BACKGROUND & AIMS:
:The potent and efficacious anti-dysrhythmic agent amiodarone (AM) can cause potentially life-threatening lung damage (amiodarone-induced pulmonary toxicity; AIPT), which is characterized by cell death in the lungs, followed by inflammation and fibrosis. AM's major metabolite, desethylamiodarone (DEA), has a greater toxic potency than AM and it has been suggested that DEA may act synergistically with AM to cause lung toxicity. The objective of this study was to determine the type of cytotoxic interaction between AM and DEA in HPL1A human peripheral lung epithelial cells. Cytotoxicity was measured by lactate dehydrogenase release. AM and DEA caused concentration-dependent cytotoxicity in HPL1A cells. The concentration of drug causing 50% cell death (LC50) and the Hill slope factor, which represents steepness of the concentration-cell death curve, were significantly different between AM and DEA (12.4μM and 1.98; 5.07μM and 5.43, for AM and DEA, respectively) indicating that they may induce cytotoxicity through different mechanisms. A combined concentration of 7.13μM AM plus DEA, equivalent to 41% of each compound's individual LC50 value, resulted in 50% cell death. Isobolographic analysis revealed this effect to be additive, although the combined concentrations were only slightly higher than the concentrations that defined the threshold of synergy (threshold of synergy=4.21±1.98μM AM plus 1.73±1.05μM DEA; experimental data point=5.06±0.47μM AM plus 2.07±0.47μM DEA). The cytotoxic interaction between AM and DEA may be clinically relevant in the development of AIPT.
背景与目标:
: 有效且有效的抗心律不齐剂胺碘酮 (AM) 可引起潜在的威胁生命的肺损伤 (胺碘酮诱导的肺毒性; AIPT),其特征是肺中的细胞死亡,随后是炎症和纤维化。AM的主要代谢产物去乙基胺碘酮 (DEA) 比AM具有更大的毒性,并且有人建议DEA可能与AM协同作用以引起肺毒性。这项研究的目的是确定HPL1A人周围肺上皮细胞中AM和DEA之间的细胞毒性相互作用的类型。通过乳酸脱氢酶释放来测量细胞毒性。AM和DEA在HPL1A细胞中引起浓度依赖性的细胞毒性。引起50% 细胞死亡的药物浓度 (LC50) 和代表浓度-细胞死亡曲线陡度的希尔斜率因子在AM和DEA之间存在显着差异 (12.4 μ m和1.98; 5.07 μ m和5.43,对于AM和DEA,分别) 表明它们可能通过不同的机制诱导细胞毒性。7.13 μ m AM加上DEA的组合浓度,相当于每种化合物的单独LC50值的41%,导致50% 细胞死亡。等射线照相分析显示这种效应是累加的,尽管组合浓度仅略高于定义协同作用阈值的浓度 (协同作用阈值 = 4.21 ± 1.98 μ m AM加1.73 ± 1.05 μ m DEA; 实验数据点 = 5.06 ± 0.47 μ m AM加2.07 ± 0.47 μ m DEA)。AM和DEA之间的细胞毒性相互作用可能与AIPT的发展有关。