CA2919140C – Utilisation de flecainide en tant qu'agent anti-connexine et methode de potentialisation des effets d'un medicament psychotrope – comment résoudre l’ejaculation précoce


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UTILISATION DE FLECAINIDE EN TANT QU'AGENT ANTI-CONNEXINE ET SON PROCEDE
POTENTIALISATION DES EFFETS D'UN MEDICAMENT PSYCHOTROPE
Résumé de l'invention La présente invention concerne l'utilisation de flécaïnide en tant qu'agent anti-connexine. Cet agent anti-connexine est utilisé avantageusement pour potentialiser l'effet thérapeutique de divers médicaments psychotropes. Plus spécifiquement, l'invention propose un produit de combinaison contenant du flécaïnide et du modafinil.
Contexte de l'invention Les jonctions lacunaires sont impliquées dans la communication intercellulaire, ce qui est important pour maintenir l'homéostasie des tissus et des organes. Des jonctions lacunaires relient le cytoplasme cellulaire, permettant ainsi l'échange d'ions (Cat et I (+), de seconds messagers (AMPc, GMPc, IP3), plusieurs petits métabolites (glucose) et assurant ainsi un couplage électrique et métabolique entre les cellules. jonctions à perméabilité sélective, formées par des canaux protéiques contenus dans la membrane plasmique et formées par des hexamères de connexines.
Les hexamères de connexine pourraient aussi bien former un hémichannel, reliant l’espace intracellulaire à un espace extracellulaire.
Les connexines sont des protéines intégrales de la membrane plasmique, synthétisées par pratiquement tous les types de cellules, quelle que soit la position d'un organisme multicellulaire dans la phylogenèse du monde animal. Chez les vertébrés, les cellules occasionnelles ne produisant pas de connexines sont les cellules musculaires striées adultes, les spermatozoïdes et les cellules sanguines circulantes.
Contrairement aux nombreuses protéines membranaires, les connexines ont une demi-vie courte (entre 3 et 6 heures), ne sont pas glycosylées et n’ont pas d’activité enzymatique. À l'heure actuelle, au moins treize connexines distinctes ont été identifiées chez des mammifères; correspondant, chez l'homme, à 21 isoformes. En pratique, divers types de connexines peuvent être présents dans une pluralité de tissus, et la plupart des cellules synthétisent une pluralité de connexines. Avant d’atteindre la membrane cellulaire, les connexines s’assemblent en groupes de six molécules pour former des structures tubulaires creuses appelées connexons, qui se joignent à la membrane plasmique au moyen de vésicules de Golgi. Lorsque le contact de cellule est établi, les connexons d'une cellule s'alignent bout à bout avec ceux de la cellule voisine, établissant un canal hydrophile continu d'environ 10 nm de long. Ce canal jonctionnel établit un contact direct entre les cytoplasmes des deux cellules en contact, sur l'espace intercellulaire.
Les connexines sont impliquées dans un grand nombre de processus physiologiques et dans plusieurs applications d'agents bloquants les connexines (également appelés ci-après "agents bloquants les connexines").
ou "agents anti-connexine") ont été décrits.
Par exemple, des agents anti-connexine ont été proposés pour traiter et / ou prévenir les affections suivantes:
– cancers (W02006 / 134494 et W02006 / 049157), – certaines maladies cardiovasculaires (W02006 / 134494), – plaies (W02006 / 134494 et W02009 / 097077), – douleurs (W02009 / 148613), – migraines (Durham et Garrett, 2009) ), – épilepsie (Juszczak et Swiergiel, 2009), – affections neurologiques (W02006 / 134494) et maladies neurodégénératives (Takeuchi et al. 2011), – ischémie (Davidson et al, 2013), – lésion hépatique d'origine médicamenteuse (Patel et al, 2012) – maladies infectieuses (W02011 / 067607), – cytotoxicité induite par des agents chimiothérapeutiques (Tong X. et al, 2013) et – troubles inflammatoires (W02006 / 134494).
En outre, les présents inventeurs ont décrit précédemment que des agents anti-connexine sont capables de potentialiser les effets thérapeutiques de médicaments psychotropes (WO 2010/029131).
Ils ont notamment décrit que l'administration d'agents anti-connexine tels que l'acide méclofénamique (MFA) augmentait les effets thérapeutiques de diverses molécules psychotropes, permettant de réduire les doses actives et donc les effets indésirables de ces molécules psychotropes. Ces effets synergiques ont été observés avec un large éventail de

2 molécules psychotropes (clozapine, paroxétine, modafinil, diazépam, venlafaxine, escitalopram, bupropion et sertraline).
Identifier de nouveaux agents anti-connexine est donc primordial pour mettre en évidence de nouveaux outils thérapeutiques visant à traiter diverses maladies et troubles, en particulier en association avec des médicaments psychotropes.
Dans ce contexte, les inventeurs ont maintenant démontré que l'agent anti-arythmique bien connu, le flécaïnide, présente une activité anti-connexine étendue. Ceci est un résultat très surprenant, car la flécaïnide a été décrite jusqu'à présent comme interférant avec les canaux sodiques, en particulier sur les cellules du muscle cardiaque, et ces canaux ne sont pas liés aux jonctions lacunaires du cerveau. De plus, il a été démontré que la flécaïnide n’influence pas la résistance jonctionnelle des paires de cellules de myocytes cardiaques (Daleau et al, 1998).
Description détaillée de l'invention Dans le contexte de l'invention, "flécaïnide" désigne un composé de formule N- (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide. Tel qu'utilisé ici, ce terme désigne toute forme de ce composé, tel que l'un de ses sels. De préférence, ledit sel est l'acétate de flécaïnide. Ce terme peut également englober les précurseurs de flécaïnide pouvant être métabolisés dans le corps humain et / ou ses dérivés (par exemple, les dérivés chimiques résultant d'une ou de plusieurs substitutions d'halogènes et / ou de l'addition de groupes protecteurs).
Comme décrit sur les figures 5A et 5B, la flécaïnide possède un centre chiral impliquant l'existence d'énantiomères R et S (S – (+) – flécaïnide et R – (-) – flécaïnide).
La figure 5 montre les formules du R-flécaïnide (Fig. 5A, (R) -N- (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide) et du S-flécaïnide (Fig. 5B, le (S) -N- (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide).
Tel qu’utilisé ici, le terme "flécaïnide" désigne la forme racémique de N- (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide, ainsi que les composés R et S
leurs énantiomères ((R) -N- (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide et (5) -N-

3 (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide, respectivement).
Dans un mode de réalisation préféré de l'invention, l'énantiomère R du flécaïnide ((R) -N- (pipéridin-2-ylméthyl) -2,5-bis (2,2,2-trifluoroéthoxy) benzamide) sera utilisé.
La flécaïnide est actuellement administrée sous forme de racémate (Kroemer et al, 1989; Lie et al, 1989).
Les paramètres pharmacocinétiques des deux énantiomères du flécaïnide ont été largement décrits, après administration chez l'homme et les rongeurs, comme décrit ci-après:
En 1989, Kroemer et al. a publié une étude chez 13 patients recevant un traitement oral prolongé par flecainide. Les concentrations plasmatiques de S-flécainide et de R-flécaïnide ont été déterminées et les concentrations plasmatiques de R-flécaïnide étaient significativement plus élevées que celles de l'énantiomère S-flécaïnide (rapport R / S = 1,10), ce qui suggère que le médicament à base de flécaïnide est modérément énantiosélective [Kroemer et al, 1989].
En 1989, Gross et al. a comparé la disposition des deux énantiomères dans deux populations humaines: métaboliseurs extensifs (EM) et cinq métaboliseurs lents (PM) de spartéine / débrisoquine après administration de 50 mg d'acétate de flécaïnide racémique [Gross et al, 1989]. Gross et al.
ont présenté des données indiquant que la demi-vie du R-flécaïnide (12,9 h) était plus longue (P <0,03) que celle du S-flécaïnide (9,8 h). La clairance rénale des deux énantiomères était cependant comparable et similaire à celle observée chez les sujets EM. La récupération urinaire de R-flécaïnide (15,6 3,7 mg) était supérieure (P <0,03) à celle de l'énantiomère S (12,0 3,7 mg). La disposition énantiosélective observée dans les particules est donc due à une plus grande altération du métabolisme du R-flécaïnide que du S-flécaïnide.
En 1991, Alessi-Severini et al. a résumé les principaux résultats sur la pharmacocinétique et a conclu qu’il n’existait aucune preuve de la disposition énantiosélective du flécaïnide chez l’homme. [ Alessi-Severini et al., 1991], citant trois rapports sur la surveillance thérapeutique stéréosélective, qui avaient trouvé des ratios de rapport R / S de 0,67 à 1,39 (moyenne 1,03,16), 0,75 à 1,44 (moyenne de 1,04) et 0,89-1,32 (moyenne de 1,10 à 0,13), et que Gross et al. L'étude de 1989 n'était pas pertinente pour la population totale.
En 1998, Hanada et al. ont démontré une absence de distribution énantiosélective des deux énantiomères de la flécaïnide dans plusieurs tissus, après l'administration intraveineuse de racémate de flécaïnide chez le rat [Hanada et al, 1998].

