阿司匹林丁香酚酯对大鼠的急性毒性研究

doi:10.16431/j.cnki.1671-7236.2017.07.039

《中国畜牧兽医》 ›› 2017, Vol. 44 ›› Issue (7): 2178-2184.doi: 10.16431/j.cnki.1671-7236.2017.07.039

阿司匹林丁香酚酯对大鼠的急性毒性研究

赵晓乐, 孔晓军, 马宁, 杨亚军, 刘希望, 申栋帅, 李剑勇

中国农业科学院兰州畜牧与兽药研究所, 农业部兽用药物创制重点实验室, 甘肃省新兽药工程重点实验室, 兰州 730050

收稿日期:2016-12-16 出版日期:2017-07-20 发布日期:2017-07-22
通讯作者: 李剑勇 E-mail:lijy1971@163.com
作者简介:赵晓乐(1989-),女,河北邢台人,硕士,研究方向:兽医药理与毒理学,E-mail:xiaole_1920@163.com
基金资助:
国家自然科学基金（31572573）；中国农业科学院科技创新工程（CAAS-ASTIP-2014-LIHPS-02）

Acute Toxicity of Aspirin Eugenol Ester on Rats

ZHAO Xiao-le, KONG Xiao-jun, MA Ning, YANG Ya-jun, LIU Xi-wang, SHEN Dong-shuai, LI Jian-yong

Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China

Received:2016-12-16 Online:2017-07-20 Published:2017-07-22

摘要/Abstract

摘要：

试验旨在评价阿司匹林丁香酚酯（aspirin eugenol ester，AEE）对大鼠的急性毒性，了解AEE毒性特点及可能的毒性靶器官，并全面地分析大鼠的致死原因。试验按照改良寇氏法进行，预试验选取50只大鼠，雌雄各半，分为5组，测定绝对致死量（LD₁₀₀）和最大非致死量（LD₀）。根据预试验结果，将80只健康大鼠，雌雄各半，随机平均分为7个药物组（剂量分别为2.62、3.25、4.03、5.00、6.20、7.69和9.53 g/kg）和1个对照组（给予0.5%的羧甲基纤维素钠（CMC-Na）进行正式试验。灌胃给药，观察并记录大鼠给药后的临床症状及体重变化。给药14 d后，统计各剂量组大鼠的死亡时间及总死亡数，并计算AEE的半数致死量（LD₅₀）及其95%可信限。同时对死亡大鼠及时进行剖检，将具有病变的组织用10%的甲醛溶液固定，以进行病理学分析。结果显示，AEE对大鼠口服的LD₅₀是5.95 g/kg，且LD₅₀的95%可信限为5.30~6.68 g/kg。对大鼠的死亡时间进行分析可得出，当口服AEE的剂量大于4.03 g/kg时，其死亡时间主要集中在染毒后的48~96 h内。大鼠染毒后3 d内，体重呈下降趋势，常规饲养第5天开始，大鼠体重可逐渐恢复。病理学检查分析发现，AEE的剂量在5.00 g/kg以上时，对大鼠的肝脏、肾脏和胃肠道有明显损伤。根据外源化学物急性毒性分级（WHO）可知，AEE为实际无毒化合物，AEE对大鼠毒性靶器官主要是肝脏、肾脏和胃肠道。

关键词: 阿司匹林丁香酚酯; 急性毒性; 灌胃; 大鼠

Abstract:

The acute toxicity study was carried out by intragastric administration in rats to evaluate the toxic characteristics of aspirin eugenol ester (AEE) and target organs and fully analyze the reason of death rats. The experiment was designed in accordance with the method provided by the Kärber arithmetic method. At first, 50 rats (half male and half female)were divided into 5 groups to calculate LD₁₀₀ and LD₀. According to the pre-test results, different doses of AEE (2.62,3.25,4.03,5.00,6.20,7.69 and 9.53 g/kg) and control group of 0.5% CMC-Na were orally administered to 80 rats, half male and half female, divided into 8 groups. After treatment, clinical signs of rats and the change of body weights were observed and recorded. The microscopic pathology of mild damages on organs was conducted. 14 days after adminstration, the death time and total deaths of rats were recorded, and the LD₅₀ and 95% confidence interual of AEE were calculated according to Kärber. Organs were fixed with 10% formaldehyde solution at the end of the experiment. The LD₅₀ of AEE in rats was 5.95 g/kg upon oral administration and its 95% confidence interval calculation was 5.30 to 6.68 g/kg. The death time of rats were centralized at 48 to 96 h after exposing to AEE more than 4.03 g/kg by the analysis of the cumulative mortality-time of AEE in each group. Significant decreases in body weights were noted after treatment of AEE for 3 days, after that body weights gradually grew and recovered at the 5th day. Remarkable damages on livers, kidney and gastrointestinal tract were found at AEE dosage of more than 5.00 g/kg. From the obtained value of LD₅₀>5.00 g/kg, AEE was classified as practically non-toxic compound according to WHO. The target organs of AEE were liver, kidney and gastrointestinal tract.

