Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity
Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABA A-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of 36Cl −...
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| Veröffentlicht in: | Life sciences (1973) 1989, Vol.45 (20), p.1903-1910 |
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| creator | Ikeda, Masaaki Knapp, Richard J. Malatynska, Ewa Yamamura, Henry I. |
| description | Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABA
A-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of
36Cl
− uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA
2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABA
A receptor selective antagonist [
3H]SR 95531 with an IC
50 value of 3.45 μM and a pseudo Hill coefficient of 0.83. In contrast, 10 μM amoxapine inhibits [
3H] flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15–1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations. These data suggest that amoxapine does not inhibit chloride conductance by acting as a benzodiazepine inverse agonist and either acts directly on the GABA
A receptor as an antagonist or blocks GABA activity at a site closely coupled to it. The ability of amoxapine to inhibit GABA-stimulated chloride conductance is a likely explanation for its proconvulsant activity observed at high doses. |
| doi_str_mv | 10.1016/0024-3205(89)90544-4 |
| format | Article |
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A-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of
36Cl
− uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA
2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABA
A receptor selective antagonist [
3H]SR 95531 with an IC
50 value of 3.45 μM and a pseudo Hill coefficient of 0.83. In contrast, 10 μM amoxapine inhibits [
3H] flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15–1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations. These data suggest that amoxapine does not inhibit chloride conductance by acting as a benzodiazepine inverse agonist and either acts directly on the GABA
A receptor as an antagonist or blocks GABA activity at a site closely coupled to it. The ability of amoxapine to inhibit GABA-stimulated chloride conductance is a likely explanation for its proconvulsant activity observed at high doses.</description><identifier>ISSN: 0024-3205</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/0024-3205(89)90544-4</identifier><identifier>PMID: 2557507</identifier><identifier>CODEN: LIFSAK</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>550201 - Biochemistry- Tracer Techniques ; AMINO ACIDS ; AMINOBUTYRIC ACID ; Amoxapine - pharmacology ; ANIMALS ; ANTIDEPRESSANTS ; AUTONOMIC NERVOUS SYSTEM AGENTS ; BASIC BIOLOGICAL SCIENCES ; BETA DECAY RADIOISOTOPES ; BETA-MINUS DECAY RADIOISOTOPES ; BIOCHEMICAL REACTION KINETICS ; Biological and medical sciences ; BODY ; BRAIN ; CARBOXYLIC ACIDS ; CELL CONSTITUENTS ; CELL MEMBRANES ; CENTRAL NERVOUS SYSTEM ; CENTRAL NERVOUS SYSTEM AGENTS ; CEREBRAL CORTEX ; Cerebral Cortex - metabolism ; CEREBRUM ; CHLORIDES ; Chlorides - metabolism ; CHLORINE 36 ; CHLORINE COMPOUNDS ; CHLORINE ISOTOPES ; Dibenzoxazepines - pharmacology ; Dose-Response Relationship, Drug ; DOSE-RESPONSE RELATIONSHIPS ; DRUGS ; ELECTRON CAPTURE RADIOISOTOPES ; Flumazenil - pharmacology ; Flunitrazepam - metabolism ; GABA Antagonists ; HALIDES ; HALOGEN COMPOUNDS ; HYDROGEN COMPOUNDS ; INHIBITION ; ISOTOPE APPLICATIONS ; ISOTOPES ; KINETICS ; Ligands ; LIGHT NUCLEI ; Male ; MAMMALS ; Medical sciences ; MEMBRANE PROTEINS ; MEMBRANE TRANSPORT ; MEMBRANES ; NERVOUS SYSTEM ; Neuropharmacology ; NEUROREGULATORS ; NUCLEI ; ODD-ODD NUCLEI ; ORGANIC ACIDS ; ORGANIC COMPOUNDS ; ORGANS ; Pharmacology. Drug treatments ; PROTEINS ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; PSYCHOTROPIC DRUGS ; Pyridazines - metabolism ; RADIOISOTOPES ; RATS ; Rats, Inbred Strains ; REACTION KINETICS ; RECEPTORS ; Receptors, GABA-A - drug effects ; Receptors, GABA-A - metabolism ; RODENTS ; TRACER TECHNIQUES ; TRITIUM COMPOUNDS ; VERTEBRATES ; YEARS LIVING RADIOISOTOPES</subject><ispartof>Life sciences (1973), 1989, Vol.45 (20), p.1903-1910</ispartof><rights>1989</rights><rights>1991 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-d6dca48e4d38250142d6a9c58b96a18d8c5a6cea2363736d7aa165ec3cb63b413</citedby><cites>FETCH-LOGICAL-c511t-d6dca48e4d38250142d6a9c58b96a18d8c5a6cea2363736d7aa165ec3cb63b413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/0024320589905444$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19596262$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2557507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/7027108$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Ikeda, Masaaki</creatorcontrib><creatorcontrib>Knapp, Richard J.</creatorcontrib><creatorcontrib>Malatynska, Ewa</creatorcontrib><creatorcontrib>Yamamura, Henry I.</creatorcontrib><title>Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABA
A-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of
36Cl
− uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA
2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABA
A receptor selective antagonist [
3H]SR 95531 with an IC
50 value of 3.45 μM and a pseudo Hill coefficient of 0.83. In contrast, 10 μM amoxapine inhibits [
3H] flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15–1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations. These data suggest that amoxapine does not inhibit chloride conductance by acting as a benzodiazepine inverse agonist and either acts directly on the GABA
A receptor as an antagonist or blocks GABA activity at a site closely coupled to it. The ability of amoxapine to inhibit GABA-stimulated chloride conductance is a likely explanation for its proconvulsant activity observed at high doses.</description><subject>550201 - Biochemistry- Tracer Techniques</subject><subject>AMINO ACIDS</subject><subject>AMINOBUTYRIC ACID</subject><subject>Amoxapine - pharmacology</subject><subject>ANIMALS</subject><subject>ANTIDEPRESSANTS</subject><subject>AUTONOMIC NERVOUS SYSTEM AGENTS</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>BETA DECAY RADIOISOTOPES</subject><subject>BETA-MINUS DECAY RADIOISOTOPES</subject><subject>BIOCHEMICAL REACTION KINETICS</subject><subject>Biological and medical sciences</subject><subject>BODY</subject><subject>BRAIN</subject><subject>CARBOXYLIC ACIDS</subject><subject>CELL CONSTITUENTS</subject><subject>CELL MEMBRANES</subject><subject>CENTRAL NERVOUS SYSTEM</subject><subject>CENTRAL NERVOUS SYSTEM AGENTS</subject><subject>CEREBRAL CORTEX</subject><subject>Cerebral Cortex - metabolism</subject><subject>CEREBRUM</subject><subject>CHLORIDES</subject><subject>Chlorides - metabolism</subject><subject>CHLORINE 36</subject><subject>CHLORINE COMPOUNDS</subject><subject>CHLORINE ISOTOPES</subject><subject>Dibenzoxazepines - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>DOSE-RESPONSE RELATIONSHIPS</subject><subject>DRUGS</subject><subject>ELECTRON CAPTURE RADIOISOTOPES</subject><subject>Flumazenil - pharmacology</subject><subject>Flunitrazepam - metabolism</subject><subject>GABA Antagonists</subject><subject>HALIDES</subject><subject>HALOGEN COMPOUNDS</subject><subject>HYDROGEN COMPOUNDS</subject><subject>INHIBITION</subject><subject>ISOTOPE APPLICATIONS</subject><subject>ISOTOPES</subject><subject>KINETICS</subject><subject>Ligands</subject><subject>LIGHT NUCLEI</subject><subject>Male</subject><subject>MAMMALS</subject><subject>Medical sciences</subject><subject>MEMBRANE PROTEINS</subject><subject>MEMBRANE TRANSPORT</subject><subject>MEMBRANES</subject><subject>NERVOUS SYSTEM</subject><subject>Neuropharmacology</subject><subject>NEUROREGULATORS</subject><subject>NUCLEI</subject><subject>ODD-ODD