4 Tel que révisé dans [Mehvar et al, 2002], il semble que les clairances rénales des énantiomères de la flécaïnide ne soient pas stéréosélectives chez les volontaires sains et les patients.
La littérature est donc globalement cohérente sur l'absence d'effets stéréosélectifs du flécaïnide sur la pharmacocinétique et le métabolisme.
Les propriétés physicochimiques des deux énantiomères de la flécaïnide ont également été décrites. En particulier, Turgeon et al. ont décrit une méthode d'analyse stéréosélective pour la détermination de l'agent anti-arythmique flécaïnide dans le plasma humain. La résolution des énantiomères est obtenue par chromatographie liquide à haute performance (HPLC) sur une colonne de silice en phase normale après transformation en dérivé avec le réactif optiquement actif (-) – chloroformiate de méthyle. [Turgeon et al., 1990].
De plus, Alessi-Severini et al. ont décrit une méthode stéréospécifique de chromatographie en phase liquide à haute performance pour la détermination de l'acétate de (R, S) -flécaïnide dans le plasma et l'urine humains. Les diastéréoisomères de flécaïnide ont été séparés après i) une extraction en une étape d'échantillons alcalinisés effectuée avec de l'éther diéthylique distillé, ii) la couche organique a été évaporée et le médicament a été transformé en dérivé avec[(4-nitrophenyl)sulfony1]-L-chlorure de propyle à 80 ° C pendant 2 h et iii) par chromatographie liquide à haute performance (CLHP) sur une colonne en phase inverse C18 avec une phase mobile consistant en acétonitrile: eau: triéthylamine (45: 55: 0,2) à un débit de 1 ml / min [Alessi-Severini et al., 1990].
L'acétate de flécaïnide racémique est un agent antiarythmique de classe lc largement utilisé, indiqué pour le traitement de divers types d'arythmie. Plus spécifiquement, il est utilisé pour réguler le rythme et le rythme du cœur. L'action de pompage du cœur est contrôlée par des signaux électriques qui traversent le muscle cardiaque. Ces signaux électriques provoquent la contraction régulière des deux paires de cavités cardiaques (artères et ventricules gauche et droit) afin de produire des battements de coeur réguliers. Si l'activité électrique dans le cœur est perturbée pour une raison quelconque, des battements de coeur irréguliers (arythmies) de différents types peuvent en résulter. Flecainide aide à traiter les arythmies en diminuant la sensibilité des cellules du muscle cardiaque aux impulsions électriques.
Ceci régule la conduction électrique dans le muscle cardiaque et réduit les perturbations du rythme cardiaque. En tant qu'agent antiarythmique de classe I, le flécaïnide interfère avec le canal sodique.

5

6 Il est important de noter que plusieurs études ont démontré que ces effets cardiovasculaires ne sont pas médiés par un seul énantiomère, les deux contribuant aux fonctions cardiovasculaires:
Les effets antiarythmiques de la flécaïnide et de ses énantiomères ont été évalués dans deux modèles animaux différents, la fibrillation ventriculaire induite par le chloroforme chez la souris et la tachycardie ventriculaire induite par la ouabaïne chez le chien. Les deux énantiomères étaient très efficaces pour supprimer ces deux arythmies expérimentales et semblaient être essentiellement équipotents. Aucune différence significative n'a été trouvée entre les deux énantiomères ou entre les énantiomères et la flécaïnide racémique [Banitt et al, 1986].
Les effets des énantiomères sur les caractéristiques de potentiel d'action dans les fibres de Purkinje cardiaque canine ont été évalués et ils ont démontré qu'ils exercent des effets électrophysiologiques similaires. [Kroemer et al, 1989].
Les effets du racémate d'acétate de flécaïnide et de ses deux énantiomères sur les canaux sodiques et potassiques à commande électrique et sur l'activité de pompe à sodium des fibres non myélinisées du nerf vague de cochon d'Inde ont été étudiés avec la méthode du saccharose-gap. Il n'y avait pas de différence significative dans l'effet causé par les énantiomères séparément [Lie et al, 1989].
Les effets des énantiomères ont été évalués sur des fibres de Purkinje canines isolées en utilisant des techniques classiques de microélectrodes. Les résultats suggèrent qu'il n'y a pas de différence significative entre les effets des énantiomères de flécaïnide sur les paramètres électrophysiologiques de base des fibres de Purkinje canines [Smallwood et al, 1989].
En conclusion, toutes ces études n'ont fourni aucune preuve indiquant que l'administration d'un seul énantiomère, plutôt que du médicament racémique, offrirait un avantage quelconque.
Selon un premier aspect, la présente invention concerne donc l'utilisation de flécaïnide, in vitro et in vivo, en tant qu'agent anti-connexine. En particulier, la présente invention concerne un flécaïnide destiné à être utilisé en tant qu'agent anti-connexine ou, en d'autres termes, à bloquer des jonctions intermédiaires.
Il existe 21 gènes codant différentes isoformes de connexine chez l’homme et différentes combinaisons de monomères de connexine intervenant dans la composition des jonctions lacunaires sont décrites. En particulier, les connexines 26 (Cx 26), 30 (Cx 30), 30,2 (Cx30.2), 32 (Cx 32), 36 (Cx 36), 37 (Cx 37), 40 (Cx 40), 43 ( Cx 43), 45 (Cx 45), 46 (Cx 46) et 47 (Cx 47) sont exprimés chez l'homme sur des cellules du système nerveux central ou périphérique (Nakase & Naus, 2004).
Les présents inventeurs ont observé que la flécaïnide était efficace pour inhiber les jonctions lacunaires constituées de toutes les connexines testées. En particulier, et comme décrit dans la partie expérimentale ci-dessous, le flécaïnide est efficace pour inhiber les jonctions lacunaires constituées de connexine Cx40, Cx26, Cx30, Cx32 et / ou Cx43. Il est important de noter que cet effet anti-connexine est similaire à celui observé pour des agents anti-connexine bien connus tels que la méfloquine et l'acide méclofénamique (MFA) (Juszczak & Swiergiel, 2009; Cruikshank et al, 2004; Harks et al, 2001).
Des niveaux d'inhibition plus élevés ont même été atteints pour les connexines gliales Cx26, Cx30 et Cx43 (voir figure 1).
La présente invention concerne donc l'utilisation in vitro de flécaïnide en tant qu'agent anti-connexine. De préférence, cet agent peut être utilisé pour inhiber les jonctions lacunaires constituées des connexines sélectionnées dans le groupe constitué de: Cx23 (SEQ ID N ° 1), Cx25 (SEQ ID N ° 2), Cx26 (SEQ ID N ° 3), Cx 30 (SEQ ID N ° 4), Cx30.2 (SEQ ID N ° 5), Cx30.3 (SEQ ID
N ° 6), Cx31 (SEQ ID N ° 7), Cx31.1 (SEQ ID N ° 8), Cx31.9 (SEQ ID N ° 9), Cx32 (SEQ ID
N °: 10), Cx36 (N ° SEQ ID: 11), Cx37 (N ° SEQ ID: 12), Cx40 (N ° SEQ ID: 13), Cx40.1 (N ° ID SEQ: 14), Cx43 (N ° SEQ ID: 15) ), Cx45 (SEQ ID N ° 16), Cx46 (SEQ ID N ° 17), Cx47 (SEQ ID N ° 18), Cx50 (SEQ ID N ° 19), Cx59 (SEQ ID N ° 20) et Cx62 ( SEQ
N ° ID: 21).
Dans un mode de réalisation préféré de l'invention, le flécaïnide est utilisé pour bloquer une ou plusieurs des connexines exprimées dans des cellules humaines du système nerveux central ou périphérique, sélectionnées dans le groupe constitué de: Cx 26 (SEQ ID NO: 3), Cx 30 (SEQ ID
NO: 4), Cx 30.2 (SEQ ID NO: 5), Cx 32 (SEQ ID NO: 10), Cx 36 (SEQ ID NO: 11), Cx 37 (SEQ ID
N ° 12), Cx 40 (SEQ ID N ° 13), Cx 43 (SEQ ID N ° 15), Cx 45 (SEQ ID N ° 16), Cx (SEQ ID N ° 17) et Cx 47 (SEQ ID N ° : 18).
Dans un mode de réalisation davantage préféré, le flécaïnide est utilisé pour bloquer une ou plusieurs des connexines sélectionnées dans le groupe constitué de: Cx40 (SEQ ID N ° 13), Cx26 (SEQ
ID
N ° 3), Cx30 (SEQ ID N ° 4), Cx32 (SEQ ID N ° 10) et Cx43 (SEQ ID N ° 15).

