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WO2018150073A1 - Composition pharmaceutique comprenant des inhibiteurs sélectifs de la recapture de la sérotonine et de la galanine (1-15) - Google Patents

Composition pharmaceutique comprenant des inhibiteurs sélectifs de la recapture de la sérotonine et de la galanine (1-15) Download PDF

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Publication number
WO2018150073A1
WO2018150073A1 PCT/ES2018/070121 ES2018070121W WO2018150073A1 WO 2018150073 A1 WO2018150073 A1 WO 2018150073A1 ES 2018070121 W ES2018070121 W ES 2018070121W WO 2018150073 A1 WO2018150073 A1 WO 2018150073A1
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pharmaceutical composition
gal
flx
composition according
administration
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Spanish (es)
Inventor
Antonio FLORES BURGESS
Carmelo MILLÓN PEÑUELA
Belén GAGO CALDERÓN
Manuel Alejandro NARVÁEZ PELÁEZ
José Ángel NARVÁEZ BUENO
Luis Javier Santín Núñez
Zaida DÍAZ CABIALE
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Universidad de Malaga
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Universidad de Malaga
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids

Definitions

  • composition comprising selective serotonin and galanin reuptake inhibitors (1-15)
  • 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.
  • IS S Selective serotonin reuptake inhibitors
  • 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.
  • HT1B 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.
  • GAL galanin
  • 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) .
  • 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 serotonin. extracellular
  • 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 further start. rapid therapeutic effect of a serotonin reuptake inhibitor or any other compound that causes an increase in the level of extracellular serotonin.
  • 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 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.
  • GAL (1-15 a pharmaceutically acceptable salt of said fragment
  • Fig. 1 Behavioral effects of co-administration of an ineffective dose of FLX (2.5mg / Kg) and a subthreshold dose of GAL (1-15) (lmol) in the forced swim test (in English, forceáswimming test or FST).
  • FLX was administered subcutaneously (se) 23, 5 and 1 hour before the test and GAL (1-15) was injected intracerebroventricularly (icv) 15 minutes before the test.
  • * p ⁇ 0.05 compared to the other groups, a p ⁇ 0.05 compared to the control group and GAL (l-15) (lnmol) 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) (lnmol) or GAL (lnmol) in the FST.
  • FLX was administered by route 23, 5 and 1 hour before the test.
  • Artificial cerebrospinal fluid (LC a), GAL (1-15) and GAL were administered icv 15 minutes before the test.
  • Fig. 3A Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and subthreshold doses of GAL (1-15) (lnmol) in Sprague-Dawley rats to which it was also administered
  • M871 (3nmol), GALR2 antagonist.
  • the FLX or the vehicle (carrier) were administered by route 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.
  • the CSF and LAG (1-15) were administered icv 15 min before the test.
  • Fig. 4 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 the co-administration of the effective dose of FLX (10mg / Kg) and the sub-threshold dose of GAL (1-15) (lnmol) in Knocdown GALR1 (siGalRl) rats. The FLX or carrier were administered via route 23, 5 and 1 hour before the test.
  • the CSF and LAG (1-15) were administered icv 15 min before the test.
  • Fig. 5 Behavioral effects of co-administration of the effective dose of FLX (10mg / Kg) and Wayl00635 (6nmol), 5-HT1A antagonist, and co-administration of the effective dose of FLX (10mg / Kg) with GAL (1-15) (lnmol) and Wayl00635 (6nmol) in the FST.
  • the FLX or carrier was administered via route 23, 5 and 1 hour before the test.
  • GAL (1-15), Wayl00635 and GAL (1-15) + Wayl00635 was administered icv 15 min before the test.
  • Fig. 6A Effects of co-administration of FLX (10mg / Kg) and GAL (1-15) (lnmol) on mRNA levels of
  • 5-HT1AR in the dorsal hippocampus (CAI 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. Density values Optics (OD), 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) (lmol) FLX was administered 23, 5 and 1.25 hours before slaughter and GAL (1-15) was injected 30 min before slaughter 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 ⁇ serotonin.
  • Fig. 7B Representative autoradiograms of rat hippocampus sections with a radioligand concentration similar to Kd (In M) showing the affinity increase of the 5-HT1AR agonist.
  • 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 or the GALR2 siRNA producing a reduction of GALR1 or GALR2, respectively.
  • GAL (1-15) / 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 effects. of all major classes of antidepressant medications.
  • 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.
  • selective serotonin reuptake inhibitors decrease immobility and increase swimming behavior.
  • 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.
  • none of these treatments affected the behaviors analyzed in the trial, indicating that GAL (1-15) and FLX interact to elicit antidepressant responses.
  • GAL (1-15) at an effective dose induces a pro-depressive effect (Millón, 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.
  • 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.
  • 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.
  • 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-HT1A antagonist, also indicates that 5-HT1AR has a significant participation in this interaction.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable salt of GAL (1-15) is a trifluoroacetate salt.
  • 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.
  • the term "increase” means to improve the therapeutic effect and / or enhance the therapeutic effect of an IS or a compound that causes an elevation in the extracellular level of 5-HT.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, in in which case the composition results from the combined use of said active ingredients, meaning "combined use” 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.
  • a serotonin reuptake inhibitor such as FLX
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • SSRIs that are particularly preferred according to the present invention include citalopram, escitalopram, FLX, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, nefazodone, imipramine, femoxetine and clomipramine.
  • FLX or a pharmaceutically acceptable acid addition salt thereof is preferred.
  • SSRI selective serotonin reuptake inhibitor
  • SSRIs selective serotonin reuptake inhibitors
  • 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.
  • the combination of GAL (1-15) with a serotonin reuptake inhibitor unexpectedly shows a synergistic effect on the CNS.
  • 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.
  • 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 ISSs specifically mentioned above, differ in both molecular weight and activity.
  • the amount of serotonin reuptake inhibitor used in combination therapy depends on the nature of said serotonin reuptake inhibitor.
  • 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.
  • the serotonin reuptake inhibitor or the compound that causes an increase in the level of extracellular 5-HT is administered in normal doses.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 serotonin reuptake inhibitor is such that the ingredients are allowed to act synergistically in the CNS.
  • a composition that contains both a serotonin reuptake inhibitor and GAL (1-15) may be particularly convenient.
  • 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
  • a dose-response curve of the FLX was performed.
  • the groups of rats received three injections of FLX at doses of 10 mg / Kg or 2.5 mg / Kg, or carrier at 23, 5 and 1 hour before the tests, in addition to an icv injection of CSF 15 min before the proof.
  • the groups of rats received three injections of FLX (2.5 mg / Kg) or FLX (10 mg / Kg) and one Single ICV injection of GAL (1-15) (lnmol) 15 minutes before the test.
  • the effects between the co-administration of FLX (10mg / Kg) and GAL (1-15) (lnmol) or GAL (lnmol) were also compared in the FST.
  • the participation of GALRl and GALR2 in mediating the effect of GAL (1-15) on FLX was determined.
  • the groups of rats received three injections of FLX (10mg / kg), a single icv injection of GAL (1-15) (lnmol) and M871 (3nmol), GALR2 antagonist, alone or in combination.
  • FLX (10mg / Kg) and GAL (1-15) (lnmol) ARNpi-knockdown GALRl or GALR2 rats were co-administered in order to analyze the participation of GALRl and GALR2 receptors in the GAL-mediated effect (1- fifteen).
  • Rats (n 6 per group) received all three 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).
  • the hybridization was performed in a humid chamber with the prehybridization buffer for 2 h at 37 9 C, the sections were hybridized under coverslips with probes of AN at 1x10 s cpm / ⁇ of the hybridization mixture for 16 h at 55 9 C. After hybridization, the sections were rinsed 4 times for 20min in SSC at 55 9 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
  • the measurements were made in the Dentate Turn (DG) and in the CAI region of the hippocampus (0.15mm 2 square). The ventral part of the midline area of the DR was analyzed using a square as the sample field (0.09mm 2 ).
  • FLX 10mg / Kg induced effects similar to antidepressants in FST in rats (Table 1).
  • 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 potent improvement of GAL (1-15) in FLX-mediated antidepressant effects was validated with an effective dose of FLX (10mg / kg).
  • GALR2 participates in this interaction since M871 (3nmol), antagonist of GALR2, significantly blocked immobility p ⁇ 0.001, post hoc, p ⁇ 0.05) and swimming
  • GAL (1-15) (inmol) injected alone has no effect on FST in knockdown animals
  • GALR2 compared to the control group in 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.
  • co-administration of three injections was from FLX and a single icv injection of WAY100635 (6nmol) did not induce any difference compared to the effect of FLX alone ( Figure 5).
  • GAL (1-15) + FLX modifies mRNA levels and binding characteristics of 5-HTlAR in the dorsal hippocampus

