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首页> 外文期刊>Journal of applied toxicology >Preclinical safety evaluation of low molecular weight heparin-deoxycholate conjugates as an oral anticoagulant
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Preclinical safety evaluation of low molecular weight heparin-deoxycholate conjugates as an oral anticoagulant

机译：低分子量肝素-脱氧胆酸盐偶联物作为口服抗凝剂的临床前安全性评估

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摘要

The preclinical safety of a newly developed oral anticoagulant, the low molecular weight heparin-deoxycholate conjugate (OH09208), was evaluated by a comprehensive evaluating program in compliance with standard guidelines. The single dose oral toxicity study in rats receiving 2000 and 5000 mg kg(-1) of OH09208 did not reveal any mortality, unusual body weight changes or necropsy findings. The results of the 4-week oral toxicity study with a 4-week recovery program in rats receiving OH09208 in doses of 100, 300 and 1000 mg kg(-1) day(-1) did not reveal any mortality, or indicate any unusual clinical signs, or show any toxicokinetic relationships to the administration of OH09208. Although the increase in liver enzymes in one male dog treated with 300 mg kg(-1) day(-1) and one female dog treated with 1000 mg kg(-1) day(-1) could not be excluded from the effect of the test substance, no other toxicologically significant changes were observed in the 4-week oral toxicity study with a 4-week recovery in beagle dogs. Thus, while the no-observed-adverse-effect level value from the 4-week study in both male and female rats was 1000 mg kg(-1) day(-1), those from the 4-week study in male and female beagle dogs were 300 and 1000 mg kg(-1) day(-1), respectively. Furthermore, OH09208 did not induce anaphylactic reactions in guinea pigs, micronucleated bone marrow cells in male ICR mice, chromosomal aberration in Chinese hamster lung cell lines, bacterial reverse mutation, and any abnormalities in hERG current assay, mouse central nervous system and dog cardiovascular studies. Overall, there were no unexpected toxicities in this preclinical study that might have precluded the safe administration of OH09208 to humans. Copyright (c) 2015 John Wiley & Sons, Ltd.
机译：根据标准指南，通过综合评估程序评估了新开发的口服抗凝剂低分子量肝素-脱氧胆酸盐结合物（OH09208）的临床前安全性。在接受2000和5000 mg kg（-1）OH09208的大鼠中进行的单剂量口服毒性研究未显示任何死亡率，异常体重变化或尸检结果。在接受OH09208的100、300和1000 mg kg（-1）day（-1）剂量的大鼠中进行为期4周恢复计划的4周口服毒性研究的结果未显示任何死亡率，或表明有任何异常临床症状，或与OH09208的给药表现出任何毒代动力学关系。尽管不能排除在用300 mg kg（-1）day（-1）处理的一只公狗和在1000 mg kg（-1）day（-1）处理的一只雌狗中肝酶的增加。在为期4周的口服毒性研究中，在测试物质中，没有观察到其他毒理学显着变化，在比格犬中恢复了4周。因此，尽管雄性和雌性大鼠在4周研究中未观察到不良作用水平值为1000 mg kg（-1）天（-1），而雄性和雌性在4周研究中未观察到不良作用水平比格犬分别为300和1000 mg kg（-1）day（-1）。此外，OH09208不会引起豚鼠过敏反应，雄性ICR小鼠的微核骨髓细胞，中国仓鼠肺细胞系的染色体畸变，细菌反向突变以及hERG当前分析，小鼠中枢神经系统和犬心血管研究的任何异常。总体而言，在这项临床前研究中没有意外的毒性可能阻止了OH09208对人类的安全给药。版权所有（c）2015 John Wiley＆Sons，Ltd.

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