7 Dans un mode de réalisation encore plus préféré, la flécaïnide est utilisée pour bloquer une ou plusieurs des connexines sélectionnées dans le groupe constitué de: Cx26 (SEQ ID NO: 3), Cx30 (SEQ
ID n ° 4) et Cx43 (SEQ ID n ° 15).
En raison de son activité anti-connexine, le flécaïnide peut être utilisé pour le traitement d'un certain nombre de troubles et d'affections dont on sait qu'ils bénéficient d'un traitement par des molécules anti-connexine.
Cancers, maladies cardiovasculaires, plaies, douleurs, migraines, épilepsie, affections neurologiques et maladies neurodégénératives, maladies infectieuses, lésions hépatiques d'origine médicamenteuse, cytotoxicité induite par des agents chimiothérapeutiques, ischémie et troubles inflammatoires. .
Plus préférablement, le flécaïnide peut être utilisé pour la prévention et le traitement des cancers, des plaies, des migraines, de l'épilepsie, des maladies infectieuses, des lésions hépatiques d'origine médicamenteuse, de la cytotoxicité induite par des agents chimiothérapeutiques, de l'ischémie et des troubles inflammatoires.
Encore plus préférablement, le flécaïnide peut être utilisé pour la prévention et / ou le traitement des plaies, des migraines, des maladies infectieuses, des lésions hépatiques d'origine médicamenteuse, de la cytotoxicité induite par des agents chimiothérapeutiques et de l'ischémie.
Encore plus préférablement, le flécaïnide peut être utilisé pour la prévention et / ou le traitement des lésions hépatiques induites par un médicament, de la cytotoxicité induite par des agents chimiothérapeutiques et de l'ischémie.
Selon un aspect particulier de la présente invention, le flécaïnide est utilisé en tant qu'agent pour potentialiser les effets d'un médicament psychotrope. Ces effets de potentialisation sont illustrés ci-dessous par des expériences réalisées avec le modafinil (voir figures 2 à 4). En tant qu'agent anti-connexine, le flécaïnide peut potentialiser les effets de tout médicament psychotrope (comme indiqué dans le document WO
2010/029131 et US 2011/172188).
Le terme "potentialiser" dans ce cas signifie que la flécaïnide augmente considérablement les effets thérapeutiques du médicament psychotrope administré au même patient.
Ainsi, l'association du médicament psychotrope avec le flécaïnide permet de réduire les doses dudit médicament psychotrope et donc de limiter les effets indésirables dudit médicament psychotrope, et / ou d'obtenir un effet thérapeutique plus fort sans augmenter la dose dudit médicament psychotrope. .

8 Dans le présent texte, un "médicament psychotrope" ou "agent psychotrope" désigne toute substance agissant principalement sur l'état du système nerveux central en modifiant certains processus biochimiques et physiologiques cérébraux. Des exemples de médicaments psychotropes qui peuvent être utilisés dans le contexte de la présente invention comprennent les anesthésiques, les analgésiques tels que les opioïdes, les antipyrétiques et les préparations antimigraineuses, les antiépileptiques, les médicaments antiparkinsoniens tels que les anti-cholinergiques et les anti-Parkinsoniens, les psycho leptiques. tels que les antipsychotiques, les anxiolytiques, les hypnotiques et les sédatifs, les psychoanaleptiques tels que les antidépresseurs, les psychostimulants et les anti-démences, ainsi que les parasymptomimétiques, les anti-toxicomanies, les préparations antivertigo, etc. Exemples non limitatifs de molécules spécifiques pouvant être utilisées avantageusement comme psychotropes les médicaments selon l'invention sont énumérés dans le tableau 1 ci-dessous.
Thérapeutique Pharmacologique Chimique Sous-classe de la catégorie d’agent actif Sous-classe des anesthésiques 1. Généralités 2. Ethers 3. éther diéthylique;
anesthésiques d'éther vinylique 4. Halogénate 5. halothane;
chloroforme;
d hydrocarbures enflurane;
le trichloréthylène;
l'isoflurane; desflurane; sévoflurane 6. Barbituriques 7. méthohexital;
l'hexobarbital;
, uni 8. Barbituriques 9. narcobarbital en association avec d'autres médicaments 10. Opioïde 11. fentanyl;
l'alfentanil;
anesthésiques sufentanil;
la phénopéridine;
l'anileridine; le rémifentanil;
12. Autres 13. droperidol;
la kétamine;
propanidide général; l'alfaxalone;
l'étomidate;
anesthésiques propofol; oxybate de sodium; protoxyde d'azote; l'esketamine; xénon;
14. Local 15. Esters de 16. métabutéthamine;
la procaïne;
anesthésiques tétracaïne aminobenzoïque;
la chloroprocaïne;
benzocaïne acide;
17. Amides 18. Bupivacaïne;
la lidocaïne;
la mépivacaïne; la prilocaïne;
butanilicaine; la cinchocaïne;
l'étidocaïne; articaine; ropivacaïne;
la lévobupivacaïne; la bupivacaïne;
19. Esters de 20. l'acide benzoïque de cocaïne 21. Autres: 22. chlorure local d'éthyle;
la cyclonine;
anesthésiques phénol; capsaïcine

9 Analgésiques 23. Opioïdes 24. Naturel 25. Opium; hydromorphone;
les alcaloïdes d'opium, la nicomorphine; l'oxycodone;
la dihydrocodéine; la diamorphine;
papaveretum; morphine; codéine, 26. Phenylpiper 27. cétobémidone;
la péthidine;
dérivés de l'idine 28. Diphénylpr 29. Dextromoramide;
la piritramide;
l'opylamine dextropropoxyphène;
les dérivés de la bezitramide; méthadone, 30. Benzomorp 31. pentazocine; dérivés de phénazocine han 32. Morphinan 33. butorphanol; dérivés de la nalbuphine 34. autres 35. tilidine; le tramadol;
la dézocine;
les opioïdes meptazinol; le tapentadol;
36. Autres 37. Salicylique 38. Acide acétylsalicylique;
l'aloxiprine;
antalgiques et salicylate d'acide et de choline;
les dérivés antipyrétiques de sodium, le salicylate;
le salicylamide;
salsalate; l'éthenzamide;
morpholine salicylate;
dipyrocétyle; benorilate;
diflunisal; salicylate de potassium; guacetisal;
le carbasalate de calcium; salicylate d'imidazole 39. Pyrazolones 40. phénazone; le métamizo le sodium; l'aminophénazone;
le propyphénazone; la nifénazone;
41. Anilides 42. paracétamol; la phénacétine;
la bucétine; le propacétamol;
43. autres 44. rimazolium; la glafénine;
analgésiques et floctafénine; viminol;
le nefopam;
antipyrétiques ziconotide; méthoxyflurane;
nabiximols 45. Antimigré 46. Ergot 47. Dihydroergotamine;
ne Préparations alcaloïdes ergotamine; le méthysergide;
lisuride;
48. Corticosteroi 49. Dérivés de flumedroxone d 50. Sélectif 51. sumatriptan; le naratriptan;
sérotonine (5HT 1) zolmitriptan; le rizatriptan;
les agonistes d'almotriptan; l'élétriptan;
frovatriptan 52. autres 53. pizotifène; la clonidine;
l'antipigraine iprazochrome; la dimétotiazine;
préparations oxétorone Antiépileptiques 54. Antiépileptiques 55. Barbituriques 56. méthylphénobarbital;
cs et dérivés Phénobarbital; la primidone;
la barbexaclone; métharbital 57. Hydantoin 58. ethotoin; la phénytoïne;
les dérivés d'acide amino (diphénylhydantoïne) valérique; la méphénytoïne; la fosphénytoïne;
59. oxazolidine 60. paraméthadione;
dérivés de triméthadione; ethadione 61. Succinimide 62. Ethosuximide;
le phensuximide;
les dérivés de mésuximide;
63. Benzodiaze 64. dérivés du pin de clonazépam 65. Carboxamid 66. carbamazépine;
e dérivés oxcarbazépine; le rufinamide;
eslicarbazépine 67. acide gras 68. acide valproïque;
le valpromide;
les dérivés d'acide aminobutyrique;
la vigabatrine;
progabide; Tiagabine 69. Autres 70. Sultiame; phénacémide;
antiépileptique lamotrigine; le felbamate;
le topiramate; la gabapentine;
le phénéturide; le lévétiracétam;
le zonisamide; la prégabaline;
le stiripentol; lacosamide;
le carisbamate; Révigabine; Beclamide Anti- 71. Doublure Anticho 72. Tertiaire 73. Trihexyphénidyle;
Biperiden;
Agents de Parkinson giques amines métixène; la procyclidine;
drogues profénamine; le dexetimide;
le phénglutarimide; le mazaticol;
bornaprine; tropatepine 74. Ethers 75. etanautine;
orphénadrine chimiquement proche des antihistaminiques 76. Ethers de 77. benzatropine;
étybenzatropine tropine ou dérivés de tropine 78. Dopaminerg 79. Dopa et 80. Lévodopa; les agents décarboxylasiques dopant un inhibiteur de dérivés; COMT
inhibiteur;
la mélévodopa; etilevodopa 81. Adamantan 82. dérivés de l'amantadine e 83. Dopamine 84. bromocriptine;
le pergolide;
les agonistes dihydroergocryptine;
l'esylate;
ropiniro le; pramipexo le;
la cabergoline; l'apomorphine;
le piribedil; rotigotine 85. Monoamine 86. sélégiline; rasagiline oxydase B
inhibiteurs 87. autres 88. olcapone; l'entacapone;
Agents budpiniques dopaminergiques Psycho-leptiques 89. Antipschotiques 90. Phénothiazi 91. Chlorpromazine;
cs nes avec lévomépromazine; la promazine;

côté-acépromazine aliphatique;
la triflupromazine;
cyamémazine en chaîne;
chlorproéthazine 92. Phenothiazi 93. dixyrazine;
la fluphénazine;
nda avec perphénazine;
la prochlorpérazine;
le thiopropazate de pipérazine;
la trifluopérazine;
structure acétophénazine;
la thiopropérazine;
la butaperazine; perazine 94. Phenothiazi 95. periciazine;
la thioridazine;
nda avec mésoridazine; Structure de la pipotiazine pipéridine 96. Butyrophène 97. Halopéridol;
le triflupéridol;
un dérivé de mélpérone; le mopérone;
pipamperone; le bromperidol;
le benperidol; le dropéridol; fluanisone 98. Indo le 99. oxypertine; le molindone;
dérivés sertindo le; ziprasidone 100. Thioxanthe 101. flupentixol;
le clopenthixol;
les dérivés ne chlorprothixène; le tiotixène;
zuclopenthixol 102. Diphénylbut 103. Fluspirflene; le pimozide;
dérivés de ylpipéridine-penfluridol 104. Diazépines, 105.1oxapine; la clozapine;
les oxazépines, l'olanzapine; la quétiapine;
l'asénapine;
thiazépines et oxépines de clotiapine 106. Benzamides 107. sulpiride; le sultopride;
le tiapride;
le remoxipride; amisulpride;
le veralipride; lévosulpiride 108. Lithium 109. Lithium 110. Autres 111. Prothipendyle;
la rispéridone;
antipsychotiques mosapramine; la zotépine;
l'aripiprazole; palipéridone 112. Anxiolytiques 113. Benzodiaze 114. Chlordiazépoxide;
les dérivés du pin, le médazépam; oxazépam;
le chlorazépate de potassium; le lorazépam;
adinazo lam; le bromazépam;
le clobazam; le kétazolam; le prazépam;
alprazo lam; l'halazépam;
le pinazépam camazépam;
le nordazépam; le fludiazépam; le loflazépate d'éthyle; etizo lam;
le clotiazépam; clo xazo lam;
le tofisopam;
115. diphénylme 116. hydroxyzine;
captodiame;
ces dérivés 117. Carbamates 118.méprobamate; emylcamate;
le mébutamate;

