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Volumn 4, Issue , 2010, Pages 124-139

Antipsychotic drug development

Author keywords

Antipsychotics; Intramolecular polypharmacy; Multifunctional drugs; Receptors

Indexed keywords

ARIPIPRAZOLE; BIFEPRUNOX; CARIPRAZINE; CLOZAPINE; DOPAMINE; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE 3 RECEPTOR BLOCKING AGENT; FLUOXETINE; GLUTAMATE RECEPTOR; GLYCINE; HISTAMINE H1 RECEPTOR; METABOTROPIC RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; N [4 [2 (6 CYANO 1,2,3,4 TETRAHYDRO 2 ISOQUINOLINYL)ETHYL]CYCLOHEXYL] 4 QUINOLINECARBOXAMIDE; N [4 [2 (8 CYANO 1,3A,4,9B TETRAHYDRO 1 BENZOPYRANO[3,4 C]PYRROL 2(3H) YL)ETHYL]PHENYL]ACETAMIDE; NEUROLEPTIC AGENT; OLANZAPINE; OPC 4293; PIMOZIDE; RISPERIDONE; SEROTONIN 1A RECEPTOR; SEROTONIN 2A AGONIST; SEROTONIN 2A RECEPTOR; SEROTONIN 2C RECEPTOR; SEROTONIN 7 RECEPTOR; TANDOSPIRONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZIPRASIDONE; ZOTEPINE; AMINO ACID RECEPTOR AFFECTING AGENT; DOPAMINE RECEPTOR; SEROTONIN RECEPTOR;

EID: 79952272122     PISSN: 18663370     EISSN: 18663389     Source Type: Book Series    
DOI: 10.1007/7854_2010_47     Document Type: Review
Times cited : (26)

