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    • 专利摘要:
    GAL (1-15) and the analogues thereof for use in the prevention and/or treatment of disorders and effects related to alcohol. The present invention relates to the use of galanin (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 an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, or a pharmaceutical composition or kit comprising any of them, for use in the prevention and/or treatment of disorders and effects related to alcohol, in particular for its use in reducing alcohol consumption. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2707210A1
    申请号:ES201731170
    申请日:2017-10-02
    公开日:2019-04-02
    发明作者:Penuela Carmelo Millon；Burgess Antonio Flores；Calderon Belen Gago；Fernandez Maria Inmaculada Garcia；Bueno Jose Angel Narvaez；Nunez Luis Javier Santin；CABIALE Mª ZAIDA DIAZ
    申请人:Universidad de Malaga；
    IPC主号:
    专利说明:

    [0001] GAL (1-15) and analogs thereof for use in the prevention and / or treatment of disorders and effects related to alcohol
    [0002]
    [0003] Field of the invention
    [0004]
    [0005] The present invention relates to the medical field, in particular to GAL (1-15) or to analogs thereof, for use in the prevention and / or treatment of disorders and effects related to alcohol, especially in the decrease of alcohol consumption.
    [0006]
    [0007] BACKGROUND OF THE INVENTION
    [0008]
    [0009] According to the World Health Organization (2014), alcohol consumption is considered an important risk factor and cause of diseases and mortality throughout the world. Current treatments for alcohol use disorders (ACT) have limited efficacy, produce serious adverse effects and have high rates of relapse. Due to the absence of effective treatments, it is important to find new biological targets that can modulate the consumption of alcohol. There are numerous neurotransmitters involved in eating disorders, such as GABA, glutamate, dopamine, noradrenaline, serotonin and several endogenous neuropeptides (Schneider et al., 2007, Marcinkiewcz etal., 2016).
    [0010]
    [0011] Galanin (GAL) is a neuropeptide (Tatemoto et al., 1983) widely distributed in neurons of the central nervous system (CNS) (Jacobowitz et al., 2004). Three subtypes of GAL receptors (GALR1-3) that have a high affinity for GAL have been cloned (Branchek et al., 2000, Mitsukawa et al., 2008). GALR1 and GALR3 mainly activate Gi-Go inhibitory G-proteins, whereas GALR2 is mainly coupled to Gq / G11 to mediate excitatory signaling (Branchek et al., 2000).
    [0012]
    [0013] GAL participates in a series of central functions that modulate neuroendocrine levels, pain control and cardiovascular functions, in addition to food intake and mood disorders (Mitsukawa et al., 2008; Diaz-Cabiale et al. , 2010; Lang et al., 2015). GAL and its recipients are involved in addictions and drug addictions (Picciotto, 2008), which include alcohol intake and alcoholism (Lewis et al., 2004, Lewis et al., 2005). The microinjection of GAL in the third ventricle increased the ethanol consumption in Sprage-Daqley rats within the test of choice between two bottles with a 7% ethanol solution in water; this increase was reversed completely with the M40 antagonist of the GAL receptor (Lewis et al., 2004). These GAL effects on ethanol consumption were also found with injections of GAL directly into the paraventricular nucleus (NPV) of the hypothalamus (Rada et al., 2004). In addition, mice overexpressing GAL show an increase in their preference and ethanol intake compared to their wild-type counterparts (Karatayev et al., 2009), whereas non-GAL expressing mice drink less ethanol and their preference for it decreases (Karatayev et al., 2010). Not only the NPV, but also the reward circuit seems to be involved in the effects of GAL that encourage drinking. GAL can increase the release of dopamine in the nucleus accumbens (NAC) (Rada et al., 1998), this effect being consistent with the ability of GAL to increase the reward effects of alcohol (Picciotto et al., 2010).
    [0014]
    [0015] Along with GAL, N-terminal fragments known as GAL (1-15) (Hedlund et al., 1996; Diaz-Cabiale et al., 2005; Diaz-Cabiale et al., 2010; Millon are also active in the SNC . et al., 2015; Millon et al., 2016; Flores-Burgess et al., 2017; Millon et al., 2017). Both GAL and GAL molecules (1-15) have specific functions in cardiovascular regulation and interact differently with other neuropeptides (Diaz-Cabiale et al., 2005). We have recently described that GAL (1-15) induces strong anxiety-like and depression-related effects in rats, and that these effects are significantly stronger than those induced by GAL. The GALR1 / GALR2 heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe, areas rich in GAL (1-15) binding sites (Hedlund et al., 1992), were implicated in these effects (Millon et al. , 2015). The presence of specific binding sites for GAL (1-15) in the dorsal hippocampus, the neocortex and the striatum (Hedlund et al., 1992), which are part of the mesolimbic dopamine system (Koob, 1992), suggest a function of GAL (1-15) within the circuits related to motivational and reward effects in drug addictions.
    [0016]
    [0017] It has now been surprisingly found that GAL (1-15) with the general formula:
    [0018] Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His-Ala or
    [0019]
    [0020] GWTLNSAGYLLGPHA,
    [0021]
    [0022] or the analogs thereof, or their pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, can be used to prevent and / or treat disorders and effects related to alcohol, especially in the reduction of their consumption.
    [0023] BRIEF DESCRIPTION OF THE INVENTION
    [0024]
    [0025] Alcohol consumption is considered an important risk factor causing diseases and mortality worldwide. Due to the absence of effective treatments for alcohol use disorders (TCU), it is important to find new biological targets that can modulate alcohol consumption. The role of GAL (1-15) in the voluntary consumption of ethanol in rats has been proved by the paradigm of choice between two bottles, likewise the effects of GAL (1-15) have been compared with the complete molecule of galanin ( GAL). In the present invention the first time that GAL (1-15), through central mechanisms, induces a strong reduction in the preference and consumption of ethanol in rats is described. These effects were significantly different than in GAL. The galanin receptor 2 (GALR2) was involved in these effects, since the GALR2-specific antagonist M871 blocked the actions mediated by GAL (1-15) in the preference and intake of ethanol. Importantly, the mechanism of this action involves changes in the expression of GALR and also in the immediate early gene C-Fos, as well as in the gene related to the internalization of Rab5 receptors in the striatum. The relevance of the striatum as a target for GAL (1-15) was supported by the effect of GAL (1-15) on the locomotor activity of rats after ethanol administration. These results form the basis for the development of novel therapies strategies through the use of GAL analogs (1-15) for the treatment of eating disorders in humans.
    [0026]
    [0027] According to the above mentioned, the present invention relates to the use, as indicated, of GAL (1-15) or an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, for the prevention and / or treatment of alcohol-related disorders such as acute intoxication, harmful use, dependency syndrome, state of withdrawal and other mental disorders, and alcohol-induced behavior due to alcohol consumption. In particular, the present invention relates to the use of GAL (1-15) or an analog thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, suitable for reducing alcohol consumption.
