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

Evaluation of Subchronic Toxicity of SU-142, an Analogue of Apixaban, After 4-Week Repeated Oral Administration in Beagle Dogs

关键词:  阿哌沙班  抗凝  Beagle犬  重复给药  毒性

Key words:  apixaban  anti-coagulation  Beagle dog  repeated administration  toxicity

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。

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.