Sub-Acute Oral Toxicity of a Novel Derivative of Agomelatine in Rats in a Sex-Dependent Manner
Sub-Acute Oral Toxicity of a Novel Derivative of Agomelatine in Rats in a Sex-Dependent Manner
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阿戈美拉汀新型衍生物对大鼠的亚急性口服毒性具有性别依赖性
DOI：
10.3389/fphar.2019.00242
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发表时间：
2019-03
影响因子：
5.6
通讯作者：
Li Xiaorong
中科院分区：
文献类型：
--
作者：
Yang Qiushi;Zhou Xuelin;Li Jingyi;Ma Yi;Lu Li;Xiong Jie;Xu Pingxiang;Li Yuhang;Chen Yi;Gu Wei;Xue Ming;Jin Zengliang;Li Xiaorong
阿戈美拉汀（Agomelatine，AGO）是一种新型抗抑郁药，具有显著的抗抑郁作用和独特的昼夜节律调节作用。然而，AGO具有肝毒性，限制了其临床应用。为了开发比AGO引起的肝损伤更小的新药，合成了一系列衍生物，由于其高受体亲和力，从衍生物中筛选出化合物GW 117。本研究将以性别依赖性方式研究其在大鼠中的亚急性经口毒性特征。GW 117和AGO通过管饲法（200、400或800 mg/kg/天）施用28天。结果表明，AGO和GW 117对血小板、肝脏和肾脏均有不良影响，且在某些指标上存在性别差异。血液学试验表明，AGO和GW 117降低雄性动物的血小板计数，但对雌性动物无影响。AGO使雄性动物血浆丙氨酸氨基转移酶（ALT）和总胆红素升高，而GW 117对这两项指标无影响。对于女性，AGO中度升高ALT、碱性磷酸酶（ALP）和总胆红素，而GW 117仅轻微升高ALP。两种药物均能引起肝重量和肝系数增加，并引起肝病理损伤，包括肝窦扩张、肝细胞脂肪沉积和点状细胞坏死。AGO在两种性别中均引起轻度至中度肝细胞和肝胆损伤，而GW 117仅在雌性中引起轻度肝胆损伤。肾功能试验表明，两种药物都能增加男性的血尿素氮水平，而AGO，而不是GW 117，可以轻微增加女性的血肌酐和尿素氮。两种药物均能显著增加雄性大鼠的肾重和肾系数，AGO中剂量和GW 117高、低剂量均能显著增加雌性大鼠的肾重和肾系数。肾脏病理损害主要表现为肾小管扩张、肾皮质变薄。GW 117对小鼠肾脏的损害较AGO轻，且无性别差异。总之，GW 117可在两种性别中引起轻度肝和肾损伤，以及在雄性中引起轻度血小板减少，而损伤程度不如AGO严重。因此，GW 117作为一种优良的衍生物值得进一步开发。
Agomelatine (AGO) is a new type of antidepressant with demonstrated antidepressant effects and a unique modulating circadian rhythm action. However, AGO has hepatotoxicity, which limits its clinical application. In order to develop new drugs that cause less liver injury than AGO, a series of derivatives were synthesized; compound GW117 was screened from derivatives due to its high receptor affinity. This study will investigate its sub-acute oral toxicity profile in rats in a sex-dependent manner. GW117 and AGO was administrated by gavage (200, 400, or 800 mg/kg/day) for 28 days. Hematological, biochemical tests, organ weights, histopathological examinations were carried out, the results showed that AGO and GW117 had adverse effects on platelet, liver and kidney, and had sex-differences in some indicators. Hematological tests showed that AGO and GW117 reduced the platelet count in male animals but had no effect in females. AGO increased plasma alanine aminotransferase (ALT) and total bilirubin in male animals, and GW117 had no effect on these two indicators. For females, AGO moderately elevated ALT, alkaline phosphatase (ALP), and total bilirubin, while GW117 only elevated ALP slightly. Two drugs could increase liver weight and coefficient, and cause liver pathological injury, including hepatic sinusoidal dilatation, hepatocyte fatty deposition and dotted cell necrosis in two genders. AGO caused mild to moderate hepatocyte and hepatobiliary injury in both genders, while only a mild hepatobiliary injury was caused by GW117 in females. Renal function tests showed that both drugs can increase blood urea nitrogen levels in males, while AGO, but not GW117, can slightly increase blood creatinine and urea nitrogen in females. The kidney weight and coefficient could be significantly increased by two drugs in males, and by AGO medium and GW117 high and low doses in females. The kidney pathological damage was mainly characterized by tubule dilatation, a thinning of the renal cortex. Kidney damage caused by GW117 was less than that of AGO, and there was no sex-difference. In summary, GW117 can cause mild liver and kidney damage in both genders, as well as mild platelets reduction in males, while degree of damage is less severe than AGO. Therefore, as an excellent derivative, GW117 deserves further development as an antidepressant.
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影响因子：
3.6
作者：
Demirdas, Arif;Naziroglu, Mustafa;Unal, Gulin Ozdamar
通讯作者：
Unal, Gulin Ozdamar
影响因子：
2.9
作者：
F. Xue;I. Strombom;B. Turnbull;Shao Zhu;J. Seeger
通讯作者：
F. Xue;I. Strombom;B. Turnbull;Shao Zhu;J. Seeger
DOI：
10.1124/jpet.103.051797
发表时间：
2003-09-01
影响因子：
3.5
作者：
Millan, MJ;Gobert, A;Cussac, D
通讯作者：
Cussac, D
影响因子：
6
作者：
Perlemuter, Gabriel;Cacoub, Patrice;Moore, Kevin
通讯作者：
Moore, Kevin
影响因子：
5.6
作者：
Molteni, Raffaella;Macchi, Flavia;Riva, Marco A.
通讯作者：
Riva, Marco A.