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

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 m L·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。

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 of5 m L·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.