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Abstract

La présente invention concerne une composition pharmaceutique qui comprend des inhibiteurs sélectifs de la recapture de la sérotonine et de la galanine (1-15). La présente invention se rapporte à l'utilisation de galanine (1-15) ou d'un de ses sels pharmaceutiquement acceptables pour être utilisé en combinaison avec un inhibiteur de la recapture de la sérotonine ou tout autre composé qui provoque une augmentation significative de la synthèse des récepteurs 5HT1A post-synaptiques dans les régions terminales. La présente invention se rapporte plus particulièrement à l'utilisation de GAL(1-15) ou d'un sel pharmaceutiquement acceptable de ce dernier utile pour augmenter et/ou produire un démarrage plus rapide de l'effet thérapeutique d'un inhibiteur de la recapture de la sérotonine ou de tout autre composé qui provoque une augmentation significative de la synthèse des récepteurs 5HT1A post-synaptiques dans les régions terminales.
PCT/ES2018/070121 2017-02-20 2018-02-20 Composition pharmaceutique comprenant des inhibiteurs sélectifs de la recapture de la sérotonine et de la galanine (1-15) Ceased WO2018150073A1 (fr)

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ES201730214A ES2659092B2 (es) 2017-02-20 2017-02-20 Composición farmaceútica que comprende inhibidores selectivos de la recaptación de la serotonina y galanina (1-15)
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Cited By (1)

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US20240325343A1 (en) * 2021-02-10 2024-10-03 David Alan Heldreth, JR. Methods of reducing symptoms of the ingestion of drugs such as cannabis or 5ht2 agonists via applications with 5ht1/2, CB1, GLP-1 allosteric modulators where the method of delivery/formulation selected from: Inhaler, nebulizer, intravenously, intramuscularly, injection, capsules, tablets, pills.

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