Key words: aspirin eugenol ester; acute toxicity; intragastric administration; rats

中图分类号:

S859.7

赵晓乐, 孔晓军, 马宁, 杨亚军, 刘希望, 申栋帅, 李剑勇. 阿司匹林丁香酚酯对大鼠的急性毒性研究[J]. 《中国畜牧兽医》, 2017, 44(7): 2178-2184.

ZHAO Xiao-le, KONG Xiao-jun, MA Ning, YANG Ya-jun, LIU Xi-wang, SHEN Dong-shuai, LI Jian-yong. Acute Toxicity of Aspirin Eugenol Ester on Rats[J]. , 2017, 44(7): 2178-2184.

参考文献

[1] FitzGerald G A,Oates J A, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man[J]. J Clin Invest, 1983, 71(3):676-688.
[2] Patrono C, García Rodríguez L A, Landolfi R, et al. Low-dose aspirin for the prevention of atherothrombosis[J]. The New England Journal of Medicine, 2005, 353(22):2373-2383.
[3] Paula-Freire L I, Molska G R, Andersen M L, et al. Ocimum gratissimum essential oil and its isolated compounds (eugenol and myrcene) reduce neuropathic pain in mice[J]. Planta Med, 2016, 82(3):211-216.
[4] Carrasco H, Raimondi M, Svetaz L, et al. Antifungal activity of eugenol analogues. Influence of different substituents and studies on mechanism of action[J]. Molecules, 2012, 17(1):1002-1024.
[5] Gong L, Li T, Chen F, et al. An inclusion complex of eugenol into beta-cyclodextrin:Preparation, and physicochemical and antifungal characterization[J]. Food Chem, 2016, 196:324-330.
[6] Hernández C,Barrachina M D, Vallecillo-Hernández J, et al. Aspirin-induced gastrointestinal damage is associated with an inhibition of epithelial cell autophagy[J]. Japanese Society of Gastroenterology, 2016, 51(7):691-701.
[7] Yogalakshmi B, Viswanathan P, Anuradha C V. Investigation of antioxidant, anti-inflammatory and DNA-protective properties of eugenol in thioacetamide-induced liver injury in rats[J]. Toxicology, 2010, 268(3):204-212.
[8] 李剑勇.阿司匹林丁香酚酯药用化合物制剂及其制备方法[P].中国专利:200810017950.X,2008-10-01.
[9] Karam I, Ma N, Liu X W, et al. Regulation effect of aspirin eugenol ester on blood lipids in Wistar rats with hyperlipidemia[J]. BMC Vet Res, 2015, 11:217.
[10] Ma N, Liu X W, Yang Y J, et al. Preventive effect of aspirin eugenol ester on thrombosis in kappa-carrageenan-induced rat tail thrombosis model[J]. PLoS One, 2015, 10(7):e0133125.
[11] 吕安,张志聪,宫平,等.宫净灌注剂急性毒性和长期毒性试验研究[J].中国畜牧兽医,2016,43(8):2143-2149.
[12] 王玲,郭志廷,张晓松,等.抗鸡球虫药常山口服液对小鼠的急性毒性作用评价[J].中国畜牧兽医,2016,43(10):2724-2729.
[13] Roberts G K, Stout M D, Sayers B, et al. 14-day toxicity studies of tetravalent and pentavalent vanadium compounds in Harlan Sprague Dawley rats and B6C3F1/N mice via drinking water exposure[J]. Toxicol Rep, 2016, 3:531-538.
[14] Song N, Li L, Li H, et al. Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats[J]. Food Chem Toxicol, 2016, 91:73-81.
[15] Kärber G. Beitrag zur kollecktiven Behandlung pharmakologischer Reihenversuche[J]. Arch Exptl Pathol Pharmakol, 1931, 162(4):480-483.
[16] 王静, 蒋万, 何生虎,等.自制中药复方片剂对小鼠的急性毒性试验[J]. 动物医学进展, 2015, 36(2):120-124.
[17] 姜玲玲,陈鸿宇,史开志,等. 一种新兽用止泻中药复方制剂对大鼠的急性及亚慢性毒性试验[J].中国畜牧兽医,2016,43(11):3073-3079.
[18] 田若辰. 活性炭灌胃对百草枯中毒胃肠道吸收影响的初步研究[D].北京:中国人民解放军军事医学科学院,2014.
[19] Toxicological Evaluation of Some Flavouring Substances and Non-Nutritive Sweetning Agents[R]. FAO Nutrition Meetings:IPCS INCHEM. 1967.
[20] Marin Municipal Water District Vegetation Management Plan[R]. Herbicide Risk Assessment:Clove Oil (Eugenol). 2008.
[21] Shen Y M, Liu X W, Yang Y J, et al. In vivo and in vitro metabolism of aspirin eugenol ester in dog by liquid chromatography tandem mass spectrometry[J]. Biomed Chromatogr, 2015, 29(1):129-138.
[22] Roberts R, Callander R, Duffy P, et al. Target organ profiles in toxicity studies supporting human dosing:Does severity progress with longer duration of exposure?[J]. Regul Toxicol Pharmacol, 2015, 73(3):737-746.