119. Dibenzo- 120. Dérivés de bicyclo-octadiène benzoctamine 121. Dérivés d'Azaspirodec 122. Dérivés de la buspirone-anédione 123. Autres 124. Méphénoxalone;
le gedocarnil;
anxiolytics etifoxine 125. Hypnotiques 126. Barbituriques 127. Pentobarbital;
l'amobarbital;
et, butobarbital simple; barbital;
aprobarbital;
sécobarbital sédatifs; talbutal;
le vinylbital;
vinbarbital; cyclobarbital;
l'heptabarbital; repositionnement;
méthohexital; thiopental;
l'étallobarbital; allobarbital;
proxibarbal 128. Aldéhydes 129. hydrate de chloral;
chloralodol;
et dérivés acétylglycinamide;
dichloralphénazone; paraldéhyde 130. Benzodiaze 131. flurazépam; le nitrazépam;
les dérivés du pin flunitrazépam; l'estazolam;
triazo lam; le lormétazépam;
le témazépam; midazo lam;
le brotizolam; le quazépam; loprazo lam;
le doxéfazépam; cinolazépam 132. Piperidinedi 133. glutéthimide;
méthyprylone;
un dérivé pyrithyldione 134. Benzodiaze 135. zopiclone; zolpidem;
médicaments liés au pin zaleplon; eszopiclone 136. Mélatonine 137. Mélatonine; agonistes des récepteurs ramelteon 138. autres 139. méthaqualone;
Clomethiazo le;
hypnotiques et bromisoval; carbromal;
scopolamine sédatifs; la propiomazine;
le triclo fos ethchlorvynol; valériane;
hexapropymate; les bromures; apronal;
le valnoctamide; méthylpentynol;
la niaprazine;
dexmedetomidine 140. Hypnotiques 141. emepronium;
et sédatifs en combinaison dipipéronylamino éthanol, excl.
barbituriques Psychoana- 142. Antidépresseur 143. Non-144. Désipramine; l'imipramine;
leptiques fourmis sélectif oxyde d'imipramine;
la clomipramine;
monoamine opipramol; la trimipramine;
recapture lofepramine; la dibenzépine;
les inhibiteurs d'amitriptyline; la nortriptyline;

la protriptyline; la doxépine; iprindo le;
le mélitracène; la butriptyline; la dosulépine;
l'amoxapine; la dimétacrine;
l'amineptine; la maprotiline;
quinupramine 145. Sélectif 146. zimeldine; la fluoxétine;
la recapture de la sérotonine, le citalopram; la paroxétine;
la sertraline;
les inhibiteurs d'alaproclate; la fluvoxamine;
l'étopéridone; escitalopram 147. Monoamine 148. isocarboxazide;
le nialamide;
les inhibiteurs de l'oxydase, la phénelzine; la tranylcypromine;
iproniazide non sélectif; iproclozide 149. Monoamine 150. moclobémide; toloxatone oxydase A
inhibiteurs 151. Autres 152. oxitriptan; tryptophane;
les antidépresseurs mianserin; la nomifensine;
le trazodone;
la néfazodone; la minaprine; le bifémélane;
la viloxazine; oxaflozane;
la mirtazapine; le bupropion;
la medifoxamine; la tianeptine;
la pivagabine; la venlafaxine;
le milnacipran; la réboxétine; la gépirone;
la duloxétine; l'agomélatine;
desvenlafaxine 153. Psychostim 154. Au centre 155. amphétamine;
les ulants, la dexamfétamine agissante; la métamfétamine;
agents utilisés méthylphénidate sympathomimétique; ligne pemo;
for ADHD s fencamfamin; modafinil;
and armodafinil; fenozolone;
nootropics atomoxetine; fenetylline ;
exmethylphenidate;
lisdexamfetamine 156. Xanthine 157. caffeine;
propentofylline derivatives 158. Other 159. meclofenoxate;
pyritinol;
psychostimulants piracetam; deanol; fipexide;
and nootropics citico line; oxiracetam;
pirisudanol;
linopirdine; nizofenone;
aniracetam; acetylcarnitine;
idebenone; prolintane; pipradrol;
pramiracetam; adrafinil;
vinpocetine ; pitolisant ;
160. Anti- 161. Anticho lines 162. tacrine; donepezil;
dementia terases rivastigmine; galantamine drugs 163. Other anti- 164. memantine; ginkgo biloba dementia drugs Other nervous 165. Parasympat 166. Anticho lines 167.
neostigmine; pyridostigmine;

