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( 12 ) United States Patent US009737531B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 737 ,531 B2 Javitt ( 45) Date of Patent : Aug . 22 , 2017 ( 54 ) COMPOSITION AND METHOD FOR 2008 /0194698 A1 * 8 / 2008 Hermanussen et al. .. .. 514 /662 TREATMENT OF DEPRESSION AND 2011/ 0207776 A18 / 2011 Buntinx 2011 /0306586 Al 12 / 2011 Khan PSYCHOSIS IN HUMANS 2012 /0041026 A12 / 2012 Waizumi (71 ) Applicant : Daniel C Javitt , Bardonia , NY (US ) FOREIGN PATENT DOCUMENTS ( 72 ) Inventor: Daniel C Javitt, Bardonia , NY (US ) CN 101090721 12 / 2007 KR 2007 0017136 A 2 / 2007 ( 73 ) Assignee : GLYTECH , LLC , Ft. Lee, NJ (US ) WO WO 2005 /000216 A2 1 / 2005 WO WO 2005 /065308 A2 7 / 2005 ( * ) Notice : Subject to any disclaimer , the term of this WO WO 2005 /079756 9 / 2005 patent is extended or adjusted under 35 WO 2011044089 4 / 2011 U . S . C . 154 ( b ) by 0 days . wo WO 2012 / 104852 Al 8 / 2012 ( 21 ) Appl. No. : 13 /936 , 198 OTHER PUBLICATIONS Ceglia et al. , “ The 5 -HT2A receptor antagonist M100 , 907 prevents ( 22 ) Filed : Jul. 7 , 2013 extracellular glutamate rising in response to NMDA receptor block ade in the mPFC ,” Journal of Neurochemistry , 2004 , 91 , 189 - 199 . * ((65 65 ) Prior Publication Data Mony et al. , “ Identification of a novel NR2B -selective NMDA US 2014 / 0018348 A1 Jan . 16 , 2014 receptor antagonist using a virtual screening approach , ” Bioorganic & Medicinal Chemistry Letters 20 ( 2010 ) 5552 - 5558 . * Ceglia et al ., “ The 5HT2A receptor antagonist M100 , 907 prevents Related U . S . Application Data extracellular glutamate rising in response to NMDA receptor block ( 60 ) Provisional application No . 61/ 741 , 114 , filed on Jul . ade in the mPFC ,” Journal of Neurochemistry , 2004 , 91 , 189 - 199 . * 12 , 2012 , provisional application No . 61 / 741 , 115 , Rogoz , Z . et al . “ Synergistic effect of uncompetitive NMDA recep tor antagonists and antidepressant drugs in the forced swimming test filed on Jul . 12 , 2012 . in rats ” Neuropharmacology , Pergamon Press , Oxford , GB , 42 ( 8 ) : 1024 - 1030 , XP002288820 ( Jun . 2002 ) . (51 ) Int. CI. Heresco - Levy , U . et al. “ Controlled trial of d - cycloserine adjuvant AOIN 43 / 00 ( 2006 .01 ) therapy for treatment- resistant major depressive disorder ” Journal A61K 31 /553 ( 2006 .01 ) of Affective Disorders , Elsevier Biochemical Press, Amsterdam , A61K 31 /554 ( 2006 .01 ) NL , 93 ( 1 - 3 ) : 239 - 243 , XP024997304 ( Jul. 2006 ) . A61K 31/ 496 ( 2006 .01 ) Crane , G . E . “ Cycloserine as an antidepressant agent” American A61K 31 /42 ( 2006 .01 ) journal of Psychiatry , American Psychiatric Publishing , Inc . , US , A61K 31 / 06 ( 2006 . 01 ) 115 (11 ) : 1025 - 1026 , XP009158563 (May 1 , 1959 ) . A61K 31/ 381 Oliver et al. " Quetiapine augmentation in depressed patients with (2006 .01 ) partial response to antidepressants ” Human Psychopharm Clin Exp , A61K 31 /55 ( 2006 . 01 ) 23 :653 - 660 , 2008 . A61K 31/ 138 (2006 .01 ) Poleszak et al “ A complex interaction between glycine/ NMDA A61K 45 / 06 ( 2006 .01 ) receptors and serotonergic /noradrenergic antidepressants in the A61K 31 /431 ( 2006 .01 ) forced swim test in mice " Journal of Neural Transmission , A61K 31/ 4525 (2006 .01 ) 118 : 1535 - 1546 , 2011 . A61K 31/ 519 ( 2006 . 