References (66)
  • 1
    • 33846426067 scopus 로고    scopus 로고
    • Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission
    • Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113:296-320
    • (2007) Pharmacol Ther , vol.113 , pp. 296-320
    • Alex, K.D.1    Pehek, E.A.2
  • 4
    • 0027421620 scopus 로고
    • Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase
    • Bard JA, Zgombick J, Adham N, Branchek TA, Weinshank RL (1993) Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem 268:23422-23426
    • (1993) J Biol Chem , vol.268 , pp. 23422-23426
    • Bard, J.A.1    Zgombick, J.2    Adham, N.3    Branchek, T.A.4    Weinshank, R.L.5
  • 5
    • 0032441894 scopus 로고    scopus 로고
    • Modulation of N-methyl-D-aspartate receptor function by glycine transport
    • Bergeron R, Meyer TM, Coyle JT, Greene RW (1998) Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci USA 95:15730-15734
    • (1998) Proc Natl Acad Sci USA , vol.95 , pp. 15730-15734
    • Bergeron, R.1    Meyer, T.M.2    Coyle, J.T.3    Greene, R.W.4
  • 6
    • 34347335477 scopus 로고    scopus 로고
    • The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study
    • Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, Khan A (2007) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 68:843-853
    • (2007) J Clin Psychiatry , vol.68 , pp. 843-853
    • Berman, R.M.1    Marcus, R.N.2    Swanink, R.3    McQuade, R.D.4    Carson, W.H.5    Corey-Lisle, P.K.6    Khan, A.7
  • 9
    • 0032754397 scopus 로고    scopus 로고
    • Neurotransmitter interactions in schizophrenia-therapeutic implications
    • Carlsson A, Waters N, Carlsson ML (1999) Neurotransmitter interactions in schizophrenia-therapeutic implications. Biol Psychiatry 46:1388-1395
    • (1999) Biol Psychiatry , vol.46 , pp. 1388-1395
    • Carlsson, A.1    Waters, N.2    Carlsson, M.L.3
  • 10
    • 33645637616 scopus 로고    scopus 로고
    • Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens
    • Chen G, Kittler JT, Moss SJ, Yan Z (2006) Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens. J Neurosci 26:2513-2521
    • (2006) J Neurosci , vol.26 , pp. 2513-2521
    • Chen, G.1    Kittler, J.T.2    Moss, S.J.3    Yan, Z.4
  • 11
    • 17444388806 scopus 로고    scopus 로고
    • Blockade of dopamine D3 receptors enhances frontocortical cholinergic transmission and cognitive function in rats
    • Dekeyne A, Di Cara B, Gobert A, Millan MJ (2004) Blockade of dopamine D3 receptors enhances frontocortical cholinergic transmission and cognitive function in rats. Soc Neurosci Abstr 29:776.4
    • (2004) Soc Neurosci Abstr , vol.29 , pp. 774-776
    • Dekeyne, A.1    Di Cara, B.2    Gobert, A.3    Millan, M.J.4
  • 13
    • 34548348729 scopus 로고    scopus 로고
    • Molecular targets for treating cognitive dysfunction in schizophrenia
    • Gray JA, Roth BL (2007a) Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull 33:1100-1119
    • (2007) Schizophr Bull , vol.33 , pp. 1100-1119
    • Gray, J.A.1    Roth, B.L.2
  • 14
    • 34748864737 scopus 로고    scopus 로고
    • The pipeline and future of drug development in schizophrenia
    • Gray JA, Roth BL (2007b) The pipeline and future of drug development in schizophrenia. Mol Psychiatry 12:904-922
    • (2007) Mol Psychiatry , vol.12 , pp. 904-922
    • Gray, J.A.1    Roth, B.L.2
  • 15
    • 41049100992 scopus 로고    scopus 로고
    • Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients
    • Gunes A, Dahl ML, Spina E, Scordo MG (2008) Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. Eur J Clin Pharmacol 64:477-482
    • (2008) Eur J Clin Pharmacol , vol.64 , pp. 477-482
    • Gunes, A.1    Dahl, M.L.2    Spina, E.3    Scordo, M.G.4
  • 19
    • 0348047434 scopus 로고    scopus 로고
    • Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: A retrospective analysis
    • Heresco-Levy U, Javitt DC (2004) Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 66:89-96
    • (2004) Schizophr Res , vol.66 , pp. 89-96
    • Heresco-Levy, U.1    Javitt, D.C.2
  • 20
    • 0035096016 scopus 로고    scopus 로고
    • 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: A possible mechanism of atypical antipsychotic-induced cortical dopamine release
    • Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY (2001) 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521-1531
    • (2001) J Neurochem , vol.76 , pp. 1521-1531
    • Ichikawa, J.1    Ishii, H.2    Bonaccorso, S.3    Fowler, W.L.4    O'Laughlin, I.A.5    Meltzer, H.Y.6
  • 21
    • 8744278883 scopus 로고    scopus 로고
    • Glutamate as a therapeutic target in psychiatric disorders
    • Javitt DC (2004) Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 9:984-997
    • (2004) Mol Psychiatry , vol.9 , pp. 984-997
    • Javitt, D.C.1
  • 22
    • 33646832723 scopus 로고    scopus 로고
    • Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients
    • Javitt DC (2006) Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry 19:151-157
    • (2006) Curr Opin Psychiatry , vol.19 , pp. 151-157
    • Javitt, D.C.1
  • 23
    • 0023091647 scopus 로고
    • Glycine potentiates the NMDA response in cultured mouse brain neurons
    • Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529-531