    [0028]
    [0029] Brief description of the figures
    [0030]
    [0031] Fig. 1. Experimental design of the voluntary intake of ethanol.
    [0032] Fig. 2. Galanin dose-response curve (1-15) [GAL15] in the paradigm of choice between two bottles with a 10% ethanol concentration (EtOH) in rats. GAL15 (at 1 or 3 nmol / rat) was administered icv 2, 14 and 24 hours before measurements. Vehicle injected rats with cerebrospinal fluid were used as a vehicle group. The vertical bars represent the mean ± SEM (n = 6-18 animals per group) of EtOH intake (g / kg; a, b, c), water intake (g / kg; d, e, f), preference for EtOH (%; g, h, i) and feed intake (g; j, k, l) during the different periods. (a) ap <0.05 compared to the rest of the groups (remaining graphs) * p <0.05 compared to the vehicle group according to the unidirectional ANOVA analysis followed by Fisher's LSD test.
    [0033]
    [0034] Fig. 3. Effect of the administration of galanin (GAL) and galanin (1-15) [GAL15] in the paradigm of choice between two bottles with a concentration of ethanol (EtOH) at 10% in rats. GAL (3 nmol / rat) and GAL15 (3 nmol / rat) were administered icv 2, 14 and 24 hours before measurements. The rats injected with cerebrospinal fluid were used as a vehicle group. The vertical bars represent the mean ± SEM (n = 7-15 animals per group) of EtOH intake (g / kg; a, b, c), water intake (g / kg; d, e, f), preference for EtOH (%; g, h, i) and feed intake (g; j, k, l) during the different periods. (a) * p <0.05 compared to the vehicle ** p <0.01 compared to the group of 3 nmol of GAL 15 (other graphs) * p <0.05 compared to the rest of the groups according to the ANOVA analysis unidirectional followed by Fisher's LSD test.
    [0035]
    [0036] Fig. 4. Effects of the coadministration of the M871 antagonist of the GALR2 receptor (3 nmol / rat) and galanin (1-15) [GAL15] in the paradigm of choice between two bottles with a concentration of ethanol (EtOH) at 10% in rats The treatments were injected icv 2 hours before the measurements. The rats injected with cerebrospinal fluid were used as the vehicle group. The vertical bars represent the mean ± SEM (n = 7-21 animals per group) of (a) EtOH intake (g / kg), (b) water intake (g / kg), (c) preference for EtOH (%) and (d) feed intake (g) during the different periods. * p <0.05 compared to the rest of the groups according to the unidirectional ANOVA analysis followed by Fisher's LSD test.
    [0037]
    [0038] Fig. 5. Effects of galanin (1-15) [GAL15] on mRNA expression in the striatum of C-Fos (a), Rab5 (b), GALR1 (c) and GALR2 (d) in rats exposed to paradigm of choice between two bottles. GAL15 was injected icv 2 hours before measurements. The rats injected with cerebrospinal fluid were used as a vehicle group. The vertical bars represent the mean ± SEM (n = 5-6 animals per group). * p <0.05; ** p <0.01; *** p <0.001 compared to the vehicle / EtOH group according to the Student t test.
    [0039]
    [0040] Fig. 6. Effects of galanin 1-15 [GAL15] on the ethanol-induced locomotor modification in rats. GAL 15 (3 nmol; icv) was injected 20 minutes before the test and the acute injection of ethanol (1.75 g / kg; ip) was administered 5 minutes before the test. The data represent the mean ± SEM (n = 6-8 of animals per group) of the total distance traveled (a) and the average speed (b) in the open field during a 5-minute test period. *** p <0.001 according to the bidirectional ANOVA analysis followed by Fisher's LSD test.
    [0041]
    [0042] Detailed description of the invention
    [0043]
    [0044] In the current invention, the role of GAL (1-15) by the intracerebroventricular route (icv) within the voluntary consumption of ethanol in rats has been evaluated by the paradigm of choice between two bottles, and in addition the effects of GAL have been compared ( 1-15) with those of GAL. Additionally, the involvement of GALR2 in the effects mediated by GAL (1-15) in this test was analyzed with the selective antagonist M871 of the GALR2 receptor. To investigate whether the effect of GAL (1-15) on the voluntary consumption of ethanol was associated with the reward circuit, the effect of GAL (1-15) on the expression of the early gene C-Fos, the gene related to the internalization of Rab5 and GALR1 receptors and GALR2, this has been studied in the striatum. Therefore, the effects of GAL treatment (1-15) on alcohol-induced locomotor activity have also been investigated.
    [0045]
    [0046] The induction of a strong reduction in the preference and consumption of ethanol in rats by GAL (1-15), through the central mechanisms, has been described here for the first time. These effects were significantly different from those of GAL which shows a different function of GAL compared to GAL (1-15) in terms of behavior related to alcohol consumption. GALR2 was implicated in these effects, since the GALR2-specific antagonist M871 blocked the actions mediated by GAL (1-15) in the preference and intake of ethanol. Importantly, the mechanism of this action involves changes in the expression of GAL receptors and also in the immediate early gene C-Fos as well as in the gene related to the internalization of Rab5 receptors in the striatum, a zone rich in points. of binding of the GAL fragment (Hedlund et al., 1992) and important in the motivational and reward effects of drug addiction (Koob, 1992). The importance of the striatum as a target for GAL (1-15) was also supported by the effect of GAL (1-15) on the locomotor activity of the rats after the administration of ethanol.
    [0047] GAL (1-15) at a dose of 3 nmol induced a pronounced reduction in the preference and consumption of ethanol in the test of choice between two bottles at 2 hours, an effect that was maintained at 24 hours. Bearing in mind that this paradigm of drinking alcohol between two bottles induces a voluntary intake of large amounts of alcohol (Simms et al., 2008), current data suggest that GAL (1-15) can be used as a drug to treat TCA in humans.
    [0048]
    [0049] It has been previously shown that GAL (1-15) increases depressive and anxiety-like behaviors in rats (Millon et al., 2015, Millon et al., 2017). Although emotional states such as anxiety are relevant variables for modulating the drinking behavior by increasing alcohol consumption and preference (Chappell et al., 2013), the effects mediated by GAL (1-15) do not seem to imply emotional regulation since a reduction in the intake and preference of alcohol was observed.
    [0050]
    [0051] In addition, a possible explanation for the reduction of alcohol intake induced by the central administration of GAL (1-15), is that GAL (1-15) itself can induce aversion rather than attenuate the reward properties of alcohol. However, the selected doses of GAL (1-15) have no effect on the intake of feed and water, which suggests that the reduction in alcohol intake is not conditioned by an aversion to alcohol.