01 ) Ishibashi et al “ Pharmacological Profile of Lurasidone , a Novel A61K 31/ 551 ( 2006 .01 ) Antipsychotic Agent with Potent 5 -Hydroxytryptamine 7 ( 5 -HT7 ) A61K 31 / 135 ( 2006 .01 ) and 5 -HT1A Receptor Activity " Journal of Pharmacology and (52 ) U . S . CI. Experimental Therapeutics , 334 : 171 - 181 , 2010 . CPC .. .. A61K 31/ 496 ( 2013 . 01 ) ; A61K 31/ 06 (Continued ) ( 2013 .01 ) ; A61K 31/ 135 ( 2013 .01 ) ; A61K 31 / 138 ( 2013 .01 ) ; A61K 31/ 381 ( 2013 . 01 ) ; A61K 31/ 42 ( 2013 . 01 ) ; A61K 31/ 431 Primary Examiner — Jared D Barsky ( 2013 .01 ) ; A61K 31 /4525 (2013 .01 ) ; A61K (74 ) Attorney , Agent, or Firm — JMB Davis Ben - David 31/ 519 ( 2013 .01 ) ; A61K 31 /55 ( 2013 . 01 ) ; A61K 31 / 551 ( 2013 . 01 ) ; A61K 31 / 553 (2013 . 01 ); A61K 31 /554 (2013 .01 ) ; A61K (57 ) ABSTRACT 45/ 06 ( 2013 . 01 ) Compositions and methods tor the treatment of depression (58 ) Field of Classification Search and psychoses in humans are disclosed . More particularly , None the invention is directed to formulations containing antip See application file for complete search history. sychotic and / or antidepressant medications and also con taining an NMDAR antagonist. The present invention is also (56 ) References Cited directed to methods for the treatment of humans suffering from depression and other psychoses , including , schizophre U . S . PATENT DOCUMENTS nia , by administration of the inventive compositions in 6 ,228 ,875 B1 * 5 / 2001 Tsai et al. .. 514 /380 antidepressant and /or antipsychotic effective amounts . 2005 / 0261340 A1 11/ 2005 Weiner 2006 / 0204486 A1 * 9 / 2006 Pyke et al. .. .. .. .. 424 / 94 . 2 2008/ 0194631 A1 * 8 / 2008 Trovero et al. .. .. .. .. 514 / 325 2 Claims, 1 Drawing Sheet US 9 ,737 ,531 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Marek et al, “ The Selective 5 -HT2A Receptor Antagonist M100907 Enhances Antidepressant- Like Behavioral Effects of the SSRI Fluoxetine” Neuropsychopharmacology 30 : 2205 -2215 , 2005. Letter to Dr. Daniel Javitt from Dr. Yehezkel Caine , CEO of Herzog Hospital , Apr. 12 , 2017 (redacted ) ( 1 page ) . Letter to Dr. Yehezkel Caine , CEO of Herzog Hospital from Dr. Daniel Javitt, May 15 , 2017 ( redacted ) ( 3 pages ) * cited by examiner U . S . Patent Aug . 22 , 2017 US 9 ,737 , 531 B2 los * 5MDL100907(0.3mg/kg,1P)+DCS30–DOI(21.P 60-6MDL100907(0.3mg/kg,1P)+DCS300–DOI2 6.48MDL100907(03mg/kg,1P)+DOI2 3.DCS(300mg/kg,1P)+2 807:2DCS(30mg/kg,1.P)+ :1.PTS(P)=DOI2mg/kg, . 20 ARMS OPEN IN SPENT TIME % US 9 ,737 ,531 B2 COMPOSITION AND METHOD FOR Current treatments for major depression consist primarily TREATMENT OF DEPRESSION AND of older antidepressants , such as monoamine oxidase inhibi PSYCHOSIS IN HUMANS tors (MAOI ) and tricyclic antidepressants ( TCAs ) ( e . g . imipramine , amitryptiline , desipramine , clomipramine ) that CROSS REFERENCE TO RELATED were first developed in the 1960 ' s , and newer agents such as APPLICATIONS tetracyclic antidepressants ( TeCAs) , e . g ., amoxapine, setip tiline , maprotiline , mianserin , mirtazapine ) , serotonin This application claims the benefit of provisional appli - (SSRI ) and serotonin /norephinephrine (SNRI ) reuptake cation No. 61/ 741, 114 , filed Jul. 12 , 2012 , and provisional inhibitors ( e . g ., fluoxetine, fluvoxamine , paroxetine , citalo application No . 