Department of Anaesthesiology, University of Düsseldorf, Düsseldorf, Germany.
Eur J Anaesthesiol. 2012 Jan;29(1):35-41. doi: 10.1097/EJA.0b013e32834cd6c4.
Local neurotoxicity of local anaesthetics is a well known phenomenon which is determined by lipophilicity. Recent reports have indicated the relevance of local anaesthetic-induced cytotoxicity also in nonneuronal tissues. This study re-evaluates the role of lipophilicity in local anaesthetic cytotoxicity in nonneuronal cells. In addition, the toxicities of pipecoloxylidine S(-) enantiomers were investigated.
Local anaesthetic-induced cytotoxicity was investigated in vitro in T-lymphoma cells (Jurkat). Cells were incubated with each of eight different local anaesthetics, two esters and six amides. Annexin V-fluorescein isothiocyanate and 7-aminoactinomycin D double staining followed by flow cytometry were used to investigate the fraction of early apoptotic cells as well as the overall cell death. The concentrations leading to 50% cell death (LC50) were calculated and compared. In a second step, we compared the toxicities of S(-) bupivacaine and the racemate as well as R(+) and S(-) ropivacaine.
Concentration-dependent cytotoxicity was observed for all investigated local anaesthetics. Apoptosis was seen at low concentrations, whereas necrosis was observed at higher concentrations. LC50 values of the different local anaesthetics yielded the following decreasing order of toxicity: tetracaine, bupivacaine, ropivacaine, prilocaine, procaine, lidocaine, articaine and mepivacaine. Toxicity correlated with octanol/buffer partition coefficients, but was independent of the ester or amide linkage. There was no effect of stereoisomerism on apoptosis and necrosis.
Moderate correlations for cytotoxicity with lipophilicity and clinical potency of local anaesthetics can be found in nonneuronal cells that are less than those reported previously with neuronal cells. Structural factors such as ester or amide linkage or stereospecificity do not have any influence on cytotoxicity. Although S(-) enantiomers may be advantageous with regard to systemic toxicity, they have no advantage in respect of local cytotoxicity in vitro.
局部麻醉剂的局部神经毒性是一种众所周知的现象，其由脂溶性决定。最近的报告表明，局部麻醉剂诱导的细胞毒性也与非神经元组织有关。本研究重新评估了脂溶性在非神经元细胞中局部麻醉剂细胞毒性中的作用。此外，还研究了哌啶氧代 S(-)对映体的毒性。
在体外 T 淋巴瘤细胞（Jurkat）中研究了局部麻醉剂诱导的细胞毒性。用 8 种不同的局部麻醉剂、2 种酯类和 6 种酰胺类药物孵育细胞。用 Annexin V-异硫氰酸荧光素和 7-氨基放线菌素 D 双重染色，然后用流式细胞术检测早期凋亡细胞的比例以及总细胞死亡。计算并比较导致 50%细胞死亡（LC50）的浓度。在第二步中，我们比较了 S(-)布比卡因和外消旋体以及 R(+)和 S(-)罗哌卡因的毒性。
所有研究的局部麻醉剂均观察到浓度依赖性细胞毒性。在低浓度下观察到凋亡，而在高浓度下观察到坏死。不同局部麻醉剂的 LC50 值呈现出以下毒性递减顺序：四卡因、布比卡因、罗哌卡因、丙胺卡因、普鲁卡因、利多卡因、阿替卡因和甲哌卡因。毒性与辛醇/缓冲分配系数相关，但与酯或酰胺键无关。立体异构对凋亡和坏死没有影响。
在非神经元细胞中，细胞毒性与脂溶性和局部麻醉剂的临床效价之间存在中等相关性，低于先前报道的神经元细胞中的相关性。结构因素，如酯或酰胺键或立体特异性，对细胞毒性没有任何影响。尽管 S(-)对映体在全身毒性方面可能具有优势，但在体外局部细胞毒性方面没有优势。