阿司匹林丁香酚酯对大鼠的急性毒性研究

Acute Toxicity of Aspirin Eugenol Ester on Rats

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	李佳豪, 李超, 臧长江, 孟军, 李宏坤, 贾怡琪, 麦丽克扎提·艾尔肯, 唐纳尔·托留别克. 灌胃和腹腔注射鼠李糖乳杆菌对妊娠期小鼠粪便菌群多样性的影响[J]. 中国畜牧兽医, 2023, 50(1): 151-160.
[2]	何炎峻, 金圣子, 王爽, 柳可欣, 刘云. 薯蓣皂苷元对顺铂诱导大鼠肾损伤的缓解作用[J]. 中国畜牧兽医, 2022, 49(9): 3633-3642.
[3]	汪瑶, 燕鸽, 刘智慧, 王玉, 辛全超, 曹新悦, 于文会, 姜晓文. 马兜铃酸Ⅰ对大鼠五脏的毒性及功能影响[J]. 中国畜牧兽医, 2022, 49(7): 2757-2767.
[4]	胡文, 霍孔林, 宋星星, 张鑫, 张多妮, 罗荣荣, 徐文镐, 李珣. 促性腺激素抑制激素对SD大鼠性腺生殖功能与糖代谢的影响[J]. 中国畜牧兽医, 2022, 49(6): 2239-2249.
[5]	张文, 覃志彪, 成静, 于美玲, 韦英益, 黎江, 胡庭俊. 辣蓼黄酮提取物的急性毒性和亚慢性毒性研究[J]. 中国畜牧兽医, 2022, 49(4): 1532-1544.
[6]	王璐, 胡盼盼, 程佳, 孙盼盼, 孙娜, 范阔海, 尹伟, 李宏全, 孙耀贵. 穿王消炎粉对LPS诱导大鼠急性肺损伤的治疗作用[J]. 中国畜牧兽医, 2022, 49(4): 1568-1576.
[7]	向蓉, 李亚晖, 高原, 魏琦麟, 舒柄垚, 罗胜军. 牡荆水提物急性毒性与30 d喂养试验研究[J]. 中国畜牧兽医, 2021, 48(6): 2262-2270.
[8]	孙长超, 高响, 李锋, 梁童, 宁航逸, 王钟煜, 单安山, 石宝明. 短期灌喂民猪源贝莱斯芽孢杆菌M2对SD大鼠生长、免疫及肠道菌群的影响[J]. 中国畜牧兽医, 2021, 48(4): 1264-1274.
[9]	史晓宇, 宋越, 冯敏, 高珍珍, 杨英. 穴位埋线对运动性疲劳大鼠能量代谢水平的影响[J]. 中国畜牧兽医, 2021, 48(2): 747-754.
[10]	王昱, 秦序, 何九军. 白肉灵芝水提物对脑缺血大鼠海马神经元的保护作用[J]. 中国畜牧兽医, 2021, 48(10): 3864-3871.
[11]	赵军杰, 陈可心, 栾业辉, 程林丽. 恩诺沙星与磺胺二甲嘧啶联合毒性探究[J]. 中国畜牧兽医, 2021, 48(10): 3872-3879.
[12]	郭羽丽, 刘俊平, 孙迪, 董志颖, 王鹏, 刘成功. 芩术安胎散的毒性和临床安全性试验研究[J]. 中国畜牧兽医, 2021, 48(10): 3880-3888.
[13]	韦芊含, 雷伟伟, 陈昕, 赵伟亚, 张蒙, 肖金吒, 张雨梅. 饲用黄丝藻粉的急性毒性和亚慢性毒性试验[J]. 中国畜牧兽医, 2020, 47(5): 1602-1610.
[14]	张多妮, 霍孔林, 李长乐, 张鑫, 宋星星, 胡文, 罗荣荣, 徐文镐, 陈磊, 陈欣仪, 李珣, 王晓晔. RF酰胺相关肽3对大鼠脾脏形态结构及免疫功能的影响[J]. 中国畜牧兽医, 2020, 47(4): 1225-1232.
[15]	马兴树, 强慧勤, 杨锴. 禽致病性大肠杆菌实验感染模型研究进展[J]. 中国畜牧兽医, 2020, 47(12): 4103-4118.