NUCLEI</subject><subject>ORGANIC ACIDS</subject><subject>ORGANIC COMPOUNDS</subject><subject>ORGANS</subject><subject>Pharmacology. Drug treatments</subject><subject>PROTEINS</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>PSYCHOTROPIC DRUGS</subject><subject>Pyridazines - metabolism</subject><subject>RADIOISOTOPES</subject><subject>RATS</subject><subject>Rats, Inbred Strains</subject><subject>REACTION KINETICS</subject><subject>RECEPTORS</subject><subject>Receptors, GABA-A - drug effects</subject><subject>Receptors, GABA-A - metabolism</subject><subject>RODENTS</subject><subject>TRACER TECHNIQUES</subject><subject>TRITIUM COMPOUNDS</subject><subject>VERTEBRATES</subject><subject>YEARS LIVING RADIOISOTOPES</subject><issn>0024-3205</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxS1EVZbCNwApQgLRQ8D_Y3NAWipakCpxgbPl2LOsIYm3trOi3x6nuyo3ehpp5vdGb-Yh9ILgdwQT-R5jyltGsXir9LnGgvOWP0IrojrdYsnIY7S6R56gpzn_whgL0bFTdEprFbhbod_rMf6xuzBBE6Zt6EMJcWriprlaf1q3uYRxHmwB37jtEFPw0Lg4-dkVOzn4UDV7qNBPu8jyotvFAlMJdmhyKHDXsq6EfSi3z9DJxg4Znh_rGfpx-fn7xZf2-tvV14v1desEIaX10jvLFXDPFBWYcOql1U6oXktLlFdOWOnAUiZZx6TvrCVSgGOul6znhJ2hV4e9sVoz2VUfblttT-CK6TDtCFYVenOAdinezPUIM4bsYBjsBHHOptMcM87YgyCpj2ed5BXkB9ClmHOCjdmlMNp0awg2S2JmicMscRilzV1iZpG9PO6f-xH8vegYUZ2_Ps5tdnbYpPr5kP_t1kJLKmnlPh44qK_dB0jL5VBT8iEth_sY_m_kL4nmsns</recordid><startdate>1989</startdate><enddate>1989</enddate><creator>Ikeda, Masaaki</creator><creator>Knapp, Richard J.</creator><creator>Malatynska, Ewa</creator><creator>Yamamura, Henry I.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>1989</creationdate><title>Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity</title><author>Ikeda, Masaaki ; Knapp, Richard J. ; Malatynska, Ewa ; Yamamura, Henry I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-d6dca48e4d38250142d6a9c58b96a18d8c5a6cea2363736d7aa165ec3cb63b413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>550201 - Biochemistry- Tracer Techniques</topic><topic>AMINO ACIDS</topic><topic>AMINOBUTYRIC ACID</topic><topic>Amoxapine - pharmacology</topic><topic>ANIMALS</topic><topic>ANTIDEPRESSANTS</topic><topic>AUTONOMIC NERVOUS SYSTEM AGENTS</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>BETA DECAY RADIOISOTOPES</topic><topic>BETA-MINUS DECAY RADIOISOTOPES</topic><topic>BIOCHEMICAL REACTION KINETICS</topic><topic>Biological and medical sciences</topic><topic>BODY</topic><topic>BRAIN</topic><topic>CARBOXYLIC ACIDS</topic><topic>CELL CONSTITUENTS</topic><topic>CELL MEMBRANES</topic><topic>CENTRAL NERVOUS SYSTEM</topic><topic>CENTRAL NERVOUS SYSTEM AGENTS</topic><topic>CEREBRAL CORTEX</topic><topic>Cerebral Cortex - metabolism</topic><topic>CEREBRUM</topic><topic>CHLORIDES</topic><topic>Chlorides - metabolism</topic><topic>CHLORINE 36</topic><topic>CHLORINE COMPOUNDS</topic><topic>CHLORINE ISOTOPES</topic><topic>Dibenzoxazepines - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>DOSE-RESPONSE RELATIONSHIPS</topic><topic>DRUGS</topic><topic>ELECTRON CAPTURE RADIOISOTOPES</topic><topic>Flumazenil - pharmacology</topic><topic>Flunitrazepam - metabolism</topic><topic>GABA Antagonists</topic><topic>HALIDES</topic><topic>HALOGEN COMPOUNDS</topic><topic>HYDROGEN COMPOUNDS</topic><topic>INHIBITION</topic><topic>ISOTOPE APPLICATIONS</topic><topic>ISOTOPES</topic><topic>KINETICS</topic><topic>Ligands</topic><topic>LIGHT NUCLEI</topic><topic>Male</topic><topic>MAMMALS</topic><topic>Medical sciences</topic><topic>MEMBRANE PROTEINS</topic><topic>MEMBRANE TRANSPORT</topic><topic>MEMBRANES</topic><topic>NERVOUS SYSTEM</topic><topic>Neuropharmacology</topic><topic>NEUROREGULATORS</topic><topic>NUCLEI</topic><topic>ODD-ODD NUCLEI</topic><topic>ORGANIC ACIDS</topic><topic>ORGANIC COMPOUNDS</topic><topic>ORGANS</topic><topic>Pharmacology. Drug treatments</topic><topic>PROTEINS</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>PSYCHOTROPIC