61 /741 , 115 , filed Jul . 12 , 2012 , the contents 10 pram , escitalopram , duloxetine , venlafaxine , dapoxetine , of each of which are hereby incorporated by reference . indalpine , valzodone ) . These agents work by modulating brain levels of monoamines , in particular norepinephrine BACKGROUND OF THE INVENTION and serotonin , and /or by blocking 5 -HT2A receptors. MAOIs and TCAs are considered “ broader spectrum ” agents Schizophrenia is a clinical syndrome associated with 15 than SSRI /SNRIs that were developed subsequently . psychotic symptoms such as delusions and hallucinations , as MAOI, TCAs . TeCAs, SSRIs , and SNRIs may collectively well as a decline in function in such areas as work , social be considered traditional antidepressants . relation or self care . Antipsychotics may also be effective in treatment of Diagnosis of schizophrenia may be determined using depression . Potentially beneficial antipsychotic medications standard textbooks of the art such as the Diagnostic and 20 include but are not limited to risperidone , olanzapine, que Statistical Manual of Mental Disorders - fourth edition tiapine , aripiprazole, clozapine, lioperidone , sertindole , ( DSM -IV ) published by the American Psychiatric Associa asenapine , lurasidone , cariprazine tion Symptoms of schizophrenia are typically measured Other antipsychotics and antidepressants in development using rating scales such as the Positive and Negative Syn - include Valdoxan (agomelatine , AGO178 ) ( Servier, Novar drome Scale (PANSS ) . 25 tis ) , Lu AA21004 (Lundbeck , Takeda ). F2695 , levomil Symptoms of schizophrenia are treated with antipsychotic nacipran (Forest , Pierre Fabre; SEP -227162 (Sepracor ) . medications , which function primarily by blocking dop - LUAA24530 ( Lundbeck , Takeda ) , SEP - 225289 ( Sepracor ) , amine D2 receptors . Epivanserine (Sanofi - Aventis ), SR46349 (Sanofi - Aventis ) , Antipsychotics may be divided into typical ( e . g . chlorpro - LY12624803 , HY10275 (Lilly , Hypnion ). TIK - 301/ mazine , haloperidol, perphenazine) vs . atypical ( e . g . amisul - 30 LY156735 ( Tikvah Therapeutics) , Lonasen ( bioanserin , pride , aripiprazole , asenapine , bioanserin , bifeprunox , car Dainippon ), LU - 31 - 130 (Lundbeck ) , SLV313 (Solvay ) , Edi iprazine , clotiapine , clozapine, iloperidone , lurasidone, voxetine (LY2216684 , Lilly ) , OPC -34712 (Otsuka / Lund mosaproamine , olanzapine , paliperidone, perospirone, que - beck Vyvanse ( lisdexamfetamine , Shire ). BCI- 224 ( sacome tiapine , remoxipride , risperidone , sertindole , sulpride, zip line , BrainCells ) , BCI- 540 ( clouracetam . BrainCells ) , BMS rasidone , zotepine ) based upon receptor binding, preclinical 35 82036 (BMS / AMRI ) . effects and side effect profile . Clinically effective doses of However, current treatment approaches have severe limi antipsychotic medication typically produce >60 % occu - tations. Only 60 -65 % of patients respond to the initial pancy of
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