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1. 发明申请

WO2008152146A1 PERIPHERICAL TISSUE SAMPLE CONTAINING CELLS EXPRESSING THE 5HTR2C AND/OR ADARS AS MARKERS OF THE ALTERATION OF THE MECHANISM OF THE 5HTR2C MRNA EDITING AND ITS APPLICATIONS 审中-公开
标题翻译：包含表达5HTR2C和/或ADARS的细胞的外周组织样品作为改变5HTR2C MRNA编码机制的标记及其应用
公开(公告)号：WO2008152146A1
公开(公告)日：2008-12-18
申请号：PCT/EP2008/057519
申请日：2008-06-13
申请人： BIOCORTECH , WEISSMANN, Dinah , PUJOL, Jean-François , VINCENT, Laurent , CAVAREC, Laurent , MANN, John
发明人： WEISSMANN, Dinah , PUJOL, Jean-François , VINCENT, Laurent , CAVAREC, Laurent , MANN, John
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6883 , C12Q2600/136 , C12Q2600/158 , G01N33/6896 , G01N33/942
摘要： The present invention relates to an in vitro method for predicting a pathology related to an alteration of the mechanism of the mRNA editing of ADAR dependent A to I mRNA editing, particularly the serotonin 2C receptor (5HTR2C), in a patient from a peripherical tissue sample containing cells expressing said mRNA, such as the 5HTR2C mRNA, and/or adenosine deaminases acting on RNA (ADARs), such as skin and/or blood tissue sample. The present invention further comprises a method for identifying if an agent is capable of in vivo modifying the editing of the 5HTR2C mRNA in brain tissue or to control the efficiency of a drug intended to prevent or to treat a pathology related to an alteration of the mechanism of the 5HTR2C mRNA editing brain tissue, these methods comprising the implementation of said peripherical tissue markers. In a particular aspect, the present invention relates to such methods wherein the 5HTR2C mRNA editing rate or profile, when it is necessary, is determined by a single strand conformation polymorphism (SSCP) method after amplification by a PCR, preferably by a nested PCR, of the specific mRNA fragment containing the edition sites, making it possible, under given analytical conditions, to obtain the editing rate and/or profile of this edited 5HTR2C mRNA from said peripherical tissue. Finally the invention relates to particular nucleic acid primers implemented in said nested PCR.
摘要翻译：本发明涉及一种用于预测来自外周组织样品的患者中ADAR依赖性A至I mRNA编辑的mRNA编辑，特别是5-羟色胺2C受体（5HTR2C）的mRNA编辑的机制的改变的病理学的体外方法含有表达所述mRNA的细胞，例如5HTR2C mRNA，和/或作用于RNA（ADAR）的腺苷脱氨酶，例如皮肤和/或血液组织样品。本发明还包括用于鉴定药物是否能够体内修饰脑组织中的5HTR2C mRNA的编辑或控制旨在预防或治疗与机制改变有关的病理学的效力的方法的5HTR2C mRNA编辑脑组织，这些方法包括实施所述外周组织标记物。在特定方面，本发明涉及这样的方法，其中当需要时，通过PCR扩增后优选通过巢式PCR，通过单链构象多态性（SSCP）方法确定5HTR2C mRNA编辑速率或分布，的具有编码位点的特异性mRNA片段，使得在给定的分析条件下可以从所述外周组织获得该编辑的5HTR2C mRNA的编辑率和/或分布。最后，本发明涉及在所述巢式PCR中实施的特定核酸引物。

