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The purpose of this study was to evaluate the toxicity and to determine potential target organs after oral (gavage) administration of the test article GW117 for 28\u2009days and to assess the reversibility after a 4\u2010week recovery phase in beagle dogs. Toxicokinetics was also evaluated. Four groups were designed in this study, including the vehicle control group and the GW117 50, 150 and 500\u2009mg\/kg\/day groups, with 5 dogs\/sex\/group. Body weight, hematology, clinical chemistry, gross necropsy, organ weight, histopathology, and other indicators were examined. Results showed that animals dosed at \u2265150\u2009mg\/kg\/day showed gastrointestinal reactions (watery feces and dark green\/red brown feces), with a dose\u2013response relationship in the incidence and severity grade. Female dogs at 500\u2009mg\/kg\/day had an increase in organ weight and ratios of the liver at the end of the dosing phase. Histopathology examination showed that some animals at 500\u2009mg\/kg\/day, especially female animals, had minimal centrilobular hepatocyte hypertrophy in the liver, which reversed after 28\u2010day recovery. With the exception of the above, no GW117\u2010related abnormality was noted. Meanwhile, there were no sexual differences in drug exposure and accumulation after the first and last dosing. The no observed adverse effect dose level (NOAEL) was 150\u2009mg\/kg\/day, under which mean C<jats:sub>max<\/jats:sub> and AUC<jats:sub>0\u2009\u2192\u2009t<\/jats:sub> were 583.5 and 2767.0\u2009ng\/ml*h for females and 663.2 and 4046.3\u2009ng\/ml*h for males on Day 28.<\/jats:p>","DOI":"10.1002\/jat.4407","type":"journal-article","created":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T04:40:00Z","timestamp":1666327200000},"page":"577-588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["28\u2010day repeated dose toxicity and toxicokinetics study on new melatonergic antidepressant GW117 in beagle dogs"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-5043","authenticated-orcid":false,"given":"Mei","family":"Gao","sequence":"first","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences Shandong Normal University  Jinan 250014 China"},{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Gu","sequence":"additional","affiliation":[{"name":"Beijing GreatWay Pharmaceutical Technology Co., Ltd.  Beijing 100850 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianbin","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Ying","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong","family":"Cao","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daizhou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiwen","family":"Yang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences Shandong Normal University  Jinan 250014 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2017.1359257"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2011.607812"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.727"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1353\/pbm.2021.0043"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1017\/neu.2014.28"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623312466452"},{"key":"e_1_2_7_9_1","unstructured":"Food and Drug Administration (US FDA). 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