system drugs homimetics terases distigmine; ambenonium;
168. Cho line 169. carbachol;
bethanechol esters 170. Other 171. pilocarpine;
choline parasympath alfoscerate; cevimeline omimetics 172. Drugs used 173. Drugs used 174. nicotine;
varenicline in addictive in nicotine disorders dependence 175. Drugs used 176. disulfiram; calcium in alcohol carbimide; acamprosate;
dependence naltrexone; baclofene 177. Drugs used 178. buprenorphine;
in opioid levacetylmethadol ;
lofexidine;
dependence 179. Antivertigo 180. Antivertigo 181. betahistine;
cinnarizine;
preparations preparations flunarizine;
acetylleucine 182. Other 183. Other 184. tirilazad; riluzo le; xaliproden nervous nervous ; amifampridine;
tetrabenazine;
system system drugs fampridine; mazindol drugs Table 1: Psychotropic molecules Preferably, the said psychotropic drug is selected in the group consisting of:
dopaminergic, GABAergic, adrenergic, acetylcholinergic, serotoninergic, opioidergic, adenosinergic, ionotropic, histaminergic, IMAO, Catechol-O-methyl transferase, DOPA
decarboxylase, noradrenergic and glutamatergic psychotropic effectors, as well as molecules having an effect on the hypocretin/orexin system (including hypocretin-1 and hypocretin-2).
The term "effector" herein refers to any substance activating or inhibiting, directly or indirectly, one or more neuroreceptors, as well as any substance that modifies the concentration of said neurotransmitter; therefore, an effector according to the present invention can be an agonist or an antagonist of said receptors.
It is shown in the examples below that said psychotropic drug is advantageously modafinil.
As a matter of fact, the present inventors have shown that flecainide potentiates the promnesiant and/or awakening effects of modafinil (see figures 2 and 3), and that the modafinil/flecainide combination shows promising effects by reducing cataplectic-like events in mice. The precise mechanism of modafinil action has not been completely elucidated yet. In fact, it is known that modafinil acts on several molecular receptors, in particular on the dopamine, norepinephrine, serotonine, glutamate, GABA, orexine and histamine receptors (Ishizuka et al, 2012; Minzenberg et al, 2008). Therefore, modafinil acts as a GABAergic, dopaminergic, norepinephrinergic, serotoninergic, histaminergic, and glutamatergic effectors, and it has an effect on the hypocretin/orexin system (including hypocretin-1 and hypocretin-2).
Any compound modulating the same molecular receptors as modafinil can be advantageously associated with flecainide.
Thus, in a preferred embodiment, the psychotropic drug which is associated with flecainide acts on the very same receptors as modafinil does. The psychrotropic drug associated with flecainide is therefore preferably selected in the group consisting of:
GABAergic, dopaminergic, norepinephrinergic, serotoninergic, histaminergic, and glutamatergic effectors. Also, it may have an effect on the hypocretin/orexin system (including hypocretin-1 and hypocretin-2).
According to a specific embodiment, the said psychotropic drug is a dopaminergic effector selected in the group consisting of: ADX-N05 (formely "YKP 1 OA", having the formula:
(R)- (beta-amino-benzenepropyl) carbamate mono- hydrochloride), amphetamine, loxapine, acepromazine, methylphenidate, pergolide, lisuride, bromocriptine, dopamine, ropiniro le, apomorphine, aripiprazole, sulpiride, amisulpride, sultopride, tiapride, pimozide, risperidone, haloperidol, penfluridol, zuclopenthixol or bupropion.
According to another specific embodiment, the said psychotropic drug is a GABAergic effector selected in the group consisting of: tiagabine, topiramate, clorazepate, diazepam, clonazepam, oxazepam, lorazepam, bromazepam, lormetazepam, nitrazepam, clotiazepam, aiprozolam, estazolam, triazolam, loprazo lam, etifoxin, meprobamate, zopiclone, zolpidem, pregabaline, gabapentine, phenobarbital, felbamate and vigabatrin.
According to another specific embodiment, the said psychotropic drug is a serotoninergic effector selected in the group consisting of: chlorpromazine, trimipramine, clozapine, olanzapine, cyamemazine, flupentixol, nefopam, fluvoxamine, clomipramine, sertraline, fluoxetine, citalopram, escitalopram, paroxetine, amitriptyline, duloxetine, venlafaxine, buspirone, carpipramine, zolmitriptan, sumatriptan, naratriptan, indoramine, ergotamine, ergotamine tartrate, pizotifene, pipamperone, methysergide, pizotyline, milnacipranõ
viloxazine, tianeptine, hypericum and lithium.
According to another specific embodiment, the said psychotropic drug is a histaminergic effector selected in the group consisting of: acrivastine, alimemazine, antazoline, astemizo le, azatadine, azelastine, brompheniramine, buclizine, carbinoxamine, carebastine, cetirizine, chlorcyclizine, chlorpheniramine, cinnarizine, clemastine, clemizo le, clocinizine, clonidine, cyclizine, cyproheptadine, des carbo ethoxyloratidine, dexchlorpheniramine, dimenhydrinate, dimethindene, dimethothiazine, diphenhydramine, diphenylpyraline, doxylamine, ebastine, efletirizine, epinastine, fexofenadine,hydroxyzine, ketotifen, levocabastine, loratidine, meclizine, mequitazine, methdilazine, mianserin, mizolastine, niaprazine, noberastine, norastemizo le, oxatomide, oxomemazine, phenbenzamine, pheniramine, picumast, promethazine, pyrilamine, temelastine, terfenadine, trimeprazine, tripelennamine, triprolidine, ranitidine, cimetidine, famotidine, nizatidine, tiotidine, zolantidine, ciproxifan, pitolisant and ritanserine.
According to another specific embodiment, the said psychotropic drug is a hypocretin/orexin modulator selected in the group consisting of: EMPA, SB-334867, SB-674042, SB-408124, GSK1059865, almorexant, suvorexant, MK-6096, DORA-1, DORA-22, DORA-12, SB-649868, JNJ-1037049 (described in Gotter et al, 2012)).
According to another specific embodiment, the said psychotropic drug is a norepinephrinergic effector selected in the group consisting of: (R)-3-nitrobiphenyline, 2-fluoronorepinephrine , 4-NEMD, 5 -fluoronorepinephrine, 6-fluoronorepinephrine, abediterol, albuterol, amibegron, amidephrine, amitraz, anisodamine, anisodine, apraclonidine, arbutamine, arformoterol, arotinolol, bambuterol, befunolol, bitolterol, brimonidine, bromoacetylalprenololmenthane, broxaterol, buphenine, cannabivarin, carbuterol, cimaterol, cirazo line, clenbuterol, denopamine, deterenol, detomidine, dexmedetomidine, dihydroergotamine, dipivefrine, dobutamine, dopexamine, ephedrine, epinephrine, esproquin, etafedrine, ethylnorepinephrine, etilefrine, fenoterol, formoterol, guanabenz, guanfacine, guanoxabenz, hexoprenaline, higenamine, indacaterol, indanidine, isoetarine, isoprenaline, isoproterenol, isoxsuprine, labetalol, levonordefrin, levosalbutamol, lofexidine, mabuterol, medetomidine, metaraminol, methoxamine, methoxyphenamine, methyldopa, midodrine, mivazerol, n-isopropyloctopamine, naphazoline, norepinephrine, octopamine, orciprenaline, oxyfedrine, oxymetazoline, phenylephrine, phenylpropanolamine, piperoxan, pirbuterol, prenalterol, procaterol, pseudoephedrine, ractopamine, reproterol, rilmenidine, rimiterol, ritodrine, romifidine, salbutamol, salmeterol, so labegron, synephrine, talipexo le, terbutaline, tetrahydrozoline, tizanidine, to lonidine, tretoquinol, tulobuterol, urapidil, xamoterol, xylazine, xylometazoline, zilpaterol, and zinterol.
According to another specific embodiment, the said psychotropic drug is a glutamatergic effector selected in the group consisting of: memantine, amantadine, MK-801, ketamine, norketamine, dextromethorphan, levometorphan, dextrorphan, levorphanol, phencyclidine, PCA, CNS-1102, remacemide, pentamidine, and 9-aminoacridine (described in Traynelis et al, 2010).
Preferably, said psychotropic drug is not flupirtine.
The potentiating effects of flecainide can be achieved by administrating same to a patient, either before, at the same time, of after administration of the psychotropic drug to said patient.
Consequently, the present invention describes a method for treating a patient with psychiatric and/or neurodegenerative disorders, including the administration to said patient of a) flecainide and b) at least one psychotropic drug as mentioned above, in which said compounds a) and b) are administered simultaneously, separately or spread out over time.
Patients needing this treatment may have psychiatric, neurologic and/or neurodegenerative disorders included in the group consisting of: excessive daytime sleepiness (EDS), sleep disorders, insufficient sleep time, central sleep apnea, narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), idiopathic hypersomnia, Kleine-Levin syndrome, circadian rhythm disorders, shift work sleep disorder, jet-lag, disorders after sleep restriction or sleep deprivation (attention disorders, alertness disorders, sleepiness), restless legs syndrome (RLS) and Periodic Lim Movement Disorders (PLMD), insomnia, parasomnia, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), disorders commonly associated with somnolence or sleepiness (such as Parkinson disease, multiple sclerosis, stroke, neuromuscular disorders or structural brain disorders, respiratory disorders, chronic renal failure, liver failure, rheumatologic disorders), medication-induced somnolence (due to benzodiazepines, barbiturates, sleeping pills, antidepressants, anti-psychotics…), mood disorders, anxiety disorders, schizophrenia, tinnitus, depression, malaise, dementia, bipolar disorder, obesity, hyperphagia, manic episode, obsessive-compulsive disorder, senility, dependence or addiction (to games, drugs, alcohol, tobacco, etc.), fecal or urinary incontinence, premature ejaculation, breathing difficulty and fatigue, notably due to cancer, neurodegenerative disorders, menopause, traumatic brain injuries, viral infection or post-myelitis, or to fibromyalgia.
Excessive daytime sleepiness (EDS) occurs daily, recurring typically every 2 h, although this can vary widely. Sleepiness is exacerbated when the patient is physically inactive. The sleep episodes have several characteristics (Dauvilliers I. et al, 2007 and Boulos et al, 2010):
= They are often irresistible, despite the individual making desperate efforts to fight the urge to sleep;
= They are usually short, although their length can vary with environmental factors (eg, the duration can increase with passive activities such as watching television);
= They are frequently associated with dreaming;
= They typically restore normal wakefulness for up to several hours.
EDS characterizes several conditions or diseases: insufficient sleep time, central sleep apnea, narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), idiopathic hypersomnia, recurrent hypersomnia (Kleine-Levin syndrome), circadian rhythm disorders (jet lag), disorders after sleep restriction or sleep deprivation (attention disorders, alertness disorders, sleepiness), restless legs syndrome (RLS) and Periodic Lim Movement Disorders (PLMD), neurological conditions commonly associated with sleepiness (such as Parkinson disease, multiple sclerosis, stroke, neuromuscular disorders or structural brain disorders), medical conditions commonly associated with sleepiness (respiratory disorders, chronic renal failure, liver failure, rheumatologic disorders), mood disorders, anxiety disorders, schizophrenia, or medication-induced somnolence (due to benzodiazepines, barbiturates, sleeping pills, antidepressants, anti-psychotics…).

Cataplexy is characterized by a sudden drop of muscle tone triggered by emotional factors, most often by positive emotions such as laughter, repartee, pleasant surprise (e.g., seeing friends in the street or scoring a goal), or by anger, but almost never by stress, fear, or physical effort. Many neurophysiological and pharmaceutical studies indicate that cataplexy shares common neurophysiological mechanisms with REM sleep atonia (Dauvilliers I. et al, 2007).
In the case of simultaneous use, the two components of the treatment are administered to the patient simultaneously. According to this embodiment of the present invention, the two components can be packaged together, in the form of a mixture, or separately, then mixed spontaneously before being administered together to the patient.
Alternatively, the two components are administered simultaneously, but separately. In particular, the routes of administration of the two components may be different. The administration can also be performed at different sites. In another embodiment, the two components are administered sequentially or spaced apart over time, for example in the same day or at an interval ranging from several minutes to several days.
Since flecainide potentiates the effects of psychotropic drugs, it can advantageously be used for reducing the doses of said psychotropic drug, thereby limiting the adverse effects of said psychotropic drug, and/or reducing the risks of failure and withdrawal.
The effective equivalent dose of a psychotropic drug, i.e., the psychotropic drug dose that, when administered in combination with flecainide, induces a physiological effect or a pharmacological signature similar or identical to that of the psychotropic drug alone administered at the active pharmacological dose, can be determined by the methods disclosed in W02010/029131 and US 2011/172188.
According to another aspect, the present invention pertains to a composition, especially a pharmaceutical composition, comprising flecainide and at least one psychotropic drug.
This composition is preferably formulated for patients with psychiatric and/or neurodegenerative disorders, as disclosed above. In addition to flecainide and to said psychotropic drug, the composition can comprise any pharmaceutical vehicle, stabilizer, adjuvant and the like as frequently used in the art.

