Augmented cytotoxic, mutagenic and genotoxic response triggered by carvedilol and celecoxib combinations

Abstract It is understood that drugs regardless of their order of administration can exhibit drug interactions. Established on the fact that treatment of hypertension may last for decades and prolong usage of multiple drug regimen may induce substantial pathophysiological changes. Hence, This study was designed to evaluate the possible synergistic toxic effects of anti-hypertensive (carvedilol), and anti-inflammatory drug (celecoxib) alone and in combinations. Well-established MTT assay, Single Cell Gel Electrophoresis (SCGE) and Ames assay were employed to evaluate the toxicity at cellular level. Results from MTT assay on Vero cell line revealed that drug combinations have more pronounced anti-proliferative activity with combine IC50 value of 13.7:47.8 µg/mL. Likewise, exposure of peripheral blood mononuclear cells with drug combinations revealed significant (P<0.05) DNA damage (Class 3) in a dose dependent manner at concentrations ≥ 0.78: 2.34 µg/mL. However, carvedilol and celecoxib were non mutagenic against either mutant strain (TA 100 and TA 98) and combinations have also shown mild to moderate mutagenic potential. Nevertheless, upon addition of metabolic activation enzyme, concentration <12.5:37.5 µg/plate exhibited significant (P<0.05) mutagenicity against both tester strains. In conclusion, this study provides additional genotoxicity and mutagenicity data that could be used in considering options for formulating regimens with reduced mutagenic potential.

摘要：众所周知，无论给药顺序如何，药物均可发生相互作用。鉴于高血压治疗往往需持续数十年，且长期使用多种药物联合方案可能诱发显著的病理生理改变，本研究旨在评估抗高血压药物卡维地洛（carvedilol）与抗炎药物塞来昔布（celecoxib）单独给药及联合给药时可能产生的协同毒性效应。本研究采用成熟的MTT实验、单细胞凝胶电泳（Single Cell Gel Electrophoresis，SCGE）及艾姆斯（Ames）实验，在细胞水平评估药物毒性。针对Vero细胞系的MTT实验结果显示，药物联合使用具有更显著的抗增殖活性，联合半数抑制浓度（IC50）为13.7:47.8 μg/mL。同样，当外周血单个核细胞暴露于药物联合方案时，在浓度≥0.78:2.34 μg/mL的条件下，会以剂量依赖方式引发显著（P<0.05）的3级DNA损伤。不过，单独使用卡维地洛或塞来昔布，以及二者的联合用药，对TA 100和TA 98这两种菌株均未表现出致突变性，且联合用药仅展现出轻度至中度的致突变潜能。然而，当添加代谢活化酶后，浓度低于12.5:37.5 μg/皿的药物对两种测试菌株均表现出显著（P<0.05）的致突变性。综上，本研究提供了额外的遗传毒性与致突变性数据，可为制定致突变潜能更低的联合用药方案提供参考依据。