Pharmaceutical composition for the treatment of autism

A method of treating a patient diagnosed with autism spectrum disorder (ASD), wherein the treatment comprises

• (i) determining whether the patient suffers from ASD phenotype 1 and
• (ii) administering a therapeutically effective amount of a pharmaceutical composition comprising a substance capable of raising intracellular cAMP levels in human neuronal cells and a substance capable of modulating intracellular calcium concentration in human neuronal cells to the patient that suffers from ASD phenotype 1,
• wherein the substance capable of raising intracellular cAMP levels and the substance capable of modulating intracellular calcium concentration are distinct from each other,
• wherein determining whether the patient suffers from ASD phenotype 1 includes at least one selected from
• a) subjecting the patient to a challenge test with Nrf2-activator,
• b) verifying for clinical signs of heightened expression of proliferation-associated pathways,
• c) verifying for upregulation of Nrf2, or
• d) verifying for low levels of protein kinase A;
• and
• wherein it is determined that the patient suffers from ASD phenotype 1 if said patient shows at least one of the following:
• negative behavioral response in the challenge test with a Nrf2 inducer;
• clinical signs of heightened expression of proliferation-associated pathways;
• upregulation of Nrf2 or low blood levels of protein kinase A, and wherein
• the substance capable of raising intracellular cAMP levels is a PDE4 inhibitor selected from the group consisting of ibudilast, caffeine, theobromine, theophylline, enprofylline, pentoxifylline, dyphylline, etazolate, roflumilast, crisaborole, resembrenone, drotaverin, apremilast, cilomilast, tetomilast, rolipram, (S)-rolipram, (R)-rolipram, daxalipram (R-mesopram), lirimilast, AWD-12-281, cipamfylline, oglemilast, tofimilast, CI-1044 ((R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)nicotinamide), HT-0712 ((3S,5S)-2-Piperidinone, 5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-((3-methylphenyl)methyl), MK-0873 (3-(2-{3-[3-(cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]phenyl}ethynyl)pyridin-1-ium-1-olate), arofylline, C1-1018 (N-(3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin-3-yl)-4-Pyridinecarboxamide), T-2585 (2-{4-2,3-bis(hydroxymethyl)-6,7-diethoxy-1-naphthalenyl}-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone), YM-976 (4-(3-chlorophenyl)-1,7-diethyl-1H,2H-pyrido[2,3-d]pyrimidin-2-one), V-11294A (3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine), piclamilast, atizoram, filaminast, SCH 351591 (N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinolinecarboxamide), IC-485, D-4418 (N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide), CDP-840 (4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride), L-826,141 (4-(2-(3,4-bis(difluoromethoxy)phenyl)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)ethyl)-3-methylpyridine 1-oxide), BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide) and TDP101, and
• the substance capable of modulating intracellular calcium concentration is a NKCC1 inhibitor selected from the group consisting of fluspirilene, pimozide, gentamycin, kanamycin, clopamide, cyproheptadine, isonepecotic acids, thalidomide, torasemide, etacrynic acid, furosemide, trichlormethiazide, hydroflumethiazide, methylclothiazide, 4-substituted derivatives of sulfamoylbenzoic acid, bumetanide, AqB007, AqB011, PF-2178, BUM13, BUM5 and bumepamine.

A method of treating a patient diagnosed with autism spectrum disorder (ASD), comprising administering to a patient in need thereof an effective amount of a first substance capable of raising intracellular c-AMP levels in human neuronal cells and an effective amount of a second substance capable of modulating intracellular calcium concentration in human neuronal cells,

• wherein the first substance and the second substance are distinct from each other,
• wherein the administration of the first and second substances are preceded by the administration of the first substance without the administration of the second substance resulting in a loss of efficacy of the first substance, which efficacy is restored upon administration of the second substance,
• and wherein
• the substance capable of raising intracellular cAMP levels is a PDE4 inhibitor selected from the group consisting of ibudilast, caffeine, theobromine, theophylline, enprofylline, pentoxifylline, dyphylline, etazolate, roflumilast, crisaborole, resembrenone, drotaverin, apremila st, cilomilast, tetomilast, rolipram, (S)-rolipram, (R)-rolipram, daxalipram (R-mesopram), lirimilast, AWD-12-281, cipamfylline, oglemilast, tofimilast, CI-1044 ((R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)nicotinamide), HT-0712 ((3S,5S)-2-Piperidinone, 5-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-((3-methylphenyl)methyl), MK-0873 (3-(2-{3-[3-(cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]phenyl}ethynyl)pyridin-1-ium-1-olate), arofylline, CI-1018 (N-(3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin-3-yl)-4-Pyridinecarboxamide), T-2585 (2-{4-2,3-bis(hydroxymethyl)-6,7-diethoxy-1-naphthalenyll-2-pyridinyll-4-(3-pvridinvl)-1(2H)-phthalazinone), YM-976 (4-(3-chlorophenyl)-1,7-diethyl-1 H,2 H-pyrido[2,3-dlpvrimidin-2-one), V-1l1294A (3-(3-Cyclopentyloxy-4-methoxv-benzvl)-8-isopropyl-adenine), piclamilast, atizoram, filaminast, SCH 351591 (N-(3,5-Dichloro-1-oxido-4-pvridinvl)-8-methoxv-2-(trifluoromethyl)-5-quinolinecarboxamide), IC-485, D-4418 (N-(2,5-dichloro-3-pvridinvl)-8-methoxv-5-quinolinecarboxamide), CDP-840 (4-[(2R)-2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride), L-826,141 (4-(2-(3,4-bis(difluoromethoxy)phenyl)-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)ethyl)-3-methylpyridine 1-oxide), BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide) and TDP101, and
• the substance capable of modulating intracellular calcium concentration is a NKCC1 inhibitor selected from the group consisting of fluspirilene, pimozide, qentamycin, kanamycin, clopamide, cyproheptadine, isonepecotic acids, thalidomide, torasemide, etacrynic acid, furosemide, trichlormethiazide, hydroflumethiazide, methylclothiazide, 4-substituted derivatives of sulfamoylbenzoic acid, bumetanide, AqB007, AqB011, PF-2178, BUM13, BUM5 and bumepamine.