2. 发明申请

WO2011161253A1 EDITING PROFILING OF PDE8A PRE -MRNA : USE AS SPECIFIC BIOMARKER OF ADARS ACTIVITIES IN HUMAN TISSUES TO DIAGNOSE AND TO PREDICT AND ASSESS THERAPEUTIC EFFICACY AND/OR EFFICIENCY OR POTENTIAL DRUG SIDE EFFECTS 审中-公开
标题翻译： PDE8A PRE-MRNA的编辑概况：用作人体组织中ADARS活动的特定生物标志物，用于诊断和预测和评估治疗效果和/或效率或潜在药物副作用
公开(公告)号：WO2011161253A1
公开(公告)日：2011-12-29
申请号：PCT/EP2011/060644
申请日：2011-06-24
申请人： BIOCORTECH , WEISSMANN, Dinah , PUJOL, Jean-François , CAVAREC, Laurent , VINCENT, Laurent
发明人： WEISSMANN, Dinah , PUJOL, Jean-François , CAVAREC, Laurent , VINCENT, Laurent
IPC分类号： C12Q1/68 , G01N33/50
CPC分类号： C12Q1/6883 , C12Q1/34 , C12Q2600/106 , C12Q2600/136 , C12Q2600/142 , C12Q2600/158 , G01N33/5023 , G01N2333/978 , G01N2800/28 , G01N2800/2821 , G01N2800/2857 , G01N2800/30 , G01N2800/302 , G01N2800/303 , G01N2800/304
摘要： The present invention relates to the use of the editing profile of PDE8A pre-mRNA as a specific bio marker of ADARs activities in evolved primate, particularly in Human tissues. The present invention also relates to an in vitro method for predicting in Human an alteration of the mechanism of the ADARs catalysed pre-mRNA editing of target genes, by analysing the PDE8A pre-mRNA editing profile in a peripheral tissue sample containing cells expressing said PDE8A pre-mRNA, such as blood sample. The present invention is also directed to an in vitro method for the screening of potential therapeutic compound and to predict and assess therapeutic efficacy and/or efficiency or to diagnose potential severe brain or peripheral drug side effects implementing said PDE8A pre-mRNA editing profile as specific biomarker. The present invention is further directed to a method for determining the PDE8A pre-mRNA editing profile in Human, particularly by capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) method after amplification by a nested PCR. Finally the invention relates to particular nucleic acid primers implemented in said nested PCR and kit comprising such sets of primers and human cells capable of expressing PDE8A and ADARs.
摘要翻译：本发明涉及PDE8A前mRNA的编辑概况在进化灵长类动物中特别是ADARs活性的特异性生物标记物的使用，特别是在人组织中。本发明还涉及通过在含有表达所述PDE8A的细胞的外周组织样品中分析PDE8A前mRNA编码谱的方法，在人类中预测ADAR催化的靶基因前mRNA编辑机制的改变前mRNA，如血液样品。本发明还涉及用于筛选潜在治疗化合物并预测和评估治疗功效和/或效率或用于诊断实施所述PDE8A前mRNA编辑简档作为具体的潜在严重脑或外周药物副作用的体外方法生物标志物。本发明还涉及一种通过巢式PCR扩增后，特别是通过毛细管电泳单链构象多态性（CE-SSCP）方法测定人类PDE8A前mRNA编码特征的方法。最后，本发明涉及在所述巢式PCR中实施的特定核酸引物和包含能够表达PDE8A和ADAR的这样一组引物和人细胞的试剂盒。

3. 发明申请

WO2010070074A2 EVALUATION OF THE POTENTIAL RISK OF DRUG INDUCED MOOD DISTURBANCE AND SUICIDE: USE OF A DEDICATED PLATFORM 审中-公开
标题翻译：评估药物诱发的肌肉障碍和副作用的潜在风险：使用专用平台
公开(公告)号：WO2010070074A2
公开(公告)日：2010-06-24
申请号：PCT/EP2009/067464
申请日：2009-12-17
申请人： BIOCORTECH , WEISSMANN, Dinah , PUJOL, Jean-François , VINCENT, Laurent , CAVAREC, Laurent
发明人： WEISSMANN, Dinah , PUJOL, Jean-François , VINCENT, Laurent , CAVAREC, Laurent
IPC分类号： C12Q1/68 , G01N33/573
CPC分类号： C12Q1/6881 , C12Q1/6883 , C12Q2600/142 , C12Q2600/158 , G01N33/5014 , G01N33/5058 , G01N33/942 , G01N2800/302 , G01N2800/303 , G01N2800/304
摘要： The present invention relates to in vitro methodsfor the determination of the potential toxicity of test compounds. The invention also comprises in vitro methods for the selection of therapeutical compounds useful for the treatment of pathology related to an alteration of the mechanism of the mRNA editing of ADAR dependent A to I mRNA editing of the serotonin 2C receptor (5HTR2C). Finally, the present invention is directed to the kits and tools for the implementation of these methods. The invention is of special utility in the pharmaceutical industry for analysis of the toxicity profile or the screening of compounds involved in drug development and/or in pharmaceutical compositions.
摘要翻译：本发明涉及测定化合物潜在毒性的体外方法。本发明还包括用于选择治疗化合物的治疗化合物的方法，所述治疗化合物可用于治疗与改变血清素2C受体（5HTR2C）的ADAR依赖性A至I mRNA编辑的mRNA编辑机制相关的病理学。最后，本发明涉及用于实施这些方法的套件和工具。本发明在制药工业中用于分析涉及药物开发和/或药物组合物的化合物的毒性特征或筛选。