    [0052]
    [0053] Since GAL (1-15) did not modify feed intake in rats that had consumed ethanol chronically, it can also be suggested that in our model, rats did not consume ethanol just because of their calories (Lewis et al., 2004).
    [0054]
    [0055] In addition, the effects of GAL (1-15) on the choice test between two bottles were significantly different from the corresponding effects induced by GAL. In our model, a GAL dose of 3 nmol had no effect with respect to the vehicle group in all parameters analyzed. In previous studies, GAL microinjected in the third ventricle increased the intake of ethanol by 7% in the test of choice between two bottles (Lewis et al., 2004), and this increase was greater during the light phase, where the animals are inactive and they usually drink very little (Lewis et al., 2004). The different results found in the present work could be explained by the differences in percentage of ethanol and the light / dark cycle used, since a choice between 10% ethanol versus water, so the percentage dissolution of ethanol could affect the result of the test (Leeman et al., 2010, Tarragon et al., 2012). In addition, measurements were made in the dark period, when the rats are more active, while the ethanol intake produced by GAL was higher in the light period (Lewis et al., 2004).
    [0056]
    [0057] However, because GAL (1-15) reduces the preference and consumption of ethanol, with GAL producing the opposite effect according to other authors, in the present invention the perspectives on the specific function of GAL are validated and expanded (1- 15) in the intake of ethanol.
    [0058]
    [0059] Previously, a different action of GAL and GAL (1-15) has been described with respect to behavioral functions (Millon et al., 2017). GAL (1-15) induces strong anxiety-type and depression-related effects in rats and these effects were significantly stronger than those induced by GAL (Millon et al., 2015). GAL (1-15) is also able to increase the antidepressant effects induced by the 8-OH-DPAT agonist of the 5HT1A receptor during the forced swimming test, an effect that results, once again, significantly stronger than that induced by GAL (Millon et al., 2016). The different action between GAL and GAL (1-15) was not only observed in behavioral functions, but also in central cardiovascular regulation (Diaz-Cabiale et al., 2005; Diaz-Cabiale et al., 2010). Our results in relation to the intake of ethanol confirm a unique action of GAL (1-15) within the brain communication.
    [0060]
    [0061] The mechanism explaining the differences between GAL and GAL (1-15) lies in the fact that the preferred site of binding of the N-terminal GAL fragment is the result of the formation of highly specific GALR1 / GALR2 heteromers for GAL fragments (Fuxe et al., 2008; Fuxe et al., 2012; Millon et al., 2015). The fact that the antagonist M871 of the GALR2 receptor blocked the reduction in the preference and intake of ethanol induced by GAL (1-15), confirms that GAL (1-15) acts through the GALR1 / GLR2 heterodimer to reduce the preference and the consumption of ethanol.
    [0062]
    [0063] The GAL receptors involved in alcoholism are not well defined; however, several studies indicate that GALR3 is involved in alcohol consumption (Belfer et al., 2007, Ash et al., 2011, Ash et al., 2014, Scheller et al., 2017). Since GALR3 is mainly restricted to the hypothalamus and pituitary gland (Smith et al., 1998, Waters et al., 2000) it has been proposed that these areas are crucial for this effect. In the present invention the importance of the GALR1 and GALR2 receptors in the reduction is demonstrated of the preference and consumption of ethanol induced by GAL (1-15) and it is suggested that the striatum, a key region in the reward effects of drugs (Koob, 1992), is involved in the effects mediated by GAL ( 1-15). In this model of voluntary ethanol consumption, GAL (1-15) induced a significant increase in C-Fos mRNA and the expression of Rab5 in the striatum, indicating an improvement in neuronal activation, as well as an internalization of the recipient in this area (Borroto-Escuela et al., 2012). Moreover, in these animals, after GAL injection (1-15), a significant reduction in GALR1 expression and a slight decrease in GALR2 mRNA in the striatum was observed, suggesting that both striatal receptors were involved in the effects mediated by GAL (1-15) on the voluntary intake of ethanol in this nucleus. Interestingly, the evidence that ethanol injections in animals not previously subjected to experimentation has no effect on the expression of GALR1 and GALR2 in the striatum, indicates that ethanol itself does not influence the expression of GALR and confirms that Effects at the GALR level of our model were induced by GAL (1-15).
    [0064]
    [0065] The importance of the striatum as a target for GAL (1-15) was supported by the ability of GAL (1-15) to favor the suppression of locomotor activity induced by ethanol. The suppression of ethanol from locomotor activity after the ip injection of ethanol results in a well-known behavioral effect mediated mainly by the dopaminergic system, where the striatum is included. Consequently, it has been shown that this effect is markedly reduced when the dopaminergic system is injured using 6-OHDA, which produces a rapid reduction of the dopamine in the striatum (Breese et al., 1984). The present invention suggests that the potentiation of GAL-induced hipolocomodation (1-15) in rats treated with alcohol may necessitate modulation of the dopaminergic system through GAL (1-15), and probably including the striatum and which is an important target of the dopammergic projections.
    [0066]
    [0067] Although previously, the increase in ethanol intake of GAL was directly related to several areas within the hypothalamus (Leibowitz et al., 2003; Rada et al., 2004; Schneider et al., 2007), the current invention suggests that GAL (1-15) acts through the striatum, an area that has specific binding sites for GAL (1-15) (Hedlund et al., 1992). The involvement of the striatum in the action mediated by GAL (1-15) would explain the different performance between GAL and GAL (1-15) in the intake of ethanol.
    [0068] Dopamine should be considered as a target neurotransmitter involved in the reduction of ethanol consumption by GAL (1-15). Supporting this hypothesis, GAL reduces the behavioral response after treatment with several addictive substances, such as morphine or amphetamines, modulating mainly dopaminergic neurotransmission (Tsuda et al., 1998, Pierce et al., 2006) and the transmission of Dopamine has a major role in the motor effects of alcohol on the striatum (Brabant et al., 2014).
    [0069]
    [0070] The results included in the present invention showed that GAL (1-15) decreases the voluntary consumption of alcohol; however, because a positive correlation has been demonstrated between alcohol intake and operant oral self-administration (Green and Grahame, 2008), we can expect that GAL (1-15) may also decrease the self-administration of alcohol in rats. In fact, other drugs related to neuropepids, such as ghrelin antagonists, reduced the preference of ethanol intake, as well as the operant self-administration of ethanol (Gomez et al., 2015). Furthermore, not only has GAL (1-15) been shown to have biological functions, other N-terminal fragments of galanin, such as GAL (1-16) have biological effects. Thus, GAL (1-16) can substantially increase the Kd values of the binding sites of the 5HT1A agonist in the ventral limbic cortex of the rat, without affecting the Bmax values (Diaz-Cabiale et al., 2000) , these results are consistent with other works where GAL (1-15) reduces the affinity of the 5HT1A receptor in the dorsal hippocampus without affecting the Bmax values (Hedlund et al., 1994). Therefore, functional studies have shown that several N-terminal fragments of galanin seem to exert similar effects (Diaz-Cabiale et al., 2000).
