Pharmaceutical composition for the treatment of autism

Abstract

Likewise, the present invention relates to methods of treating patients suffering from autism spectrum disorder (ASD) phenotype 1 by administering an effective amount of a substance capable of intracellular cAMP levels and, optionally, an effective amount of a substance capable of modulating intracellular calcium concentration.

1 . A pharmaceutical composition comprising
 (i) a first substance capable of raising intracellular cAMP levels in human neuronal cells and   (ii) a second substance capable of modulating intracellular calcium concentration in human neuronal cells,   
       wherein the first substance is different from the second substance, wherein the composition does not comprise any additional active ingredients, wherein the first substance is selected from a PDE4 inhibitor and a substance capable of activating a G protein coupled adenosine A 2A  receptor and the second substance is selected from a diuretic, an antiarrhythmic agent and a retinoic acid-related orphan receptor-alpha (RORA) agonist. 
     
     
         2 . (canceled) 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the substance capable of raising intracellular cAMP levels is a PDE4 inhibitor. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the PDE inhibitor is selected from the group consisting of theophylline, caffeine, reuteri, cilostazol, etazolate, rollumilast, crisaborole, drotaverin, ibudilast, cilomilast, rolipram, (S)-rolipram, (R)-rolipram, amrinone, milrinone, enoximone, daxalipram (R-mesopram), lirimilast, cipamfylline, tofimilast, CI-1044, HT-0712, MK-0873, CI-1018, T-2585, V-11294A, piclamilast, atizoram, filaminast, IC-485, CDP-840, and L-826,141. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the substance capable of raising intracellular cAMP levels is a substance capable of activating a G protein coupled adenosine A 2A  receptor. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the substance capable of activating a G protein-coupled adenosine A 2A  receptor is selected from the group consisting of regadenoson, bidenoson, 2-phenilaminoadenosine, 2-amino-4-(4-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridinecarbonitrile, 4-[2-[(6-amino-9-b-D-ribofuranosyl-9H-purin-2-yl)thio]ethyl]benzenesulfonic acid ammonium salt and 2-hexynyl-5′-N-ethylcarboxamidoadenosine, CGS-21680 and UK-432,097. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the substance capable of modulating intracellular calcium concentration is a retinoic acid-related orphan receptor-alpha (RORA) agonist. 
     
     
         8 . The pharmaceutical composition according  claim 1 , wherein the substance capable of modulating intracellular calcium concentration is a calcium channel inhibitor of solute carrier family 12 members 1, 2, 4 or 5. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the substance capable of modulating intracellular calcium concentration is selected from the group consisting of dihydropyridines, phenylakylamines, benzothiazepines, indolazines, aminoglycosides and 4-substituted derivatives of sulfamoylbenzoic acid. 
     
     
         10 . The pharmaceutical composition according to  claim 9 , wherein the 4-substituted derivative of sulfamoylbenzoic acid is a derivative of 4-substituted-3-amino-5-sulfamoylbenzoic acid. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein the derivative of 4-substituted-3-amino-5-sulfamoylbenzoic acid is selected from the group consisting of bumetanide, AqB007, AqB011, PF-2178, BUM13, BUM5, bumepamine and mixtures thereof. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the substance capable of modulating intracellular calcium concentration is selected from the group consisting of nifedipine, niludipine, nicardipine, nimodipine, NZ-105, amlodipine, felodipine, isradipine, diperdipine, emopamil, devapamil, verapamil, diltiazem, flunarizine, fluspirilene, pimozide, fantofarone, nicergoline, neomycin, gentamycin, kanamycin, cisapride, clopamide, cyproheptadine, loratadine, domperidone, fentanyl, alfentanil, sufentanil, flecainide, indoramin, isonepecotic acids, ketotifen, lobeline, loperamide, mepivacaine, methylphenidate, minoxidil, nipecotic acid, paroxetine, pempidine, penfluridol, perhexiline, pipecolics acid, bupivacaine, cyclohexemide, thalidomide, terfenadine, trihexyphenidyl, clevidipine, lomerazine, fostedil, anipamil, torasemide, chlorthalidone, etacrynic acid, furosemide, trichlormethiazide, hydroflumethiazide, methylclothiazide, bumetanide, ibutilde, mibefradil, dronedarone, amiodarone, nisoldipine, nitrendipine, nilvadipine, gabapentine and ambroxol hydrochloride. 
     
     
         13 - 22 . (canceled) 
     
     
         23 . The pharmaceutical composition according to  claim 1 , wherein the PDE inhibitor is selected from the group consisting of theophylline, theobromine, aminophylline, prepentofylline, cilostazol, etazolate, roflumilast, crisaborole, drotaverin, ibudilast, cilomilast, rolipram, (S)-rolipram, (R)-rolipram, amrinone, milrinone, enoximone, daxalipram (R-mesopram), lirimilast, cipamfylline, tofimilast, CI-1044, HT-0712, MK-0873, CI-1018, T-2585, V-11294A, piclamilast, atizoram, filaminast, IC-485, CDP-840, and L-826,141. 
     
     
         24 . The pharmaceutical composition according to  claim 1 , wherein the substance capable of activating a G protein-coupled adenosine A 2A  receptor is not adenosine. 
     
     
         25 . The pharmaceutical composition according to  claim 1 , which is in the form of a tablet or capsule suitable for oral administration to a human, which consists of said first substance and said second substance as active ingredients and one or more pharmaceutically acceptable carriers, excipients and/or diluents.