4. 发明申请

WO2005103047A1 DERIVES DU 14.15-DIHYDRO 20.21-DINOREBURNAMENIN-14-OL, ET LEURS APPLICATIONS 审中-公开
标题翻译： 14.15-二氢O O O O O IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN OF OF OF OF OF OF OF OF OF OF OF OF OF OF
公开(公告)号：WO2005103047A1
公开(公告)日：2005-11-03
申请号：PCT/FR2005/000902
申请日：2005-04-14
申请人： BIOCORTECH , CIAPETTI, Paola , DEYON, Laurence , WERMUTH, Camille-Georges , PUJOL, Jean-François , WEISSMANN, Dinah
发明人： CIAPETTI, Paola , DEYON, Laurence , WERMUTH, Camille-Georges , PUJOL, Jean-François , WEISSMANN, Dinah
IPC分类号： C07D461/00
CPC分类号： C07D461/00
摘要： L'invention a pour objet de nouveaux dérivés du 14,15-dihydro 20,21 dinoréburnaméninl4-ol, de formule (I) dans laquelle R représente un radical -AR', dans lequel A représente un hétéroatome et R' représente un groupement choisi dans le groupe constitué par les radicaux alkyles en C 1 -C 6 , alcényles en C 1 -C 6 , alcynyles en C 1 -C 6 , aralkyles; les esters de formule - R 1 -CO-O-R 2 ; les amides de formule -R 3 -CO-NZY dans laquelle Y et Z peuvent former ensemble un radical cycloalkyle ou un radical hétérocyclique, éventuellement substitué par un ou plusieurs radicaux alkyles; un radical choisi dans le groupe constitué par les radicaux alkyles, alcényles ou alcynyles, substitués par au moins une amine de formule -NZY; ou l'un de ses sels pharmaceutiquement acceptables, y compris ses isomères, ses énantiomères, ses diastéréoisomères et leurs mélanges. L'invention a également pour objet l'utilisation de ces nouveaux dérivés pour la préparation d'une composition pharmaceutique, notamment destinée au traitement et/ou la prévention chez l'Homme des dépressions, des troubles du cycle veille-sommeil et des troubles symptomatiques frontaux dans leur composantes cognitives.
摘要翻译：本发明涉及具有式（I）的14,15-二氢20,21二辛烷亚胺-14-醇的新衍生物，其中R表示一个自由基-AR'，其中A表示杂原子，R'表示选自该基团包括C1-C6的烷基，C1-C6的烯基，C1-C6的炔基，芳烷基; 具有式-R1-CO-O-R2的酯; 具有式-R3-CO-NZY的酰胺，其中Y和Z一起可以形成任选被一个或多个烷基取代的环烷基或杂环基; 选自由至少一个具有式-NZY的胺取代的烷基，烯基或炔基的基团; 或其药学上可接受的盐之一，包括其异构体，对映体和非对映异构体及其混合物。本发明还涉及所述新型衍生物用于制备药物组合物的用途，该药物组合物特别用于治疗和/或预防人类中认知成分中的抑郁症，睡眠/觉醒周期障碍和症状性正面疾病。