    [0071]
    [0072] In conclusion, the present invention indicates that GAL (1-15) induces a strong reduction in the preference and consumption of ethanol in rats, probably with the implication of the striatum, a key region in the reward effects of drugs, putting the foundations for the development of novel therapeutic strategies through the use of GAL analogues (1-15) for the treatment of TCA in humans.
    [0073]
    [0074] The present invention provides as follows:
    [0075]
    [0076] The present invention relates to the use of GAL (1-15) or an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, ie, the compounds of the invention, for preventing and / or treating disorders and effects related to alcohol, especially through the reduction of alcohol consumption.
    [0077]
    [0078] GAL (1-15) or its analogs may be in their crystalline form as free compounds or as solvates. In this regard, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates; ie solvates that can be used in the manufacture of a medicament, such as pharmaceutically unavailable solvates, which may be useful in the preparation of solvates or pharmaceutically acceptable salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. The solvates can be obtained by conventional solvation methods known to those skilled in the art.
    [0079]
    [0080] For use in therapy, GAL (1-15) or its analogs, or their salts, esters, tautomers, solvates or hydrates, would preferably be in a substantially pure or pharmaceutically acceptable form, ie, at a pharmaceutically acceptable level of purity and excluding normal pharmaceutical additives such as diluents and vehicles, and not including materials considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably above 50%, more preferably above 70%, and even more preferably above 90%. In a preferred embodiment, they are greater than 95% in GAL (1-15) or their analogs, or their salts, esters, tautomers, solvates or hydrates.
    [0081]
    [0082] The aforementioned alcohol-related disorders include acute intoxication, harmful use, dependency syndrome, abstinence and other mental and behavioral disorders induced by alcohol due to alcohol consumption.
    [0083]
    [0084] According to the international classification system of diseases (International Classification for Diseases, ICD-10), mental and behavioral disorders due to alcohol consumption (F10) are classified based on the use of psychoactive substance (F10-F19) and include the following subsections: F10. Mental and behavioral disorders due to alcohol consumption. F10.0 Acute intoxication. F10.1. Harmful use F10.2. Dependence syndrome F10.3. State of abstinence. F10.4. State of abstinence with delirium. F10.5. Psychotic disorder F10.6. Amnesic syndrome F10.7. Psychotic disorder of late and residual onset. F10.8. Other mental and behavioral disorders. F10.9. Other nonspecific mental and behavioral disorders.
    [0085] Acute intoxication (F.10.0) is the transitory state after the ingestion of alcohol that causes alterations in the level of consciousness, intellectual capacity, perception, affective state, behavior or other functions and psychological or physiological responses. It includes, among others, acute drunkenness and pathological intoxication.
    [0086]
    [0087] Harmful use (F10.1) means that in which mental or physical health is affected, without fully complying with the dependency criteria or any other of those indicated within F10.
    [0088]
    [0089] The dependency syndrome (F.10.2) supposes a set of physiological manifestations (somatic symptoms, tolerance), behavioral and cognitive in which the consumption of the substance supposes the major priority for the individual.
    [0090]
    [0091] The state of abstinence (F10.3) involves a set of somatic and psychological symptoms that appear when there is a relative or absolute abstinence of the substance after consumption of high, usually prolonged, and repeated doses. It is one of the indicators of the presence of the dependency syndrome.
    [0092]
    [0093] In one embodiment, the alcohol-related disorder is acute drunkenness or pathological intoxication. Preferably, effects linked to acute drunkenness or pathological intoxication include sedative effect, motor incoordination, confusion, neurodegeneration or any of its combinations.
    [0094]
    [0095] In another embodiment, the alcohol-related disorder is dependency syndrome or abstinence state. Preferably, the effects linked to the syndrome of dependence or to the state of abstinence include, anxiety, depression, tremors, agitation and malaise, emotional or cognitive deterioration composed of negative mood, anhedonia or memory problems; tolerance or inability to control alcohol consumption; neuroinflammation, neurotoxicity, neuronal death or any of its combinations.
    [0096]
    [0097] In the present document "alcohol" is understood, mainly, but not exclusively, as alcoholic beverages containing ethanol. It is also possible that other types of alcohols may cause the same symptoms after ingestion.
    [0098]
    [0099] In one embodiment, the present invention relates to the use of GAL (1-15) or an analog thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate for the preparing a pharmaceutical composition for preventing and / or treating disorders and effects related to alcohol, especially through the reduction of alcohol consumption, as a pharmaceutical composition comprising GAL (1-15) or an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate. Preferably, said pharmaceutical composition comprises GAL (1-15) or an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, although said pharmaceutical composition may optionally comprise pharmaceutically acceptable carriers and / or diluents or excipients. .
    [0100]
    [0101] Finally, the present invention relates to a method for the prevention and / or treatment of disorders and effects related to alcohol, in particular to a method for the reduction of alcohol consumption, which comprises the administration of GAL (1-15) or an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, or a pharmaceutical composition comprising GAL (1-15) or an analogue thereof, or its salt, ester, tautomer, solvate or pharmaceutically acceptable hydrate.
    [0102]
    [0103] In one embodiment, the use is preventive and the administration of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, is carried out before the ingestion of alcohol or any of its derivatives. In another embodiment, the use is preventive and the administration of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, is carried out during the ingestion of alcohol or any of its derivatives. In another embodiment, the use is for the treatment and administration of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, is carried out during the ingestion of alcohol or any of its derivatives. In another embodiment, the use is for the treatment and administration of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, is carried out after the ingestion of alcohol or any of its derivatives.
    [0104]
    [0105] The compound of the invention, or a pharmaceutical composition comprising a compound of the invention, can be administered together with another active ingredient in a simultaneous or sequential combination.
    [0106]
    [0107] To prepare the pharmaceutical compositions of this invention, an appropriate amount of the active ingredient (s), in salt form or in base form, is combined in a mixture. intimate with a pharmaceutically acceptable carrier, which can acquire a variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a unit dosage form suitable for administration by nasal, oral, rectal, percutaneous or parenteral injection. For example, when preparing the compositions in oral dosage form, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and others in the case of oral liquid preparations such as suspensions, syrups, may be employed. , the elixirs and the solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used.
    [0108]
    [0109] It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage forms for easy administration and uniformity of dosage. As used in the specifications and claims, the unit dosage form refers to physically separate units suitable as unit doses, wherein each unit contains a predetermined amount of active principle (s) calculated to produce the unit. desired therapeutic effect in association with the necessary pharmaceutical vehicle. Examples of these unit dosage forms are tablets (including coated or scored tablets), capsules, pills, powder bags, wafers, injectable solutions or suspensions, teaspoons of coffee, soup spoons and others, and segregated multiples of the tablets. same.
