DR (Table 3, F3i9 = 0.983, p = 0.422).
     Control GAL (l-15) (lnmol) FLX (lOmg / Kg) FLX (lOmg / Kg) + GAL (1-15) (Inmol)
     RNA levels m of 5HT1AR (% with respect to control)  100 + 4 95.7 + 5 98.2 ± 5 108.3 + 7
    Table 3. Effects of co-administration of FLX (10mg / kg) and GAL (1-15) (Inmol) on mRNA levels of 5-HT1AR in the DR. FLX or carrier were administered sc 23, 5 and 1.25 hours before sacrifice and GAL (1-15) or LCRa were injected icv 30min before sacrifice. The values of the mRNA levels are represented as mean ± SEM (n = 6 per group) of the percentages with respect to the control values (100%) of the optical density measurements (O.D.). No statistical differences were observed between treatments according to the one-way ANOVA.
    Representative autoradiograms illustrate the increase in mRNA levels of 5HT1AR in both areas, CA1 and DG, after co-administration of the three sc injections of FLX (10mg / kg) and the single icv injection of GAL (1-15) ( Inmol) (Figure 6B).
    In the autoradiography experiment, co-administration of the three injections of sc FLX (10mg / kg) and a single icv injection of GAL (1-15) (Inmol) produced a significant decrease in Kd (Figure 5; t9 = 2,916, p <0.01) and the Bmax (Figure 7A, t9 = 2,277, p <0.05) of the agonist [3H] -8-OH-DPAT in the DG of the dorsal hippocampus compared to FLX (10mg / kg) separately .
    Representative autoradiograms at a low concentration of radioligands (1nM) illustrate the increase in labeling (decrease in Kd values) in the DG 10 minutes after co-administration of the three sc injections of FLX (10mg / Kg) and the only one icv injection of GAL (1-15) (Inmol) (Figure 7B).
    These effects were not observed in the CA1 region of the hippocampus in Bmax (Table 4, t9 = 0.9420, p = 0.1854) or in Kd (Table S3; t9 = 0.01385, p = 0.4946) , nor in the DR in the Bmax (Table 4; t9 = 0.8648, p = 0.2048) or in the Kd (Table 4 t9 = 0.9941, p = 0.173).
     DR CAI
     Bmax (fm / mg prot) Kd (nM) Bmax (fm / mg prot) Kd (nM)
     FU (10 mg / kg) ♦ CSF  4940 ± 1240 14.5 + 6 483.8 + 17 1.4 + 0.2
     FLX (10mg / Kg) + GAL (l-15) (lnmol)  7781 ± 2794 29.1 ± 12 455.2 + 26 1.4 + 0.2
    Table 4. Effects of co-administration of FLX (10mg / kg) and GAL (1-15) (Inmol) on the binding characteristics of [3H] -8-OH-DPAT, 5-HT1AR agonist in the DR and in the CA1 region of the hippocampus. FLX or carrier were administered sc 23, 5 and 1.25 hours before slaughter and GAL (1-15) or LCRa were injected icv 30min before slaughter. Saturation experiments were performed with ten concentrations of [3 H] -8-OH-DPAT (0.26-10 nM) in sections of the DR or in the CA1 region of the hippocampus. Non-specific binding was defined as binding in the presence of 10 ^ M serotonin. The values of Kd and Bmax are shown as mean ± SEM (n = 6 per group). No statistical differences were observed between treatments according to the t-Student test.
    10
    权利要求:
    Claims (11)
    [1]
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    Claims
    1. Pharmaceutical composition for use in the treatment of depression, anxiety disorders and eating disorders selected from the list consisting of bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, disorder due to attention deficit hyperactivity and drug abuse; comprising galanin (1-15) or a pharmaceutically acceptable salt of said fragment, and a compound, which is a selective serotonin reuptake inhibitor.
    [2]
    2. Pharmaceutical composition according to the preceding claim characterized in that the pharmaceutically acceptable salt of galanin (1-15) is a trifluoroacetate salt.