5. 发明申请

WO2005082365A1 UTILISATION DU 14,15-DIHYDRO 20,21-DINOREBURNAMENIN14-OL POUR TRAITER ET/OU PREVENIR LES DEPRESSIONS MAJEURES ET LES DESORDRES DU CYCLE VEILLE-SOMMEIL 审中-公开
标题翻译：用于治疗和/或预防严重呕吐和休眠/排卵周期性疾病的14,15-二氢-20,21-多巴酚丁胺素-14-OL的用途
公开(公告)号：WO2005082365A1
公开(公告)日：2005-09-09
申请号：PCT/FR2005/000178
申请日：2005-01-27
申请人： BIOCORTECH , PUJOL, Jean-François , WEISSMANN, Dinah
发明人： PUJOL, Jean-François , WEISSMANN, Dinah
IPC分类号： A61K31/437
CPC分类号： A61K31/4375
摘要： L'invention a pour objet une nouvelle application thérapeutique du 14,15-dihydro 20,2 1 -dinoréburnaménin 1 4-ol pour le traitement des dépressions majeures chez l'Homme, notamment pour le traitement de patient résistant aux traitements antidépresseurs classiques, ou pour le traitement des désordres du cycle veille-sommeil.
摘要翻译：本发明涉及用于治疗人类严重抑郁症的14,15-二氢-2,2,2-dinoreburnamaminin-14-醇的新型治疗用途，特别是用于治疗耐常规抗抑郁药物治疗和治疗睡眠/唤醒循环障碍。

6. 发明申请

WO2007006922A2 NOUVEAUX DERIVES 1H-INDOLE-PYRIDINECARBOXAMIDES ET 1H-INDOLE-PIPERIDINECARBOXAMIDE, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT 审中-公开
标题翻译：新的1H-吲哚吡啶甲酰胺和1H-吲哚 - 哌啶甲酰胺衍生物，其制备方法和包含它们的药物组合物
公开(公告)号：WO2007006922A2
公开(公告)日：2007-01-18
申请号：PCT/FR2006/001610
申请日：2006-07-06
申请人： LES LABORATOIRES SERVIER , CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE , UNIVERSITE PARIS SUD , BRION, Jean-Daniel , BINTEIN, Fabrice , RAZET, Rodolphe , RAZON, Patrick , RENKO, Zafiarisoa, Dolor , LEVOIRIER, Eric , PUJOL, Jean-François , WEISSMAN, Dinah , LE RIDANT, Alain , HARPEY, Catherine
发明人： BRION, Jean-Daniel , BINTEIN, Fabrice , RAZET, Rodolphe , RAZON, Patrick , RENKO, Zafiarisoa, Dolor , LEVOIRIER, Eric , PUJOL, Jean-François , WEISSMAN, Dinah , LE RIDANT, Alain , HARPEY, Catherine
IPC分类号： C07D401/12
CPC分类号： C07D401/12
摘要： Composés de formule (I) dans laquelle A représente un radical bivalent dans lesquels Z représente un atome d'oxygène ou un atome de soufre, R 6 représente un atome d'hydrogène, un groupement alkyle, alkényle, arylalkyle, ou polyhalogénoalkyle, ou une chaîne alkyle linéaire ou ramifié substituée, ------- représente une liaison simple ou une liaison double, R 1 , R 2 , R 3 , R 4 représentent un atome d'hydrogène ou d'halogène, un groupement alkyle, alkoxy, hydroxy, cyano, nitro, polyhalogénoalkyle, ou amino éventuellement substitué, alkényle, ou une chaîne alkyle linéaire ou ramifiée substituée par un ou plusieurs groupements, R 5 représente un atome d'hydrogène, un groupement alkyle, aminoalkyle, ou hydroalkylkyle, X, Y représentent un atome d'hydrogène, ou un groupement alkyle, R a , R b , R c , R d représentent un atome d'hydrogène, ou d'halogène, un groupement alkyle, hydroxy, alkoxy, cyano, nitro, polyhalogénoalkyle, amino éventuellement substitué, alkyle, ou une chaîne alkyle linéaire ou ramifiée substituée, Re représente un atome d'hydrogène, ou un groupement alkyle, arylalkyle, ou alkényle, ou une chaîne alkyle linéaire ou ramifiée substituée, leurs énantiomères, diastéréoisomères, N-oxydes, ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable. Médicaments.
摘要翻译：本发明涉及式（I）化合物，其中A代表Z代表氧原子或硫原子的二价基团; R 6表示氢原子，烷基，烯基，芳基烷基或多卤代烷基或取代的直链或支链烷基， - 表示单键或双键; R 1，R 2，R 3，R 4代表氢或卤素原子，烷基，烷氧基，羟基，氰基，硝基或多卤代烷基，或任选取代的氨基，烯基或被一个或多个基团取代的直链或支链烷基链; R 5表示氢原子，烷基，氨基烷基或氢烷基; X，Y表示氢原子或烷基; R a，R b，R c，R d，R d表示氢或卤素原子，烷基，羟基烷氧基，氰基，硝基或多卤代烷基，任选取代的氨基，烷基或取代的直链或支链烷基链; Re表示氢原子或烷基，芳基烷基或烯基或取代的直链或支链烷基链，它们的对映体，非对映异构体，N-氧化物，以及它们的药学上可接受的酸或碱加成盐。本发明还涉及相应的药物。