    [0110]
    [0111] The compound of the invention, or a pharmaceutical composition comprising a compound of the invention, can be administered before, during or after the administration of the other active principle, preferably after the administration of the serotonin reuptake inhibitor, provided that the time between the administration of the compound of the invention, or the pharmaceutical composition comprising a compound of the invention, and the administration of the other active principle is such that the principles are allowed to act synergistically in the CNS. When simultaneous administration is contemplated, a composition containing both the compound of the invention and the other active ingredient may be particularly convenient. Or the compound of the invention, or the pharmaceutical composition comprising a compound of the invention, and the other active ingredient, can be administered separately in the form of suitable compositions. The compositions can be prepared as described above.
    [0112] The present invention also comprises products containing the compound of the invention, or the pharmaceutical composition comprising a compound of the invention, and the other active ingredient as a combination preparation for simultaneous, independent or sequential use, separate or in prevention or the treatment of disorders and effects related to alcohol, especially decreasing alcohol consumption. These products may comprise, for example, a kit comprising independent unit dosage forms containing the compound of the invention, or the pharmaceutical composition comprising a compound of the invention, and separate unit dosage forms containing the active ingredient, all it contained in the same package or package, for example, in a blister.
    [0113]
    [0114] As used in this invention, the term "active ingredient", "active substance", "pharmaceutically active substance or substance" or "pharmaceutically active ingredient" means any component that potentially provides a pharmacological or other effect in diagnosis, cure, palliation, treatment or prevention of a disease, or that affects the structure or function of the human body or other animals. The term includes those components that promote a chemical change in the manufacture of the drug and that are present therein in a modified and intended form that provides a specific activity or effect.
    [0115]
    [0116] The aforementioned invention is further detailed in the following non-limiting and merely illustrative examples.
    [0117]
    [0118] EXAMPLES
    [0119]
    [0120] MATERIALS AND PROCEDURES
    [0121]
    [0122] Animals
    [0123]
    [0124] Male Sprague Dawley rats (body weight 225-250 g, 8 weeks old) were obtained from Criffa and kept in a room with controlled humidity and temperature (20-22 ° C). The rats of the paradigm of choice between two bottles were maintained throughout the protocol, with light / dark cycles reversed for 12 hours (without light starting at 10 o'clock in the morning) while the other rats were maintained with a cycle of light / 12 hours darkness. The animals had free access to feed pellets and running water. All animal experimentation was carried out in accordance with the guidelines for the care and use of laboratory animals of the University of Malaga.
    [0125]
    [0126] Intracerebroventricular injections
    [0127]
    [0128] This protocol has been previously used (Diaz-Cabiale et al., 2011; Millon et al., 2015). Briefly, the rats were anesthetized intraperitoneally with Equitesin (3.3 ml / kg body weight), and a chronic unilateral 22 gauge stainless steel guide cannula was stereotactically implanted into the right lateral cerebral ventricle using the coordinates following: 1.4 mm lateral and 1 mm posterior to the bregma, and 3.6 mm below the surface of the skull (Paxinos, 1986). After the surgery, the animals were housed individually and were given a recovery period of 7 days. Injections into the lateral ventricle were made using a 26-gauge stainless steel injection cannula connected through a PE-10 tube to a Hamilton syringe. The total volume was 5 pl per injection and the infusion time was 1 minute.
    [0129]
    [0130] The solutions were fresh preparations and the peptides were dissolved in artificial cerebrospinal fluid (composition of 120 nM NaCl, 20 nM NaH2CO3, 2 nM KCl, 0.5 nM KH2PO40, 1.2 nM CaCl2, 1.8 nM MgCl2, Na2SO40.5 nM and 5.8 nM D-glucose, pH 7.4). GAL was obtained from NeoMPS, Strasbourg, France; GAL (1-15) and the M871 antagonist of the GALR2 receptor were obtained from Tocris Bioscience, Bristol, United Kingdom.
    [0131]
    [0132] Choice test between two bottles for preference and voluntary consumption of ethanol
    [0133]
    [0134] The test of choice between two bottles was used to determine the voluntary ethanol consumption of the rats as previously described (Castilla-Ortega et al., 2016). Briefly, after 7 days of water consumption (both bottles), the choice between water and increasing concentrations of ethanol [3, 6 and 10% (v / v)] was offered for 7 days for each. The choice between 10% (v / v) ethanol and water was offered for several days until a stable initial value was reached. The consumption of water and ethanol was recorded daily. The position of the jars was changed every day to avoid location preference. The water intake (g / kg), the intake of ethanol (g / kg) and the preference (ethanol consumption / total liquid consumption [water plus ethanol] x 100]) for each animal were calculated. Throughout the experiment, estimated evaporation and splashing were calculated using an empty cage with two bottles, one with water and the other with the appropriate ethanol solution. In the experiments, the choice between ethanol (10%) and water was offered.
    [0135] Three groups of experiments were carried out with the paradigm of choice between two bottles. In the first group of experiments, the dose-response curve of GAL (1-15) was carried out. For this, groups of rats received via i.c.v. 1 nmol or 3 nmol GAL (1-15) or vehicle 2, 14 and 24 hours before measurements. In the second group of experiments, the effects of the choice test between two bottles for GAL and GAL (1-15) were compared. For this, groups of rats received via i.c.v. 3 nmol of GAL, 3 nmol of GAL (1-15) or vehicle, 2, 14 and 24 hours before the test. In the last group of experiments, the role of GALR2 was studied for this, groups of rats received via i.c.v. 3 nmol GAL (1-15) combined with 3 nmol GAL8 antagonist M87122 hours before measurements.
    [0136]
    [0137] In Fig. 1 the general scheme of the experimental design is shown.
    [0138]
    [0139] Expression of the mRNA of galanin receptors, C-Fos genes and Rab5 in the striatum during the voluntary consumption of ethanol.
    [0140]
    [0141] The groups of rats of the paradigm of choice between two bottles were decapitated 2 hours after administration by i.c.v. of 3 nmol GAL (1-15) or vehicle and the striatum was dissected and frozen in solid CO2 until analysis of mRNA expression.
    [0142]
    [0143] RNA isolation and quantitative analysis by real-time PCR
    [0144]
    [0145] The procedure to perform RNA isolation and RT-PCR has been previously described (Millon et al., 2015). The total RNA of the striatum was isolated by the RNeasy Lipid Tissue kit (Qiagen, Hilden, Germany). The cDNA was obtained by the Reverse Transcriptase Core kit (Eurogentec, Seraing, Belgium). These steps were performed according to the manufacturer's instructions.