Examples of pharmaceutically acceptable vehicles include, but are not limited to: water;
aqueous vehicles such as, but not limited to, sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, and lactated Ringer's solution;
water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
According to a preferred embodiment, this composition is formulated for oral administration (including buccal cavity or sublingually). Other interesting formulations include formulations for intraperitoneal (i.p.), intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.), transcutaneous, transdermal, intrathecal and intracranial administrations. Still other formulations include epidural, submucosal, intranasal, ocular cul-de-sac and rectal routes of administration, as well as administration by pulmonary inhalation.
A variety of administration means, including but not limited to capsules, tablets, syrups, creams and ointments, suppositories, patches or any reservoir capable of containing and dispensing flecainide and the psychotropic drug, can be used for formulating the above-described compositions.
In the compositions according to the invention, the psychotropic drug is as described above.
In a preferred embodiment, said psychotropic drug is used for treating narcolepsy and is therefore selected in the group consisting of: caffeine, mazindol, sodium oxybate, pitolisant, amphetamine, methylphenidate, (R)- (beta-amino-benzenepropyl) carbamate mono- hydrochloride, modafinil and armodafinil.
In a preferred embodiment, the composition of the invention contains between 1 to 1000 mg, preferably 5 to 800 mg of the psychotropic drug, depending of its nature.
A preferred posology would be to administer to the patient between 1 to 1000 mg/day, more preferably between 5 to 800 mg/day of the psychotropic drug.

According to another preferred embodiment, the composition of the invention contains between 1 to 200, preferably 1 to 100 mg of flecainide. A preferred posology would be to administer to the patient between 1 to 200, preferably 1 to 100 mg/day of flecainide.
More preferably, said flecainide is the R enantiomer disclosed on figure 5A.
In a more preferred embodiment, flecainide is associated with the psychotropic drug modafinil.
By "modafinil" is herein meant the 2-[(diphenylmethyl) sulfinyl] acetamide (Provigil, see figure 5C), as well as its precursors or prodrugs such as adrafinil (Dubey et al, 2009) which can be metabolized in the human body and its active derivatives. More precisely, the term "Modafinil" herein designates any form of modafinil (racemate, R-modafinil, S-modafinil, etc.), as well as its precursors which can be metabolized in the human body and its derivatives. Figure 5 shows the formulas of R-Modafinil (Fig. 5C) and S-Modafinil (Fig.
5D).
Modafinil is an analeptic drug prescribed essentially for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. Besides these wake-promoting properties, modafinil also improves working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control (Minzenberg MJ et al, 2008).
The present inventors have shown that, surprisingly, flecainide strongly potentiates in vivo the waking effects of Modafinil, whereas it has no effect on wake duration on its own (example 2). Moreover, flecainide strongly potentiates in vivo the cognitive activity of Modafinil, whereas it has no promnesiant effect on its own (example 3). This synergistic activity could be explained by the fact that flecainide strongly extends the duration of Modafinil treatment (example 4). On the other hand, the present inventors herein describes that the flecainide / modafinil combination has a synergistic effect on cataplectic-like phenotype in narcoleptic mice (example 5) and is all the more surprising than either flecainide or modafinil has no effect on this phenotype (figure 6B). In a preferred embodiment, the present invention thus pertains to flecainide, for use for potentiating the promnesiant and/or awakening effects of modafinil, and/or for improving its safety, and/or for increasing the duration of action of modafinil in patients in need thereof, especially in patients suffering from: excessive daytime sleepiness (EDS), sleep disorders, insufficient sleep time, central sleep apnea, narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), idiopathic hypersomnia, Kleine-Levin syndrome, circadian rhythm disorders, shift work sleep disorder, jet-lag, disorders after sleep restriction or sleep deprivation (attention disorders, alertness disorders, sleepiness), restless legs syndrome (RLS) and Periodic Lim Movement Disorders (PLMD), insomnia, parasomnia, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), disorders commonly associated with somnolence or sleepiness (such as Parkinson disease, multiple sclerosis, stroke, neuromuscular disorders or structural brain disorders, respiratory disorders, chronic renal failure, liver failure, rheumatologic disorders), medication-induced somnolence (due to benzodiazepines, barbiturates, sleeping pills, antidepressants, anti-psychotics…), mood disorders, anxiety disorders, schizophrenia, tinnitus, depression, malaise, dementia, bipolar disorder, obesity, hyperphagia, manic episode, obsessive-compulsive disorder, senility, dependence or addiction (to games, drugs, alcohol, tobacco, etc.), fecal or urinary incontinence, premature ejaculation, breathing difficulty and fatigue, notably due to cancer, neurodegenerative disorders, menopause, traumatic brain injuries, viral infection or post-myelitis, or to fibromyalgia, which have been proposed to be treated by modafinil.
In a more preferred embodiment, the present invention specifically pertains to flecainide, for use for potentiating the awakening effects of modafinil, and/or for improving its safety, and/or for increasing the duration of action of modafinil in patients suffering from:
excessive daytime sleepiness (EDS), sleep disorders, insufficient sleep time, central sleep apnea, narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), idiopathic hypersomnia, Kleine-Levin syndrome, circadian rhythm disorders, shift work sleep disorder, jet-lag, disorders after sleep restriction or sleep deprivation (attention disorders, alertness disorders, sleepiness), restless legs syndrome (RLS) and Periodic Lim Movement Disorders (PLMD), insomnia, parasomnia, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), disorders commonly associated with somnolence or sleepiness (such as Parkinson disease, multiple sclerosis, stroke, neuromuscular disorders or structural brain disorders, respiratory disorders, chronic renal failure, liver failure, rheumatologic disorders), medication-induced somnolence (due to benzodiazepines, barbiturates, sleeping pills, antidepressants, anti-psychotics…), mood disorders, anxiety disorders, schizophrenia, tinnitus, depression, malaise, dementia, bipolar disorder, obesity, hyperphagia, manic episode, obsessive-compulsive disorder, senility, dependence or addiction (to games, drugs, alcohol, tobacco, etc.), fecal or urinary incontinence, premature ejaculation, breathing difficulty and fatigue, notably due to cancer, neurodegenerative disorders, menopause, traumatic brain injuries, viral infection or post-myelitis, or to flbromyalgia, for which modafinil has been proposed or authorized.
In a preferred embodiment, the present invention specifically pertains to flecainide, for use for potentiating the awakening effects of modafinil, and/or for improving its safety, and/or for increasing the duration of action of modafinil in patients suffering from excessive daytime sleepiness (EDS).
In another preferred embodiment, the present invention relates to flecainide, for use for potentiating the awakening effects of modafinil, and/or for improving its safety, and/or for increasing the duration of action of modafinil in patients suffering from conditions or diseases involving EDS, that are for example: insufficient sleep time, central sleep apnea, narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), idiopathic hypersomnia, recurrent hypersomnia (Kleine-Levin syndrome), circadian rhythm disorders (jet lag), disorders after sleep restriction or sleep deprivation (attention disorders, alertness disorders and sleepiness), restless legs syndrome (RLS) and Periodic Lim Movement Disorders (PLMD), neurological conditions commonly associated with sleepiness (such as Parkinson disease, multiple sclerosis, stroke, neuromuscular disorders or structural brain disorders), medical conditions commonly associated with sleepiness (respiratory disorders, chronic renal failure, liver failure, rheumatologic disorders), mood disorders, anxiety disorders, schizophrenia, or medication-induced somnolence (due to benzodiazepines, barbiturates, sleeping pills, antidepressants, anti-psychotics…).
In another preferred embodiment, the present invention relates to a modafinil/flecainide combination product, for use for treating cataplexy in narcoleptic patients.
It is to be noted that the potentiation of the effects of modafinil by flecainide enables a reduction of the dose of modafinil, and hence a reduction of its side-effects.
As a consequence, some applications of modafinil, for which this drug was not approved because of its side-effects and possible risks associated thereto, can now be envisioned, such as its use as a performance-enhancing and/or brain-boosting agent.
According to a particular embodiment, the present invention thus pertains to a performance-enhancing product comprising flecainide and modafinil.
In another preferred embodiment, the present invention specifically pertains to the use of flecainide and modafinil for enhancing the memory of healthy subjects and/or to maintain them awake for long-lasting periods of time and/or to treat cataplexy in narcoleptic patients. These subjects can be for example individuals that need to memorize a lot of information and/or to remain awake for long lasting periods. In a preferred embodiment, said subjects are humans (e.g., security agents, students, etc.).
In a particular embodiment, the present invention also relates to a composition comprising flecainide and modafinil, which can advantageously be used for treating diseases and conditions including but not limited to excessive daytime sleepiness (EDS), narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), shift work sleep disorder, disorders after sleep restriction or sleep deprivation (attention disorders, alertness disorders, sleepiness), restless leg syndrome, hypersomnia, idiopathic hypersomnia and fatigue, notably due to cancer, jet-lag, neurodegenerative disorders, menopause, traumatic brain injuries, viral infection or post-myelitis, or to fibromyalgia. In particular, this composition can be used for treating cataplexy in narcoleptic patients.
This composition can also be used for enhancing the memory of healthy subjects and/or for maintaining them awake for long-lasting periods of time. Typical periods of time are for example 6 hours, preferably 12 hours.
The present invention moreover relates specifically to the use of flecainide and modafinil in the preparation of a medicament that is intended to be used for treating diseases and conditions such as excessive daytime sleepiness (EDS), narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), shift work sleep disorder, restless leg syndrome, hypersomnia, idiopathic hypersomnia and fatigue, notably due to cancer, neurodegenerative disorders, menopause, traumatic brain injuries, viral infection or post-myelitis, or to fibromyalgia.