    • (1987) Nature , vol.325 , pp. 529-531
    • Johnson, J.W.1    Ascher, P.2
  • 25
    • 0034741123 scopus 로고    scopus 로고
    • Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs
    • Joyce JN (2001) Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs. Pharmacol Ther 90:231-259
    • (2001) Pharmacol Ther , vol.90 , pp. 231-259
    • Joyce, J.N.1
  • 26
    • 21544439847 scopus 로고    scopus 로고
    • Dopamine D3 receptor antagonists as therapeutic agents
    • Joyce JN, Millan MJ (2005) Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today 10:917-925
    • (2005) Drug Discov Today , vol.10 , pp. 917-925
    • Joyce, J.N.1    Millan, M.J.2
  • 27
    • 0035094264 scopus 로고    scopus 로고
    • Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis
    • Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158:360-369
    • (2001) Am J Psychiatry , vol.158 , pp. 360-369
    • Kapur, S.1    Seeman, P.2
  • 29
    • 0038727272 scopus 로고    scopus 로고
    • Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex
    • Lacroix LP, Hows MEP, Shah AJ, Hagan JJ, Heidbreder CA (2003) Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex. Neuropsychopharmacology 28:839-849
    • (2003) Neuropsychopharmacology , vol.28 , pp. 839-849
    • Lacroix, L.P.1    Hows, M.E.P.2    Shah, A.J.3    Hagan, J.J.4    Heidbreder, C.A.5
  • 30
    • 0037115061 scopus 로고    scopus 로고
    • Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor
    • Laplante P, Diorio J, Meaney MJ (2002) Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor. Brain Res Dev Brain Res 139:199-203
    • (2002) Brain Res Dev Brain Res , vol.139 , pp. 199-203
    • Laplante, P.1    Diorio, J.2    Meaney, M.J.3
  • 31
    • 18744405105 scopus 로고    scopus 로고
    • Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats
    • Laszy J, Laszlovszky I, Gyertyán I (2005) Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology 179:567-575
    • (2005) Psychopharmacology , vol.179 , pp. 567-575
    • Laszy, J.1    Laszlovszky, I.2    Gyertyán, I.3
  • 34
    • 34648830603 scopus 로고    scopus 로고
    • Differential effects of aripiprazole on D2, 5-HT2, and 5-HT1A receptor occupancy in patients with schizophrenia: A triple tracer PET study
    • Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S (2007) Differential effects of aripiprazole on D2, 5-HT2, and 5-HT1A receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 164:1411-1417
    • (2007) Am J Psychiatry , vol.164 , pp. 1411-1417
    • Mamo, D.1    Graff, A.2    Mizrahi, R.3    Shammi, C.M.4    Romeyer, F.5    Kapur, S.6
  • 35
    • 0346995465 scopus 로고    scopus 로고
    • 8-OH-DPAT facilitated memory consolidation and increased hippocampal and cortical cAMP production
    • Manuel-Apolinar L, Meneses A (2004) 8-OH-DPAT facilitated memory consolidation and increased hippocampal and cortical cAMP production. Behav Brain Res 148:179-184
    • (2004) Behav Brain Res , vol.148 , pp. 179-184
    • Manuel-Apolinar, L.1    Meneses, A.2
  • 36
    • 0742271350 scopus 로고    scopus 로고
    • What's atypical about atypical antipsychotic drugs
    • Meltzer HY (2004) What's atypical about atypical antipsychotic drugs? Curr Opin Pharmacol 4:53-57
    • (2004) Curr Opin Pharmacol , vol.4 , pp. 53-57
    • Meltzer, H.Y.1
  • 37
    • 0345131659 scopus 로고    scopus 로고
    • Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo
    • Millan MJ, Dekeyne A, Gobert A (1998) Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 37:953-955
    • (1998) Neuropharmacology , vol.37 , pp. 953-955
    • Millan, M.J.1    Dekeyne, A.2    Gobert, A.3
  • 38
    • 38749136624 scopus 로고    scopus 로고
    • S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent. I. Receptor-binding profile and functional actions at G-protein-coupled receptors
    • Millan MJ, la Cour CM, Novi F, Maggio R, Audinot V, Newman-Tancredi A, Cussac D, Pasteau V, Boutin JA, Dubuffet T, Lavielle G (2008) S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent. I. Receptor-binding profile and functional actions at G-protein-coupled receptors. J Pharmacol Exp Ther 324:587-599
    • (2008) J Pharmacol Exp Ther , vol.324 , pp. 587-599
    • Millan, M.J.1    la Cour, C.M.2    Novi, F.3    Maggio, R.4    Audinot, V.5    Newman-Tancredi, A.6    Cussac, D.7    Pasteau, V.8    Boutin, J.A.9    Dubuffet, T.10    Lavielle, G.11
  • 39
    • 12344326514 scopus 로고    scopus 로고
    • Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs
    • Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2005) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10:79-104
    • (2005) Mol Psychiatry , vol.10 , pp. 79-104
    • Miyamoto, S.1    Duncan, G.E.2    Marx, C.E.3    Lieberman, J.A.4
  • 40
    • 0032575715 scopus 로고    scopus 로고
    • Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats
    • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349-1352
    • (1998) Science , vol.281 , pp. 1349-1352
    • Moghaddam, B.1    Adams, B.W.2
  • 42
    • 0032806873 scopus 로고    scopus 로고
    • Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus
    • Mullins UL, Gianutsos G, Eison AS (1999) Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus. Neuropsychopharmacology 21:352-367