    [0146] All PCR analyzes were performed in triplicate using the Power SYBR Green PCR Master Mix (Applied Biosystems, Foster City, USA) in the 7500 RT-PCR system (Applied Biosystems, Foster City, USA). The sequences of the primers used in this study are:
    [0147]
    [0148] GAPDH-Direct: 5 -GCTCTCTGCTCCTCCCTGTTC;
    [0149] GAPDH-Reverse: 5 -GAGGCTGGCACTGCACAA;
    [0150] GALR1-Direct: 5 -AAAACTGGACAAAACTTAGCC;
    [0151] GALR1 - Reverse: 5 -GGAT ACCTTTGTCTTT GCTC;
    [0152] GALR2-Direct: 5 -AACAGGAATCCACAGACC;
    [0153] GALR2-Reverse: 5 -CCCTTTGGTCCTTTAACAAG;
    [0154] C-FOS-Direct: 5'-AAACGGAGAATCCGAAGG;
    [0155] C-FOS-Reverse: 5'-CGTCTTCAAGTTGATCTGTC;
    [0156] RAB5-Direct: 5'-AAAAGAGCTGTTGACTTCC;
    [0157] RAB5-Reverse: 5'-AGGTCTACTCCTCTTCCTC.
    [0158]
    [0159] The data were analyzed by the comparative method Ct and normalized with respect to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA measurements.
    [0160]
    [0161] Test of the enzyme alcohol dehydrogenase
    [0162]
    [0163] The activity of the hepatic cytosolic alcohol dehydrogenase (ADH) enzyme was analyzed in the rats of the test of choice between two bottles. The activity of ADH has a good correlation with ethanol elimination rates in vivo (Lumeng et al., 1979) and the administration of chronic ethanol causes an increase in the activity of ADH (Buris et al., 1985).
    [0164]
    [0165] The livers were removed 2 hours after the icv injections and were frozen in solid CO2 until used. The determination of ADH activity was carried out in liver tissue homogenized in a solution of TrisHCl (10 mM, pH = 8.8, 0.5 mM dithiothreitol) centrifuged at 12,000 g for 10 minutes. The ADH activity was evaluated using a microassay adapted to the Cobas Mira analyzer according to Shephard et al. (Shephard et al., 1987). Briefly, 300 μl of NAD solution (2.9 mM in 0.1 M Glycine / NaOH, p = 10) was added to 30 μl of sample. The first optical reading was recorded before the addition of 20 pl of 17 mM ethanol, and then the rate of change in the absorption of the chromogen NADH at 340 nm was followed over time with a Cobas Mira analyzer at 37 oC. One unit of activity was defined as the reduction of 1 mole of NAD to NADH / min at 37 oC.
    [0166]
    [0167] Locomotive activity experiments
    [0168]
    [0169] In this experiment, the effects of GAL (1-15) (3 nmol) on reduced locomotion by ethanol (1.75 g / kg, intraperitoneal (ip)) were investigated (Vallof et al., 2016). The locomotor activity was recorded in the open field for rats (100 x 100 x 50 cm) where the animals They were individually placed and allowed to explore freely. Its behavior was recorded during a period of 30 minutes by means of a video camera placed on the roof, and the locomotive activity was analyzed by the EthovisionXT object tracking software . After each test, all surfaces were cleaned with an absorbent paper and 70% ethanol solution. For the locomotor activity, the total distance traveled (cm) and the average speed (cm / s) were recorded. It was administered to groups of rats GAL (1-15) or vehicle via icv 20 minutes before the test; administration of ethanol ip (1.75 g / kg) or saline was performed 5 minutes before the test.
    [0170]
    [0171] Expression of GALR1 and GALR2 mRNA after acute administration of ethanol
    [0172]
    [0173] Groups of rats previously experimentally treated with ethanol ip at 4 g / kg were injected (Bilbao et al., 2016), dissolved in a sterile 0.9% (w / v) saline solution, and 0, 2 and 4 hours After the injection, the brains were removed after rapid decapitation. The striatum bodies were rapidly removed from all the animals and immediately frozen in solid CO2 until use. The procedure to perform RNA isolation and RT-PCR has been previously described.
    [0174]
    [0175] Statistic analysis
    [0176]
    [0177] The data are presented as the means ± standard error of the mean and the numbers of the sample (n) are indicated in the legends of the figures. All data was analyzed using GraphPad PRISM 4.0 ( GraphPad software ). To compare two experimental conditions, statistical analyzes were performed using the unpaired Student's t -test. Otherwise, unidirectional variance analysis (ANOVA) or bidirectional ANOVA followed by subsequent Fisher LSD comparison tests were performed. The differences were significant with p <0.05 (* p <0.05; ** p <0.01; *** p <0.001).
    [0178]
    [0179] Example 1. Activity of ADH in the liver in the voluntary consumption of ethanol
    [0180]
    [0181] The voluntary intake of ethanol through the protocol of the choice test between two bottles induced a significant increase in the activity of ADH compared to the initial group (t11 = 3.281 p <0.01), which confirmed the validity of our model (Table 1).
    [0182] ADH activity
    [0183]
    [0184] Treatment Initial value Vehicle / EtOH
    [0185]
    [0186] ADH (Ul protein / g) 251.4 ± 14.8 313.1 ± 10.6 *
    [0187]
    [0188] Table 1. Activity of ADH in the liver of animals of the paradigm of choice between two bottles. Effects of the voluntary ingestion of ethanol in animals of the test of choice between two bottles on the activity of ADH in the liver. Rats injected with cerebrospinal fluid were used as the vehicle group, and rats with which it had not previously been experimented were used as the initial group. The data represent the mean ± SEM (n = 6 7 animals per group). ** p <0.01 against the reference group according to the Student's t- test.
    [0189]
    [0190] Example 2. GAL (1-15) induced a decrease in ethanol intake and alcohol preference in the paradigm of choice between two bottles
    [0191]
    [0192] GAL (1-15) at 3 nmol significantly decreased the ethanol intake at 2 hours (unidirectional ANOVA, F2,30 = 3.54 p <0.05, Fisher's LSD test post hoc: p <0.05; 2a), at 2 o'clock (unidirectional ANOVA, F2,30 = 3.44 p <0.05, Fisher's post hoc LSD test : p <0.05, Fig.2b) and at 24 hours (unidirectional ANOVA, F2.29 = 3.59 p <0.05, Fisher's post hoc LSD test : p <0.05, Fig. 2c) after its administration. GAL (1-15) at a dose of 1 nmol had no effect on the intake of ethanol at all time points analyzed.