In a preferred embodiment, the present invention relates to the use of flecainide and modafinil in the preparation of a medicament that is intended to be used for treating cataplexy in narcoleptic patients.
In addition to modafinil and flecainide, the composition / medicament of the invention can comprise other agents such as vitamin C, vitamin B6, magnesium, L-arginine, L-glutamine, L-citrulline, taurine, caffeine, etc. According to a particular embodiment, this product can be sold over-the-counter. It can be formulated, for example, as an OTC
medicine or as a food supplement.
In a preferred embodiment, the composition of the invention contains between 1 to 1000 mg, preferably between 5 to 800 mg, and more preferably between 5 to 600 mg of the modafinil. According to another preferred embodiment, the composition of the invention is formulated so that 5 to 800, preferably 5 to 600 mg/day of modafinil are administered to a patient in need thereof, in one, two or more takings.
According to another preferred embodiment, the composition of the invention contains between 1 to 200, preferably 1 to 100 mg of flecainide. According to another preferred embodiment, the composition of the invention is formulated so that 1 to 200, preferably 1 to 100 mg/day of flecainide are administered to a patient in need thereof, in one, two or more takings. In a more preferred embodiment, said flecainide is the R
enantiomer disclosed on figure 5A.
In a final aspect, the present invention relates to a combination product comprising flecainide and modafinil, for simultaneous, separated or staggered use for preventing and/or treating excessive daytime sleepiness (EDS), narcolepsy (with or without cataplexy), obstructive sleep apnea/hypopnea (SAHOS), shift work sleep disorder, restless leg syndrome, hypersomnia, idiopathic hypersomnia and fatigue, notably due to cancer, jet-lag, neurodegenerative disorders, menopause, traumatic brain injuries, viral infection or post-myelitis, or to fibromyalgia. This combination product is preferably used for preventing and/or treating cataplexy in narcoleptic patients.

Other characteristics of the invention will also become apparent in the course of the description which follows of the biological assays which have been performed in the framework of the invention and which provide it with the required experimental support, without limiting its scope.
Legends to the figures Figure 1: Inhibition of the human connexins functionality by flecainide. Rin-Cx26 cells, Rin-Cx30 cells, Rin-Cx32 cells, Rin-CX40 cells and Rin-Cx43 cells are cultured in the presence of flecainide (280 M), mefloquine (10 M) and MFA (100 M) for 4 hours. The transfer of fluorochrome by gap junctions (composed of connexins) is evaluated by flow cytometry (1A and 1B). Viability of the cells treated with flecainide is shown on figure 1B.
Figure 2: Efficiency of flecainide for potentiating the awakening effect of modafinil. Mice (n = 8 per batch) were orally treated by either modafinil (32 mg/kg) or modafinil (32mg/kg) and flecainide (lmg/kg) (figure 2A) or flecainide alone (lmg/kg) (figure 2B) and replaced in their home cage. The wake duration was measured using polygraphic analyses.
Figure 3: Efficacy of flecainide for potentiating the promnesiant effect of modafinil. Mice (n = 6 to 23 per batch) are tested in the T-maze. They were intraperitoneally treated by either modafinil (64 mg/kg or 128mg/kg) or modafinil (64mg/kg) and flecainide (lmg/kg) or flecainide alone (lmg/kg). The graphic represents the percentage of alternation after 6 trials, 50% corresponding to a random alternation.
Figure 4 : Efficacy of flecainide for potentiating the locomotor effect of modafinil. Mice (n=8 per batch) were orally treated by either modafinil (64 mg/kg) or modafinil (64mg/kg) and flecainide (lmg/kg) or flecainide alone (lmg/kg) and replaced in their home cage. The locomotor activity was measured using videotracking device.
Figure 5: Molecular structure of A. R-flecainide; B. S-flecainide; C. R-Modafinil, D. S-Modafinil.

Figure 6: Number of episodes of OREM/DREM phases in narcoleptic mice (0x-/-) treated by modafinil/flecainide (A) or flecainide alone (B). (A). Oral treatment of Ox-/- male mice with modafinil 64 mg/kg with flecainide 1 mg/kg was compared to Modafinil 64 mg/kg and vehicle. **: p<0,01 ; ***:p<0,005, Two-Way ANOVA. (B) Oral treatment of Ox-/-male mice with flecainide 1 mg/kg was compared to vehicle.
Figure 7: Number of episodes of OREM/DREM phases in narcoleptic mice (0x-/-) treated by the combination between modafinil and one of the two enantiomers of flecainide (R-flecainide and S-flecainide). Oral treatment with modafinil 64 mg/kg with R-flecainide 1 mg/kg or S-flecainide 1 mg/kg was compared to vehicle.
EXAMPLES
Example 1: Effect of Flecainide on gap junctions 1.1. Materials and methods Cell culture The rat insulinoma RIN cell line, deficient in GJIC (del Corsso et al, 2006), was grown in OptiMem medium, supplemented with 10% fetal calf serum. GJB6 (Cx30), GJB1 (Cx32), GJB2 (Cx26), GJA5 (Cx40) and GJA1 (Cx43) open reading frames were amplified from human cDNA. The open reading frames were cloned in pcDNA3.11V5-His-TOPO
(Invitrogen). Cells were transfected using Lipofectamine and further selected using geneticin.
Dye transfer experiments Cells were seeded and loaded with two fluorochromes, calcein acetoxymethyl ester, a gap junction permeable dye, and Vybrant Dil, a membrane lipophilic dye. The next day, cells were dissociated and incubated for four hours in presence of previously seeded non-loaded cells and in the presence of flecainide racemate 70, 140 or 280 M, mefloquine

10 M or meclofenamic acid (MFA) 100 M. Flow cytometry was conducted on a FACScan.

Inhibition was quantified as the relative number of receiver cells that gained fluorescence to the total number of receiver cells (non GJ-mediated dye transfer was then substracted to these ratio based on connexin non-expressing RIN cells, defined at background dye transfer ratio). This ratio of cellular coupling was then normalized, after each treatment, on the vehicle one.
Toxicity analysis Twenty thousand RIN were seeded in 100 1 of culture medium in 96-wells plates. After 48h culture, cells were treated for 4 hours with previously identified chemical compounds at several concentrations. Cells were rinsed in PBS and grown 24h in fresh medium. Cell viability was measured by using WST-1 (Roche).
1.2. Experimental results Cellular models were validated by using two classical inhibitors described in litterature, meclofenamic acid (MFA) (Dhein, 2004) (100 M) and mefloquine (Cruikshank et al, 2004) (10 M). Results are shown on figure 1A. Flecainide is as efficient in blocking connexin as the other anti-connexin agents.
Cell viability tests (using WST-1, dotted curve on Figure 1B) after one day of treatment, indicate that flecainide has no cell toxicity at the dose inhibiting cerebral connexins.
In addition, flecainide inhibits all the tested isoforms of cerebral connexin using dye-transfer cell-parachute assay (Cx30, Cx32, Cx26, Cx40, Cx43) (it is estimated that a more than a significant 10% reduction in gap junction cellular is considered as physiologically relevant). In addition, higher inhibition levels are reached for glial connexins Cx26, Cx30 and Cx43.
Example 2: Flecainide potentiates the waking effects of Modafinil Preclinical and clinical data indicated that modafinil modifies sleep-cycle rhythm and promotes wake phases (Lin et al, 2008). Here we tested in rodents whether such activity was potentiated by flecainide after oral challenge with modafinil, using polysomnographic analysis on implanted mice. Using a sub-efficient dosage of modafinil (32 mg/kg), the inventors demonstrated a new feature of the combination of modafinil and flecainide since it significantly increases the total duration of wake episodes.
2.1. Materials and Methods Wild-type C57b1/6 male mice (n=9/groups) were implanted with EEG/EMG/EOG
electrodes for polysomnographic analyses. After a two-week recovery period, mice were orally treated with vehicle, Modafinil 32 mg/kg and Modafinil 32 mg/kg +
flecainide racemate 1 mg/kg and wake periods were quantified using Spike2 scripts. Here the inventors represented the duration of wake during the first three hours (after a one-hour period post-administration). **: p<0,01 in a One-Way ANOVA analysis.
2.2. Results Modafinil is a molecule that promotes wakefulness in humans and mice, increasing in mice their activity in a dose-dependent manner (Simon et al, 1994). The activity of mice treated with modafinil at 32 mg/kg was compared with that of mice treated with the combination modafinil 32 mg/kg + flecainide 1 mg/kg or vehicle.
Figure 2A shows that flecainide significantly increases the waking effects of modafinil.
Figure 2B shows that this effect is not mediated by flecainide alone.
Thus, flecainide significantly potentiates modafinil waking activity in wild type mice, while being devoid of own effect on wake duration.
Exemple 3: Flecainide significantly enhances modafinil cognitive activity Modafinil induces a cognitive enhancing effect (Beracochea et al, 2003), such property can be assessed using the alternating sequential test, a widely used apparatus to assess spatial working memory in mice (Beracochea & Jaffard, 1987). Spontaneous alternation is the innate tendency of rodents to alternate their choices to enter into the compartments of arrival of a T-maze device, over successive trials. To alternate during a given trial N, the animal must remember the choice made selectively in test N-1, and the response in alternating is performance measure. Acute administration of modafinil before entering the maze, can improve the performance of mice in this test (Beracochea et al, 2001). The inventors' results showed that flecainide significantly potentiates the promnesiant effect of a subefficient dose of modafinil, while flecainide alone is devoid of any own promnesiant effect.
3.1. Materials and methods The alternating sequential test is widely used to assess spatial working memory in mice (Beracochea & Jaffard, 1987). Spontaneous alternation is the innate tendency of rodents to alternate their choices to entry into the compartments of arrival of a T-maze device, over successive trials. To alternate during a given trial N, the animal must remember the choice made selectively in test N-1, so the decline in alternating will reflect the phenomenon of oblivion. The response in alternating is performance measure. Sequential alternating assesses more specifically the sensitivity to interference, a major factor in oblivion.
The experiment takes place in a T-maze (50 cm x 10 cm x 25 cm). All the subjects were given 7 successive trials separated by a 120-s intertrial interval. To begin a trial, the mouse was placed in the start box for 120 s before the door to the stem was opened.
When the subject entered one of the goal arms, the door to that arm was closed. The chosen arm and the time that elapsed between opening the door and the arrival to the end of the chosen arm (task achievement time) were registered. Following a 30-s confinement period (fixed and invariant) in the chosen arm, the animal was removed and placed in the start box for a new trial. Between each test, the unit is cleaned with a cloth soaked in water and alcohol to avoid olfactory detection. The index memory is represented by the average of alternating percentage (number of alternation choices / total number of tests X 100). (n=6 to 23 for each group). Mice were intraperitoneally treated by either modafinil (64 mg/kg or 128mg/kg) or modafinil (64mg/kg) and flecainide racemate (lmg/kg) or flecainide racemate alone (lmg/kg) or vehicle.
# p<0,05 in one sample t-test vs random 50% alternance ; * p<0,05 One way ANOVA
followed by Tukey's multiple comparison vs modafinil group.