7. 发明公开

EP1737856A1 DERIVES DU 14.15-DIHYDRO 20.21-DINOREBURNAMENIN-14-OL, ET LEURS APPLICATIONS 有权
标题翻译： DERIVES DU 14.15-DIHYDRO 20.21-DINOREBURNAMENIN-14-OL，ET LEURS应用
公开(公告)号：EP1737856A1
公开(公告)日：2007-01-03
申请号：EP05757149.9
申请日：2005-04-14
申请人： Biocortech
发明人： CIAPETTI, Paola , DEYON, Laurence , WERMUTH, Camille-Georges , PUJOL, Jean-François , WEISSMANN, Dinah
IPC分类号： C07D461/00 , A61K31/437 , A61P25/24 , A61P25/18
CPC分类号： C07D461/00
摘要： The invention relates to novel derivatives of 14,15-dihydro 20,21 dinoreburnamenin-14-ol, having formula (I), in which R represents a radical -AR', wherein A represents a heteroatom and R' represents a group selected from the group comprising alkyl radicals at C1-C6, alkenyls at C1-C6, alkynyls at C1-C6, aralkyls; esters having formula -R1-CO-O-R2; amides having formula -R3-CO-NZY, wherein Y and Z together can form a cycloalkyl radical or a heterocyclic radical, optionally substituted by one or more alkyl radicals; a radical selected from the group comprising alkyl radicals, alkenyls or alkynyls, substituted by at least one amine having formula -NZY; or one of the pharmaceutically-acceptable salts thereof, including the isomers, enantiomers and diastereoisomers thereof and mixtures of same. The invention also relates to the use of said novel derivatives for the preparation of a pharmaceutical composition which is intended, in particular, for the treatment and/or prevention of depression, sleep/wake cycle disorders and symptomatic frontal disorders in cognitive components among humans.
摘要翻译：本发明涉及具有式（I）的新颖的14,15-二氢20,21 ore铃啉-14-醇的衍生物，其中R表示基团-AR'，其中A表示杂原子且R'表示选自该基团包含C1-C6烷基，C1-C6烯基，C1-C6炔基，芳烷基; 具有式-R1-CO-O-R2的酯; 具有式-R3-CO-NZY的酰胺，其中Y和Z一起可以形成任选被一个或多个烷基取代的环烷基或杂环基团; 选自包含烷基，烯基或炔基的基团，其被至少一种具有式-NZY的胺取代; 或其药学上可接受的盐之一，包括其异构体，对映异构体和非对映异构体及其混合物。本发明还涉及所述新衍生物在制备药物组合物中的用途，所述药物组合物特别旨在用于治疗和/或预防人类认知成分中的抑郁症，睡眠/觉醒周期障碍和症状性前额障碍。

