Objective

Researchers have confirmed that chronic administration of drugs at high doses causes genotoxicity which serve as first step in development of cancers. Apremilast, a phosphodiesterase-4 inhibitor is Food and Drug Administration (FDA) approved drug for Psoriatic Arthritis. The present study designed to conduct genotoxicity testing using the genotoxic study which give simple, sensitive, economical and fast tools for the assessment of damage of genetic material.

Methods

To conduct genotoxicity study of Apremilast, 60 Swiss albino male mice divided into 6 groups (n = 10). Group1 served as a normal control group without any treatment, Group 2 treated as a disease control and administered with cyclophosphamide 40 mg/kg, IP. Group 3, 4, 5 and 6 treated as test groups and received 10, 20, 40 and 80 mg/kg/day Apremilast respectively. The total duration of study was 13 weeks. At termination day animals were sacrificed and chromosomal aberration assay (BMCAA) and micronucleus assay (BMMNA) were performed to know the genotoxicity potential of Apremilast.

Results

The results indicates significant rise in chromosomal aberrations (CA) frequency in bone marrow cells and decrease in the MI of the disease control animals as well as Apremilast treated groups. Further significant (p < 0.001; p < 0.0001) increase in score of micronucleated polychromatic erythrocytes (MNPCEs) and percentage of micronucleated PCEs per 1000 PCEs and decrease in the ratio of polychromatic/normochromatic erythrocytes (PCE/NCE) was observed in micronucleus assay. Genotoxic effect increases with the increase of Apremilast dose. Conclusion: Finding of present indicates that Apremilast shows genotoxic potential on high administration although further detailed toxicity studies required for confirmations.

中文翻译：

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一种新型 PDE-4B 抑制剂阿普司特的基因毒性潜力，通过小鼠染色体畸变和微核测定。

客观的

研究人员已经证实，长期服用高剂量药物会导致基因毒性，这是癌症发展的第一步。Apremilast 是一种磷酸二酯酶 4 抑制剂，是美国食品和药物管理局 (FDA) 批准的治疗银屑病关节炎的药物。本研究旨在使用遗传毒性研究进行遗传毒性测试，该研究为评估遗传物质的损害提供了简单、灵敏、经济和快速的工具。

方法

为进行阿普司特的遗传毒性研究，将 60 只瑞士白化雄性小鼠分为 6 组 (n = 10)。第1组作为正常对照组，不做任何处理，第2组作为疾病对照组，给予环磷酰胺40mg/kg，IP。第3、4、5和6组作为试验组，分别接受10、20、40和80mg/kg/天的阿普司特。研究的总持续时间为 13 周。在终止日处死动物并进行染色体畸变试验（BMCAA）和微核试验（BMMNA）以了解阿普司特的遗传毒性潜力。

结果

结果表明骨髓细胞中染色体畸变 (CA) 频率显着升高，疾病对照动物和阿普司特治疗组的 MI 降低。在微核试验中观察到微核多染性红细胞 (MNPCE) 得分和每 1000 个 PCE 中微核化 PCE 百分比的进一步显着增加 (p < 0.001; p < 0.0001) 以及多染/正染色红细胞比率 (PCE/NCE) 的降低。遗传毒性作用随着阿普司特剂量的增加而增加。结论：目前的发现表明阿普司特在高剂量给药时显示出遗传毒性潜力，尽管需要进一步详细的毒性研究来确认。