3 .2 .Results The T-maze is a device for assessing working memory in mice. Acute administration of modafinil before entering the maze, can improve the performance of mice in this test (Beracochea et al, 2001).
The validity of the test was performed by comparing the responses of mice intraperitoneally treated with an effective dose of modafinil alone (128 mg/kg), a dose of flecainide alone (1 mg/kg) and a sub-effective dose of modafinil (64 mg/kg) with or without flecainide alone (1 mg/kg). The results are shown in Figure 3.
These results show that flecainide significantly potentiates modafinil promnesiant activity, while flecainide alone shows no own cognitive effect.
Exemple 4: Flecainide significantly prolongs modafinil activity Modafinil is a molecule that promotes wakefulness in humans and mice, increasing in mice their activity in a dose-dependent manner (Simon et al, 1994). The inventors' results showed that flecainide significantly potentiates the locomotor effect of a sub efficient dose of modafinil, while flecainide alone is devoid of any own locomotor effect in rodents.
4.1. Materials and methods Mice (n=8 per batch) were orally treated by either modafinil (64 mg/kg) or modafinil (64mg/kg) and flecainide racemate (lmg/kg) or flecainide racemate alone (lmg/kg) or vehicle and replaced in their home cage. Locomotor activity is evaluated by video tracking.
Videos have been analyzed using Ethovision XT software (Noldus0).*: p<0,01 in a Two-Way ANOVA analysis 4.2.Results The activity of mice treated with modafinil at 64 mg/kg was compared with that of mice treated with the combination modafinil 64 mg/kg + flecainide 1 mg/kg. Figure 4 shows that flecainide significantly increases the duration of effect of modafinil on the activity of mice.

To conclude, the above results show that Flecainide significantly inhibits the functionality of gap junctions, without inducing cellular toxicity. In addition, this compound potentiates the efficacy and duration of effect of modafinil, notably in its promnesiant and awakening side.
Exemple 5: Modafinil/Flecainide combination has a surprising efficient profile on DREM cataplectic-like phenotype in narcoleptic mice.
5.1. Material and methods Animals Prepro-orexin knockout (KO) mice were offspring of the mouse strain generated by Chemelli et al. [1999] and kept on C57BL/6J genomic background. After backcrossing male orexin-/- mice and female wild-type (WT) mice for nine generations, the obtained orexin+/- mice were crossed to produce heterozygote and homozygote WT and KO
littermates. To determine their genotypes with respect to orexin gene, tail biopsies were performed at the age of 4 weeks for DNA detection using PCR.
Surgery At the age of 12 weeks and with a body weight of 30 2 g, mice used for EEG and sleep-wake studies were chronically implanted, under deep gas anesthesia using isoflurane (2%, 200 ml/min) and a TEM anesthesia system (Bordeaux, France), with six cortical electrodes (gold-plated tinned copper wire, 0 = 0.4 mm, Filotex, Draveil, France) and three muscle electrodes (fluorocarbon-coated gold-plated stainless steel wire, 0 = 0.03 mm, Cooner Wire Chatworth, CA, U.S.A.) to record the electroencephalogram (EEG) and electromyogram (EMG) and to monitor the sleep¨wake cycle. All electrodes were previously soldered to a multi-channel electrical connector and each was separately insulated with a covering of heat-shrinkable polyolefin/polyester tubing.
Cortical electrodes were inserted into the dura through 3 pairs of holes made in the skull, located respectively in the frontal (1 mm lateral and anterior to the bregma), parietal (1 mm lateral to the midline at the midpoint between the bregma and lambda), and occipital (2 mm lateral to the midline and 1 mm anterior to the lambda) cortex. Muscle electrodes were inserted into the neck muscles. Finally, the electrode assembly was anchored and fixed to the skull with Super-Bond (Sun Medical Co., Shiga, Japan) and dental cement.
This implantation allows stable and long-lasting polygraphic recordings [Parmentier et al, 2002].
Polygraphic recording in the mouse and data acquisition and analysis After surgery, the animals were housed individually, placed in an insulated sound-proof recording room maintained at an ambient temperature of 23 1 C and on a 12 h light/dark cycle (lights-on at 7 a.m.). After a 7-day recovery period, mice were habituated to the recording cable for 7 days before polygraphic recordings were started. Direct REM sleep onset (DREMs) episodes, also called narcoleptic episodes or sleep onset REM
periods by some authors [Chemelli et al, 1999; Mignot et al, 2005; Fujiki et al, 2006], were defined as the occurrence of REM sleep directly from wake, namely a REM episode that follows directly a wake episode lasting more than 60 s without being preceded by any cortical slow activity of more that 5 s during the 60 s.
Drug administration and experimental procedures in the mouse After recovery from the surgery and habituation to the recording cables, each mouse was subjected to a recording session of two continuous days, beginning at 7 a.m.
Administrations were performed at 6:45 p.m. just before lights-off (7:00 p.m.), since orexin-/- mice display narcoleptic attacks only during lights-off phase [Chemelli et al, 1999]. The order of administration was randomized. Polygraphic recordings were made immediately after administration and were maintained during the whole lights-off period (12 h). Two administrations were separated by a period of 7 days (washout).
Mice (n=8 per batch) were orally treated by either modafinil (64 mg/kg) or modafinil (64mg/kg) and flecainide racemate (lmg/kg) or flecainide racemate alone (lmg/kg) or vehicle.

5.2. Results Orexins (also known as hypocretins) are two hypothalamic neuropetides identified in 1998 [Sakurai et al, 1998; De Lecea L. et al, 1998]. Neurons containing orexins have been identified in the hypothalamic dorsolateral and peri-fornical areas, these neurons play a key role in behavioral arousal. A large body of evidence indicates that an orexin deficiency is responsible for the pathogenesis of human and animal narcolepsy[Linetal1999;[Linetal1999;[Linetal1999;[Linetal1999;
Chemelli et al, 1999]. It has been recently shown that the most major phenotypes of orexin KO mice are a behavior/motor deficit during waking and the occurrence, during the dark phase, of episodes of sleep onset REM (DREM, as known as SOREM) – defined on EEG, EMG and video recordings as sudden onset of paradoxical sleep directly from wakefulness [Anaclet et al, 2009]. Thus SOREM/DREM constitutes a main phenotype of murine narcolepsy which is frequently seen in narcoleptic patients [Lin et al, 20011]. Using this model, it was shown that modafinil allows DREM episodes to persist [Lin et al, 2008], a situation similar to that in the clinic in which modafinil improves excessive daytime sleepiness without clear effect in cataplexy.
Moreover, as disclosed on figure 6B, flecainide racemate (alone), at 1 mg/kg dose, has no effect on DREM cataplectic-like phenotype in narcoleptic Ox-/- mice.
However, and importantly, the results disclosed on figure 6A show that modafinil/flecainide combination decreases the occurrence of DREM episode.
Hence, flecainide and modafinil do not have any significant effect on a DREM
cataplectic-like phenotype when used alone, whereas their combination importantly decreases the DREM cataplectic-like phenotype.
These results highlight the synergy existing between flecainide and modafinil, said synergy being due to the potentiation of the modafinil efficiency by flecainide, since no effect is seen with either modafinil or flecainide alone in narcoleptic mice.

Exemple 6: Modafinil/R-flecainide is surprisingly more efficient than Modafinil/S-flecainide on DREM cataplectic-like phenotype in narcoleptic mice The same materials and methods than in example 5 were used, except that the flecainide racemate has been replaced by the R-flecainide enantiomer.
As disclosed on figure 7, R-flecainide enantiomer combined with modafinil is more efficient on DREM cataplectic-like phenotype in narcoleptic Ox-/- mice than the S-flecainide enantiomer combined with modafinil.

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