DRUGS</topic><topic>Pyridazines - metabolism</topic><topic>RADIOISOTOPES</topic><topic>RATS</topic><topic>Rats, Inbred Strains</topic><topic>REACTION KINETICS</topic><topic>RECEPTORS</topic><topic>Receptors, GABA-A - drug effects</topic><topic>Receptors, GABA-A - metabolism</topic><topic>RODENTS</topic><topic>TRACER TECHNIQUES</topic><topic>TRITIUM COMPOUNDS</topic><topic>VERTEBRATES</topic><topic>YEARS LIVING RADIOISOTOPES</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ikeda, Masaaki</creatorcontrib><creatorcontrib>Knapp, Richard J.</creatorcontrib><creatorcontrib>Malatynska, Ewa</creatorcontrib><creatorcontrib>Yamamura, Henry I.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ikeda, Masaaki</au><au>Knapp, Richard J.</au><au>Malatynska, Ewa</au><au>Yamamura, Henry I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>1989</date><risdate>1989</risdate><volume>45</volume><issue>20</issue><spage>1903</spage><epage>1910</epage><pages>1903-1910</pages><issn>0024-3205</issn><eissn>1879-0631</eissn><coden>LIFSAK</coden><abstract>Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABA
A-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of
36Cl
− uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA
2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABA
A receptor selective antagonist [
3H]SR 95531 with an IC
50 value of 3.45 μM and a pseudo Hill coefficient of 0.83. In contrast, 10 μM amoxapine inhibits [
3H] flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15–1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations. These data suggest that amoxapine does not inhibit chloride conductance by acting as a benzodiazepine inverse agonist and either acts directly on the GABA
A receptor as an antagonist or blocks GABA activity at a site closely coupled to it. The ability of amoxapine to inhibit GABA-stimulated chloride conductance is a likely explanation for its proconvulsant activity observed at high doses.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>2557507</pmid><doi>10.1016/0024-3205(89)90544-4</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Life sciences (1973), 1989, Vol.45 (20), p.1903-1910 |
| issn | 0024-3205 1879-0631 |
| language | eng |
| recordid | cdi_osti_scitechconnect_7027108 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 550201 - Biochemistry- Tracer Techniques AMINO ACIDS AMINOBUTYRIC ACID Amoxapine - pharmacology ANIMALS ANTIDEPRESSANTS AUTONOMIC NERVOUS SYSTEM AGENTS BASIC BIOLOGICAL SCIENCES BETA DECAY RADIOISOTOPES BETA-MINUS DECAY RADIOISOTOPES BIOCHEMICAL REACTION KINETICS Biological and medical sciences BODY BRAIN CARBOXYLIC ACIDS CELL CONSTITUENTS CELL MEMBRANES CENTRAL NERVOUS SYSTEM CENTRAL NERVOUS SYSTEM AGENTS CEREBRAL CORTEX Cerebral Cortex - metabolism CEREBRUM CHLORIDES Chlorides - metabolism CHLORINE 36 CHLORINE COMPOUNDS CHLORINE ISOTOPES Dibenzoxazepines - pharmacology Dose-Response Relationship, Drug DOSE-RESPONSE RELATIONSHIPS DRUGS ELECTRON CAPTURE RADIOISOTOPES Flumazenil - pharmacology Flunitrazepam - metabolism GABA Antagonists HALIDES HALOGEN COMPOUNDS HYDROGEN COMPOUNDS INHIBITION ISOTOPE APPLICATIONS ISOTOPES KINETICS Ligands LIGHT NUCLEI Male MAMMALS Medical sciences MEMBRANE PROTEINS MEMBRANE TRANSPORT MEMBRANES NERVOUS SYSTEM Neuropharmacology NEUROREGULATORS NUCLEI ODD-ODD NUCLEI ORGANIC ACIDS ORGANIC COMPOUNDS ORGANS Pharmacology. Drug treatments PROTEINS Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology PSYCHOTROPIC DRUGS Pyridazines - metabolism RADIOISOTOPES RATS Rats, Inbred Strains REACTION KINETICS RECEPTORS Receptors, GABA-A - drug effects Receptors, GABA-A - metabolism RODENTS TRACER TECHNIQUES TRITIUM COMPOUNDS VERTEBRATES YEARS LIVING RADIOISOTOPES |
| title | Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity |
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