8. 发明公开

EP2162550A1 PERIPHERICAL TISSUE SAMPLE CONTAINING CELLS EXPRESSING THE 5HTR2C AND/OR ADARS AS MARKERS OF THE ALTERATION OF THE MECHANISM OF THE 5HTR2C MRNA EDITING AND ITS APPLICATIONS 失效转让
标题翻译：与5HTR2C AND / OR ADAR表达细胞作为标记修订5HTR2C体mRNA加工及其应用的机制外周组织样本
公开(公告)号：EP2162550A1
公开(公告)日：2010-03-17
申请号：EP08761038.2
申请日：2008-06-13
申请人： Biocortech
发明人： WEISSMANN, Dinah , PUJOL, Jean-François , VINCENT, Laurent , CAVAREC, Laurent , MANN, John
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6883 , C12Q2600/136 , C12Q2600/158 , G01N33/6896 , G01N33/942
摘要： The present invention relates to an in vitro method for predicting a pathology related to an alteration of the mechanism of the mRNA editing of ADAR dependent A to I mRNA editing, particularly the serotonin 2C receptor (5HTR2C), in a patient from a peripherical tissue sample containing cells expressing said mRNA, such as the 5HTR2C mRNA, and/or adenosine deaminases acting on RNA (ADARs), such as skin and/or blood tissue sample. The present invention further comprises a method for identifying if an agent is capable of in vivo modifying the editing of the 5HTR2C mRNA in brain tissue or to control the efficiency of a drug intended to prevent or to treat a pathology related to an alteration of the mechanism of the 5HTR2C mRNA editing brain tissue, these methods comprising the implementation of said peripherical tissue markers. In a particular aspect, the present invention relates to such methods wherein the 5HTR2C mRNA editing rate or profile, when it is necessary, is determined by a single strand conformation polymorphism (SSCP) method after amplification by a PCR, preferably by a nested PCR, of the specific mRNA fragment containing the edition sites, making it possible, under given analytical conditions, to obtain the editing rate and/or profile of this edited 5HTR2C mRNA from said peripherical tissue. Finally the invention relates to particular nucleic acid primers implemented in said nested PCR.

9. 发明公开

EP1727543A1 UTILISATION DU 14,15-DIHYDRO 20,21-DINOREBURNAMENIN14-OL POUR TRAITER ET/OU PREVENIR LES DEPRESSIONS MAJEURES ET LES DESORDRES DU CYCLE VEILLE-SOMMEIL 有权
标题翻译： 14,15二氢20,21-dinoreburnamenine-14-OL用于治疗和防止严重抑郁症的用途
公开(公告)号：EP1727543A1
公开(公告)日：2006-12-06
申请号：EP05717501.0
申请日：2005-01-27
申请人： Biocortech
发明人： PUJOL, Jean-François , WEISSMANN, Dinah
IPC分类号： A61K31/437
CPC分类号： A61K31/4375
摘要： The invention relates to a novel therapeutic use of 14,15-dihydro-20,21-dinoreburnamenin-14-ol for the treatment of serious depression in humans, particularly for the treatment of patients resistant to conventional anti-depressant treatments and for treatment of sleep/waking cycle disorders.

10. 发明授权

EP1737856B1 DERIVES DU 14.15-DIHYDRO 20.21-DINOREBURNAMENIN-14-OL, ET LEURS APPLICATIONS 有权
标题翻译： 14,15二氢20,21-dinoreburnamenine-14-OL衍生物及其
公开(公告)号：EP1737856B1
公开(公告)日：2010-11-17
申请号：EP05757149.9
申请日：2005-04-14
申请人： Biocortech
发明人： CIAPETTI, Paola , DEYON, Laurence , WERMUTH, Camille-Georges , PUJOL, Jean-François , WEISSMANN, Dinah
IPC分类号： C07D461/00 , A61K31/437 , A61P25/24 , A61P25/18
CPC分类号： C07D461/00
摘要： The invention relates to novel derivatives of 14,15-dihydro 20,21 dinoreburnamenin-14-ol, having formula (I), in which R represents a radical -AR', wherein A represents a heteroatom and R' represents a group selected from the group comprising alkyl radicals at C1-C6, alkenyls at C1-C6, alkynyls at C1-C6, aralkyls; esters having formula -R1-CO-O-R2; amides having formula -R3-CO-NZY, wherein Y and Z together can form a cycloalkyl radical or a heterocyclic radical, optionally substituted by one or more alkyl radicals; a radical selected from the group comprising alkyl radicals, alkenyls or alkynyls, substituted by at least one amine having formula -NZY; or one of the pharmaceutically-acceptable salts thereof, including the isomers, enantiomers and diastereoisomers thereof and mixtures of same. The invention also relates to the use of said novel derivatives for the preparation of a pharmaceutical composition which is intended, in particular, for the treatment and/or prevention of depression, sleep/wake cycle disorders and symptomatic frontal disorders in cognitive components among humans.

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