{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T08:26:04Z","timestamp":1787905564623,"version":"build-2784847793"},"reference-count":20,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,9,15]],"date-time":"2017-09-15T00:00:00Z","timestamp":1505433600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Grants-in-Aid for Scientific Research C, Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan","award":["16K08421"],"award-info":[{"award-number":["16K08421"]}]},{"name":"Grants-in-Aid for Scientific Research C, Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan","award":["24590219"],"award-info":[{"award-number":["24590219"]}]},{"name":"The Adaptable and Seamless Technology Transfer Program Through Target-driven R&D, Japan Science and Technology Agency (JST)","award":["AS251Z03018"],"award-info":[{"award-number":["AS251Z03018"]}]},{"name":"Meijo University Research Institute Grant, Meijo University Research Institute"},{"name":"Smoking Research Foundation Grant for Biomedical Research (SRF)"},{"name":"Nagai Memorial Research Scholarship, Pharmaceutical Society of Japan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Human Psychopharmacology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Clozapine is an atypical antipsychotic prescribed for treatment\u2010resistant schizophrenic patients, but treatment with clozapine is strictly limited because it can induce lethal\u2010hematologic side effects. We investigated the effects of short\u2010 and long\u2010term exposure of human neutrophils derived from healthy subjects to clozapine and compared them with the effects of reactive metabolite of clozapine, olanzapine, and doxorubicin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neutrophils were exposed to clozapine and olanzapine (1, 10, 50, or 100\u00a0\u03bcM), reactive metabolite of clozapine (50 or 100\u00a0\u03bcM), or doxorubicin (0.2\u00a0\u03bcM) and cultured for a short (2\u00a0hr) or long (24 or 48\u00a0hr) duration, and then the survival rate of neutrophils was calculated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Decreased human neutrophil survival was observed in short\u2010term exposure to clozapine (100\u00a0\u03bcM) and long\u2010term exposure to clozapine even at a lower concentration (50\u00a0\u03bcM). A similar phenomenon was observed in reactive metabolite of clozapine and long\u2010term exposure to doxorubicin (0.2\u00a0\u03bcM), but not to olanzapine (1\u2013100\u00a0\u03bcM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The effect of long\u2010term exposure to clozapine on neutrophil survival is plausibly associated with delayed onset of agranulocytosis after initial exposure. Our results suggest that human neutrophils are vulnerable to clozapine and its reactive metabolite in a concentration\u2010 and time\u2010dependent manner.<\/jats:p><\/jats:sec>","DOI":"10.1002\/hup.2629","type":"journal-article","created":{"date-parts":[[2017,9,15]],"date-time":"2017-09-15T07:26:38Z","timestamp":1505460398000},"source":"Crossref","is-referenced-by-count":6,"title":["Human neutrophils show decreased survival upon long\u2010term exposure to clozapine"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7536-0877","authenticated-orcid":false,"given":"Aya","family":"Goto","sequence":"first","affiliation":[{"name":"Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy Meijo University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Yoshimi","sequence":"additional","affiliation":[{"name":"Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy Meijo University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Nagai","sequence":"additional","affiliation":[{"name":"Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy Meijo University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mako","family":"Ukigai","sequence":"additional","affiliation":[{"name":"Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy Meijo University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Mouri","sequence":"additional","affiliation":[{"name":"Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy Meijo University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Ozaki","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Graduate School of Medicine Nagoya University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Noda","sequence":"additional","affiliation":[{"name":"Division of Clinical Sciences and Neuropsychopharmacology, Faculty and Graduate School of Pharmacy Meijo University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,9,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199307153290303"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.5.2936"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2012.12081036"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V80.8.2012.2012"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004850-200015040-00008"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.jcp.0000177668.42640.fe"},{"issue":"6","key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S0026-895X(24)13268-3","article-title":"A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes","volume":"53","author":"Gardner I.","year":"1998","journal-title":"Molecular Pharmacology"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1994.tb04786.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2016.06.028"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(98)00110-3"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2006.01.008"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/hup.1181"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1A417"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0020141"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2015.12.006"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0191"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-283184"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.2012.01567.x"},{"issue":"3","key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0022-3565(24)37177-0","article-title":"Neutrophil cytotoxicity of the chemically reactive metabolite(s) of clozapine: Possible role in agranulocytosis","volume":"283","author":"Williams D. 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