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阿哌沙班类似物SU-142口服给药4周对Beagle犬的亚慢性毒性研究
引用本文:赵白云,张晶,孔文婷,叶英,何丹,田静. 阿哌沙班类似物SU-142口服给药4周对Beagle犬的亚慢性毒性研究[J]. 中国现代应用药学, 2018, 35(4): 475-478
作者姓名:赵白云  张晶  孔文婷  叶英  何丹  田静
作者单位:杭州师范大学附属医院, 杭州 310000,济宁医学院附属医院, 山东济宁 272000,杭州师范大学附属医院, 杭州 310000,杭州师范大学附属医院, 杭州 310000,解放军第163医院, 长沙 410003,杭州市西溪医院, 杭州 310023
基金项目:浙江省自然科学基金项目(LQ16H290003);浙江省中医药科技计划项目(2015ZB092)
摘    要:目的 研究阿哌沙班的新型结构类似物SU-142重复口服给药4周对Beagle犬产生的毒性反应。方法 40条健康Beagle犬按体质量随机分为溶媒对照组、SU-142低剂量组、SU-142中剂量组和SU-142高剂量组,每组10条,♀♂各半。低、中、高剂量组给药剂量分别为50,150,300 mg·kg-1,溶媒对照组给予0.5% CMC-Na,给药体积均为5 mL·kg-1。每天给药1次,共给药4周,恢复2周,期间对各项毒理学指标进行检测,并分别于首次和末次给药后1,2,4,8 h对血凝指标进行监测。结果 中剂量组1条犬首次给药后开始出现呕吐症状,至第7天恢复,未见其他异常反应。由于该症状比较轻微,且发生率低,认为是动物的个体差异导致的偶发性反应。其他动物的一般体征均未见明显异常。血凝学检测结果显示,SU-142处理组的凝血酶原时间(PT)和凝血酶时间(TT)自首次给药后1 h开始上升,给药期间显著高于溶媒对照组,至末次给药后4 h达峰,至此,高剂量组PT和TT均为溶媒对照组的约2倍,呈现明显的量效和时效关系。活化部分凝血活酶时间(APTT)给药后,均呈现剂量依赖性升高,但时效关系不明显。停药2周后,PT、TT和APTT基本恢复至基础水平。其他心电图、血液学、血液生化和病理组织学等指标均未见明显的与SU-142处理相关的改变。结论 SU-142口服给药4周对Beagle犬的主要毒性靶标为凝血系统,为SU-142药效作用的延伸和放大所致,作用可逆。本研究未发现供试品作用机制以外的脱靶毒效应。

关 键 词:阿哌沙班  抗凝  Beagle犬  重复给药  毒性
收稿时间:2017-08-28
修稿时间:2018-02-27

Evaluation of Subchronic Toxicity of SU-142, an Analogue of Apixaban, After 4-Week Repeated Oral Administration in Beagle Dogs
Zhao Baiyun,Zhang Jing,Kong Wenting,Ye Ying,He Dan and Tian Jing. Evaluation of Subchronic Toxicity of SU-142, an Analogue of Apixaban, After 4-Week Repeated Oral Administration in Beagle Dogs[J]. The Chinese Journal of Modern Applied Pharmacy, 2018, 35(4): 475-478
Authors:Zhao Baiyun  Zhang Jing  Kong Wenting  Ye Ying  He Dan  Tian Jing
Affiliation:The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310000, China,Affiliated Hospital of Jining Medical College, Jining 272000, China,The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310000, China,The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310000, China,The 163 Central Hospital of PLA, Changsha 410003, China and Xixi Hospital of Hangzhou, Hangzhou 310023, China
Abstract:OBJECTIVE To evaluate the toxicity of SU-142, an new analogue of apixaban, in Beagle dogs following repeated oral administration for 4 weeks. METHODS The 40 Beagle dogs were randomly divided into 4 groups included control group and SU-142 (50, 150, 300 mg·kg-1) groups with 10 animals (5 male and 5 female) in each group. Dogs were treated orally once a day for 4 weeks with SU-142 (50, 150, 300 mg·kg-1) or 0.5% CMC-Na as vehicle with a volume of 5 mL·kg-1, following a recovery period of 2 weeks. During the experiment, toxicological indexes were detected, and the coagulation indexes were monitored 1, 2, 4 and 8 h after the first and last administration. RESULTS Only mild vomiting occurred in a dog in 150 mg·kg-1 group after the first administration, and last for 7 d, without other abnormal reactions. Due to the lower incidence and mild degree, vomiting was seen to be not related with SU-142. Coagulation test showed that prothrombin time (PT) and thrombin time (TT) were significantly increased at 1 h after the first administration, and lasted through the whole treatment with markedly dose-effect and time-effect relationship. PT and TT achieved to the peak at 4 h after the last administration, while PT and TT in 300 mg·kg-1 group reached approximately 2 times of control. Activated partial thromboplastin time (APTT) also showed a significantly increase with a dose-effect relationship. After recovered for 2 weeks, PT, TT and APTT fell to baseline. No other marked changes were observed in electrocardiogram, hematology, clinical chemistry and histopathology. CONCLUSION The main toxic target of SU-142 is coagulation (increased PT, TT and APTT), which should be an amplification of the anti-coagulation of SU-142. The toxic effect is reversible. The study don''t find the effect of the miss target effect outside the mechanism of the trial product.
Keywords:apixaban   anti-coagulation   Beagle dog   repeated administration   toxicity
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