    [0193]
    [0194] Additionally, 2 hours after the icv administration of 3 nmol of GAL (1-15), a significant decrease of 90% was observed in the preference for ethanol (unidirectional ANOVA, F2.31 = 3.46 p <0.05, Fisher's post hoc LSD test: p <0.05, Fig. 2g). This effect was maintained for 24 hours (unidirectional ANOVA, F2.31 = 3.57 p <0.05, Fisher's post hoc LSD test : p <0.05, Fig. 2i). Again, the dose of 1 nmol of GAL (1-15) had no effect on ethanol preference.
    [0195]
    [0196] In the water intake (Fig. 2d, e, f) and feed (Fig. 2j, k, l), no differences were found in any temporary point after administration by icv of GAL (1-15) at any dose.
    [0197]
    [0198] These results indicate that GAL (1-15) causes a strong decrease in alcohol preference and intake in rats.
    [0199]
    [0200] Example 3. Comparison between GAL and GAL (1-15) in the paradigm of choice between two bottles.
    [0201]
    [0202] In the ethanol intake, the global unidirectional ANOVA analysis showed a significant difference between LAG and the GAL N-terminal fragment (1-15) at 2, 14 and 24 hours after the treatments. Two hours after the injection, GAL (1-15) significantly decreased the intake of ethanol compared to GAL (unidirectional ANOVA, F2.31 = 4.208 p <0.05, Fisher's LSD test post hoc: p <0.01 Fig. 3a). The same response pattern was observed in the other time points, GAL (1-15) significantly decreased the ethanol intake compared to the GAL 14 groups (unidirectional ANOVA, F2,30 = 3.97 p <0.05, test Fisher's post hoc LSD : p <0.05, Fig. 3b) and 24 hours (unidirectional ANOVA, F2.30 = 2.53 p <0.05, Fisher's LSD test post hoc: p <0.05; 3c) after the icv injection
    [0203]
    [0204] Regarding the preference for ethanol, the difference between GAL and GAL (1-15) was observed again. GAL (1-15) decreased the preference for ethanol compared to GAL, 2 hours after its administration (unidirectional ANOVA, F2,30 = 3.55 p <0.05, Fisher's LSD test post hoc: p <0, 05; Fig. 3g), effect that was maintained 24 hours later (unidirectional ANOVA, F2,32 = 3.43 p <0.05, Fisher's LSD test post hoc: p <0.05, Fig. 3i).
    [0205]
    [0206] GAL has no effect on the preference and intake of ethanol compared to the vehicle at any time point (Fig. 3).
    [0207]
    [0208] No differences were found between GAL and the GAL (1-15) fragment in water intake (Fig. 3d, e, f) or in feed intake (Fig. 3j, k, l).
    [0209]
    [0210] Example 4. Effects mediated by GAL (1-15) blocked by the antagonist M871 of the GALR2 receptor in the paradigm of choice between two bottles.
    [0211]
    [0212] In the test of choice between two bottles, the antagonist M871 of GALR2 significantly blocked the decrease in the intake of ethanol (unidirectional ANOVA, F2,34 = 3.72 p <0.05, Fisher's LSD test post hoc: p <0 , 05; Fig. 4a) induced by GAL (115) 2 hours after its administration.
    [0213]
    [0214] Regarding the preference for ethanol, the same type of change was observed. Thus, GALR2 participated in the effect mediated by GAL (1-15), since the antagonist M871 of GALR2 significantly blocked the decrease in the preference for ethanol induced by GAL (1-15) (unidirectional ANOVA, F2,32 = 3, 39 p <0.05, Fisher LSD post hoc test: p <0.05, Fig.4c).
    [0215]
    [0216] The antagonist M871 of GALR2 isolated at a dose of 3 nmol had no effect on the intake of ethanol (0.13 ± 0.06 g / kg) or on the preference for ethanol (12.65 ± 8.23%).
    [0217]
    [0218] Neither the water intake (Fig. 4b) nor the feed intake (Fig. 4d) were modified with M871 (water intake: 8.26 ± 2.00 g / kg; feed intake: 6.67 ± 0.95 g) or GAL (1-15) + M871 2 hours after injection.
    [0219]
    [0220] Example 5. Effects of GAL (1-15) on the expression of the galanin receptor mRNA and on the C-Fos and Rab5 genes of the striatum in the voluntary consumption of ethanol.
    [0221]
    [0222] As shown in Fig. 5, GAL (1-15) at a dose of 3 nmol produced a significant increase in the mRNA levels of the C-Fos genes (t8 = 5.488 p <0.001, Fig. 5a) and Rab5 (t6 = 4.148 p <0.01, Fig. 5b) in the test of choice between two bottles 2 hours after administration.
    [0223]
    [0224] The administration of GAL (1-15) also modified the expression of the GALR1 and GALR2 receptors in the striatum, which produced a significant decrease in GALR1 mRNA levels , (t10 = 2.341 p <0.05; 5c) and a slight reduction in the expression of GALR2, (t10 = 1.360 p = 0.101; Fig. 5d), suggesting the involvement of both receptors in the effects of GAL (1-15).
    [0225]
    [0226] Example 6. Effects of GAL (1-15) on reduced locomotion by ethanol
    [0227]
    [0228] As described above, the ip administration of ethanol at 1.75 g / kg reduced the distance traveled (unidirectional ANOVA, F1.25 = 62.2 p <0.001) and the average velocity (unidirectional ANOVA, F1.25 = 62, 2 p <0.001) five minutes after its administration (Fig. 6).
    [0229] The effect of the dose of 3 nmol of GAL (1-15) on locomotion (distance traveled and average speed), depended on ethanol ip (distance traveled: bidirectional ANOVA for alcohol interaction / icv treatment; F1,25 = 7, 19 p <0.01, mean velocity: bidirectional ANOVA for alcohol interaction / icv treatment, F1.25 = 7.19 p <0.01) (Fig. 6). Therefore, in rats after ip administration of ethanol, GAL (1-15) decreased the distance traveled (Fisher's LSD test post hoc: p <0.001, Fig. 6a), whereas these effects were not observed in the rats with systemic administration of saline solution (Fisher's post hoc LSD test : p = 0.71, Fig. 6a). Similar to the distance traveled, GAL (1-15) decreased the average velocity exclusively in the rats treated systemically with ethanol (Fisher's LSD test: p <0.001, Fig. 6b).
    [0230]
    [0231] Example 7. Expression of GALR1 and GALR2 in the striatum after acute administration of ethanol
    [0232]
    [0233] To determine whether ethanol influenced the expression of GALR1 and GALR2 in the striatum, we evaluated the effects in the acute administration of ethanol on the levels of GALR1 and GALR2 mRNA in the striatum at 2 and 4 hours.
    [0234]
    [0235] As shown in Table 2, a single injection of ethanol (4g / kg ip) had no effect on the expression of GALR1 in the striatum at 2 and 4 hours after administration (unidirectional ANOVA, F2,14 = 1 , 19 p = 0.24).