    [3]
    3. Pharmaceutical composition according to the preceding claim characterized in that the selective serotonin reuptake inhibitor is selected from the list consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline and paroxetine or a pharmaceutically acceptable salt of any of these compounds .
    [4]
    4. Pharmaceutical composition according to the preceding claim characterized in that the selective serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt thereof.
    [5]
    5. Pharmaceutical composition according to any of the preceding claims comprising pharmaceutically acceptable carriers or diluents.
    [6]
    6. Pharmaceutical composition according to any of the preceding claims characterized in that the active ingredients are contained in the same unit dosage form.
    [7]
    7. Pharmaceutical composition according to any of claims 1-5 characterized in that the active ingredients are contained in discrete unit dosage forms.
    [8]
    8. Use of a pharmaceutical composition according to any of claims 1-5 for the manufacture of a medicament for the treatment of depression, anxiety disorders and eating disorders selected from the list consisting of bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse.
    [9]
    9. Use of a pharmaceutical composition according to any of claims 1-5 for the manufacture of a medicament for the treatment of anxiety disorders selected from the list consisting of panic anxiety, obsessive compulsive disorder, acute stress disorder , or disorder
    5 social anxiety.
    [10]
    10. Use of a pharmaceutical composition according to any of claims 1-5 for the manufacture of a medicament for the treatment of depression.
    10. Use of a pharmaceutical composition according to any of claims 8-10
    characterized in that the administration of the manufactured medicament comprises the simultaneous administration of the active ingredients of said pharmaceutical composition.
    [12]
    12. Use of a pharmaceutical composition according to any of claims 8-10 15 characterized in that the administration of the manufactured medicament comprises the sequential administration of the active ingredients of said pharmaceutical composition.
    Duration (s)
    image 1
    (AD (XlOUIUlXSl-l) TWO ♦ (08¡Cx, «ioS'Z Xld
    image2

    Duration (s) Duration (s) Duration (s)
    image3
    25CH
    Swimming time
    □ Control
    □ FlxlOmgJitl + LCHa | icv |
    image4
    image5
    image6
    150i
    image7
    Swimming time
    250-1
    image8
    □ Control
    | Flxlümg (vcJ LCRa (icv)
    FlxiOmg¡ic | ♦ GAL¡1-15) lnmollcvl I FlxiOrng¡ic | ♦ GAL¡1 15 | lnmo4 + M87I 3nmol (icv)
    Duration (s) Duration (s)
    150-i
    Immobility Time siRNA GALR2
    image9
    150-1
    Swim Time SiRNA GALR2
    100-
    image10
    **
    image11
    image12
    image13
    Control
    FlxlOmg | sc | 4 LCR¿ (»cv |
    FlidOmg (vc) 4 GAL ^ l-15) lnmol {icv)
    image14
    image15
    Duration (s)
    (TO
    C
    •or
    k_
    3
    OR
    image16
    1 oo-
    image17
    Swimming time
    image18
    FlxlOmg (sc) + LCRa (icv)
    FlxlOmg (sc) + Wayl00635 6nmol (¡cv)
    FlxlOmg (sc) + GAL (1-15) lnmol (icv)
    FlxlOmg (sc) + GAL (1-15) Inmol + Wayl00635 6nmol (¡cv)
    image19

    FlxlOmg control
    image20
    Figure 6B
    nM
    Kd-DG
    image21
    1 Sn
    Uh
    0 s-
    00
    Bmax - DG
    image22
    image23
    FlxlOmg (sc) + LCRa (icv)
    FlxlOmg (sc) + GAL (1-15) lnmol (icv)
    Figure 7A
    [(3H) 8-OH DPAT] = InM
    image24
    FlxlOmg + GAL (l-5) lnmol [(3H) 8-OH-DPAT] = InM
    Figure 7B
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    同族专利:
    公开号 | 公开日
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    引用文献:
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