    • (1999) Neuropsychopharmacology , vol.21 , pp. 352-367
    • Mullins, U.L.1    Gianutsos, G.2    Eison, A.S.3
  • 44
    • 0032694066 scopus 로고    scopus 로고
    • NMDA receptor hypofunction model of schizophrenia
    • Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523-533
    • (1999) J Psychiatr Res , vol.33 , pp. 523-533
    • Olney, J.W.1    Newcomer, J.W.2    Farber, N.B.3
  • 45
    • 0033058970 scopus 로고    scopus 로고
    • Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist
    • Reavill C, Kettle A, Holland V, Riley G, Blackburn TP (1999) Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist. Br J Pharmacol 126:572-574
    • (1999) Br J Pharmacol , vol.126 , pp. 572-574
    • Reavill, C.1    Kettle, A.2    Holland, V.3    Riley, G.4    Blackburn, T.P.5
  • 50
    • 0027183389 scopus 로고
    • Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation
    • Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC (1993) Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci USA 90:8547-8551
    • (1993) Proc Natl Acad Sci USA , vol.90 , pp. 8547-8551
    • Ruat, M.1    Traiffort, E.2    Leurs, R.3    Tardivel-Lacombe, J.4    Diaz, J.5    Arrang, J.M.6    Schwartz, J.C.7
  • 51
    • 0035902983 scopus 로고    scopus 로고
    • Ziprasidone: A novel antipsychotic agent with a unique human receptor binding profile
    • Schmidt AW, Lebel LA, Howard HR Jr, Zorn SH (2001) Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol 425:197-201
    • (2001) Eur J Pharmacol , vol.425 , pp. 197-201
    • Schmidt, A.W.1    Lebel, L.A.2    Howard Jr., H.R.3    Zorn, S.H.4
  • 52
    • 0034055689 scopus 로고    scopus 로고
    • Possible implications of the dopamine D3 receptor in schizophrenia and in antipsychotic drug actions
    • Schwartz J, Diaz J, Pilon C, Sokoloff P (2000) Possible implications of the dopamine D3 receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev 31:277-287
    • (2000) Brain Res Brain Res Rev , vol.31 , pp. 277-287
    • Schwartz, J.1    Diaz, J.2    Pilon, C.3    Sokoloff, P.4
  • 53
    • 34248197120 scopus 로고    scopus 로고
    • Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia
    • Stahl SM (2007a) Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia. CNS Spectr 12:265-268
    • (2007) CNS Spectr , vol.12 , pp. 265-268
    • Stahl, S.M.1
  • 54
    • 34447134211 scopus 로고    scopus 로고
    • Novel therapeutics for schizophrenia: Targeting glycine modulation of NMDA glutamate receptors
    • Stahl SM (2007b) Novel therapeutics for schizophrenia: targeting glycine modulation of NMDA glutamate receptors. CNS Spectr 12:423-427
    • (2007) CNS Spectr , vol.12 , pp. 423-427
    • Stahl, S.M.1
  • 55
    • 34948817131 scopus 로고    scopus 로고
    • Novel mechanism of antidepressant action: Norepinephrine and dopamine disinhibition (NDDI) plus melatonergic agonism
    • Stahl SM (2007c) Novel mechanism of antidepressant action: norepinephrine and dopamine disinhibition (NDDI) plus melatonergic agonism. Int J Neuropsychopharmacol 10:575-578
    • (2007) Int J Neuropsychopharmacol , vol.10 , pp. 575-578
    • Stahl, S.M.1
  • 57
    • 43249084428 scopus 로고    scopus 로고
    • Do dopamine partial agonists have partial efficacy as antipsychotics
    • Stahl SM (2008b) Do dopamine partial agonists have partial efficacy as antipsychotics? CNS Spectr 13:279-282
    • (2008) CNS Spectr , vol.13 , pp. 279-282
    • Stahl, S.M.1
  • 58
    • 44549087928 scopus 로고    scopus 로고
    • Antipsychotic drug action: Antagonism, inverse agonism or partial agonism
    • Strange PG (2008) Antipsychotic drug action: antagonism, inverse agonism or partial agonism. Trends Pharmacol Sci 29:314-321
    • (2008) Trends Pharmacol Sci , vol.29 , pp. 314-321
    • Strange, P.G.1
  • 63
    • 32144442536 scopus 로고    scopus 로고
    • D-Alanine added to antipsychotics for the treatment of schizophrenia
    • Tsai GE, Yang P, Chang YC, Chong MY (2006) D-Alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 59:230-234
    • (2006) Biol Psychiatry , vol.59 , pp. 230-234
    • Tsai, G.E.1    Yang, P.2    Chang, Y.C.3    Chong, M.Y.4
  • 64
    • 0032974130 scopus 로고    scopus 로고
    • D-Cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: A double-blind, parallel, placebo-controlled study
    • van Berckel BN, Evenblij CN, van Loon BJ, Maas MF, van der Geld MA, Wynne HJ, van Ree JM, Kahn RS (1999) D-Cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. Neuropsychopharmacology 21:203-210
    • (1999) Neuropsychopharmacology , vol.21 , pp. 203-210
    • van Berckel, B.N.1    Evenblij, C.N.2    van Loon, B.J.3    Maas, M.F.4    van der Geld, M.A.5    Wynne, H.J.6    van Ree, J.M.7    Kahn, R.S.8
  • 66
    • 0036316782 scopus 로고    scopus 로고
    • D3 receptor ligands modulate extracellular dopamine clearance in the nucleus accumbens
    • Zapata A, Shippenberg TS (2002) D3 receptor ligands modulate extracellular dopamine clearance in the nucleus accumbens. J Neurochem 81:1035-1042
    • (2002) J Neurochem , vol.81 , pp. 1035-1042
    • Zapata, A.1    Shippenberg, T.S.2


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