    [0236]
    [0237] Time after injection i.p. of EtOH (4g / kg)
    [0238]
    [0239] MRNA expression 0 hours 2 hours 4 hours
    [0240]
    [0241]
    [0242]
    [0243]
    [0244]
    [0245] Table 2. Effects of the administration of ethanol on the expression of GALR1 and GALR2 in the striated body. The effects of acute ip administration of EtOH (4 g / kg) on the expression of GALR1 and GALR2 mRNA in the striatum were measured at 0, 2 and 4 hours after injection. The data represent the mean ± SEM (n = 4-8 animals per group). No significant differences were found by unidirectional ANOVA analysis.
    [0246]
    [0247] Neither were effects observed on GALR2 mRNA levels at any time point (unidirectional ANOVA, F2,14 = 1.15 p = 0.34).
    [0248]
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    权利要求:
    Claims (20)
    [1]
    1. A compound that is galanin (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 an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, for use in the prevention and / or treatment of disorders and effects related to alcohol.
    [2]
    2. A compound for use in the prevention and / or treatment of disorders and effects related to alcohol according to claim 1 wherein said compound is galanin (1-15), having the general formula Gly-Trp-Thr- Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His-Ala or GWTLNSAGYLLGPHA, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate.
    [3]
    3. A compound for use in the prevention and / or treatment of disorders and effects related to alcohol according to claim 2 wherein said compound is galanin (1-15), having the general formula Gly-Trp-Thr- Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His-Ala or GWTLNSAGYLLGPHA.
    [4]
    4. A compound for use in the prevention and / or treatment of alcohol-related disorders and effects according to any of claims 1 to 3, wherein the alcohol-related disorder or effect is selected from the composite list for acute intoxication, harmful use, dependency syndrome, state of abstinence and other mental or behavioral disorders induced by alcohol due to its consumption.
    [5]
    5. A compound for use in the prevention and / or treatment of disorders and effects related to alcohol according to claim 4, wherein the disorder or effect related to alcohol is acute intoxication or pathological intoxication.
    [6]
    6. A compound for use in the prevention and / or treatment of disorders and effects related to alcohol according to claim 4, wherein the disorder or effect related to alcohol is dependency syndrome or state of abstinence.
    [7]
    A compound for use in the prevention and / or treatment of disorders and effects related to alcohol according to any of claims 1 to 6, wherein said compound is used for the reduction of alcohol consumption.
    [8]
    A compound for use in the prevention and / or treatment of disorders and effects related to alcohol according to any of claims 1 to 7 wherein said compound is used in the preparation of a pharmaceutical composition for use in said prevention and / or treatment of disorders and effects related to alcohol.
    [9]
    9. A pharmaceutical composition or kit comprising galanin (1-15), having the general formula Gly-T rp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His- Ala or GWTLNSAGYLLGPHA, or an analogue thereof, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, for use in the prevention and / or treatment of disorders and effects related to alcohol.
    [10]
    10. A pharmaceutical composition or kit comprising galanin (1-15), having the general formula Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His-Ala or GWTLNSAGYLLGPHA, or its pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, for use in the prevention and / or treatment of disorders and effects related to alcohol.
    [11]
    11. A pharmaceutical composition or kit comprising galanin (1-15), having the general formula Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-His-Ala or GWTLNSAGYLLGPHA, for use in the prevention and / or treatment of disorders and effects related to alcohol.
    [12]
    12. A pharmaceutical composition or kit according to any of claims 9 to 11, wherein the disorder or effect related to alcohol is selected from the list composed of acute intoxication, harmful use, dependency syndrome, abstinence and other mental or behavioral disorders induced by alcohol due to its consumption.
    [13]
    13. A pharmaceutical composition or kit according to claim 12, wherein the disorder or effect related to alcohol is acute drunkenness or pathological intoxication.
    [14]
    14. A pharmaceutical composition or kit according to claim 12, wherein the effect or disorder related to alcohol is dependency syndrome or withdrawal state.
    [15]
    15. A pharmaceutical composition or kit according to any of claims 9 to 14, wherein said pharmaceutical composition or kit is used in reducing the consumption of alcohol.
    [16]
    16. A pharmaceutical composition or kit according to any of claims 9 to 15, wherein said pharmaceutical composition or kit further comprises another active ingredient and is adapted for simultaneous or sequential combination.
    [17]
    17. A pharmaceutical composition or kit according to claim 16, wherein the pharmaceutical composition or kit prepared is adapted for the simultaneous administration of the active principles.
    [18]
    18. A pharmaceutical composition or kit according to claim 17, wherein the active ingredients are in the same unit dosage form.
    [19]
    19. A pharmaceutical composition or kit according to claim 16, wherein the pharmaceutical composition or kit prepared is adapted for the sequential administration of the active ingredients.
    [20]
    20. A pharmaceutical composition or kit according to claim 19, wherein the active ingredients are in separate unit dosage forms.
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    同族专利:
    公开号 | 公开日
    EP3693002A1|2020-08-12|
    ES2707210B2|2020-09-30|
    WO2019068948A1|2019-04-11|
    EP3693002A4|2021-12-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2005080427A1|2004-02-17|2005-09-01|Neurotargets Limited|Galanin receptors and brain injury|
    US7493171B1|2000-11-21|2009-02-17|Boston Scientific Neuromodulation Corp.|Treatment of pathologic craving and aversion syndromes and eating disorders by electrical brain stimulation and/or drug infusion|
    WO2004028552A1|2002-09-25|2004-04-08|Garvan Institute Of Medical Research|Method for inducing mammary epithelial cell differentiation|
    ES2644978B1|2015-11-20|2018-09-25|Universidad De Málaga|SCREENING METHOD FOR THE IDENTIFICATION OF GALANINE TYPE 2 RECEIVER AGONISTS AND / OR NEUROPEPTIDE TYPE Y1 RECEIVER AGONISTS AND CAPABILITIES TO PROMOTE THE INTERACTION BETWEEN GALR2 AND ASYLOR FORMATION / NPYY1R|
    法律状态:
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    优先权:
    申请号 | 申请日 | 专利标题
    ES201731170A|ES2707210B2|2017-10-02|2017-10-02|GALand analogs thereof for use in the prevention and / or treatment of alcohol-related disorders and effects.|ES201731170A| ES2707210B2|2017-10-02|2017-10-02|GALand analogs thereof for use in the prevention and / or treatment of alcohol-related disorders and effects.|
    EP18865023.8A| EP3693002A4|2017-10-02|2018-10-02|Gal and analogues thereof for use in the prevention and/or treatment of alcohol-related effects and disorders|
    PCT/ES2018/070634| WO2019068948A1|2017-10-02|2018-10-02|Gal and analogues thereof for use in the prevention and/or treatment of alcohol-related effects and disorders|
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