Mager Maximilian L, Ciotu Cosmin I, Gold-Binder Markus, Heber Stefan, Fischer Michael J M
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Front Pharmacol. 2023 Oct 4;14:1248558. doi: 10.3389/fphar.2023.1248558. eCollection 2023.
Addition of preservatives ensures microbial stability, especially in multidose containers of parenterally administered pharmaceuticals. These compounds can cause side effects, and particularly at the site of application, might elicit or facilitate pain. TRPA1 is a cation channel expressed in peripheral neurons which contributes to pain and inflammation and is sensitive to many irritants. The most commonly used preservatives, in particular with a focus on parenteral formulations, were investigated for their potential to activate TRPA1. Sixteen preservatives were screened for mediating calcium influx in human TRPA1-transfected HEK293t cells. Untransfected cells served as control, results were further validated in mouse sensory neurons. In addition, proinflammatory mediators serotonin, histamine and prostaglandin E2 were co-administered to probe a potential sensitisation of preservative-induced TRPA1 activation. Butylparaben, propylparaben, ethylparaben, bronopol, methylparaben, phenylethyl alcohol and phenol induced a TRPA1-dependent calcium influx in transfected HEK293t cells at concentrations used for preservation. Other preservatives increased calcium within the used concentration ranges, but to a similar degree in untransfected controls. Serotonin, histamine, and prostaglandin enhanced TRPA1 activation of phenylethyl alcohol, bronopol, ethylparaben, propylparaben and butylparaben. Systematic screening of common preservatives applied for parenterally administered drugs resulted in identifying several preservatives with substantial TRPA1 channel activation. This activation was enhanced by the addition of proinflammatory meditators. This allows selecting a preservative without TRPA1 activation, particularly in case of pharmaceuticals that could act proinflammatory.
添加防腐剂可确保微生物稳定性，尤其是在肠胃外给药的多剂量容器药物中。这些化合物可能会引起副作用，特别是在应用部位，可能引发或加剧疼痛。TRPA1是一种在外周神经元中表达的阳离子通道，它与疼痛和炎症有关，并且对许多刺激物敏感。研究了最常用的防腐剂，特别是针对肠胃外制剂，以探究它们激活TRPA1的可能性。筛选了16种防腐剂，以检测其在人TRPA1转染的HEK293t细胞中介导钙内流的情况。未转染的细胞用作对照，结果在小鼠感觉神经元中得到进一步验证。此外，还共同施用了促炎介质5-羟色胺、组胺和前列腺素E2，以探究防腐剂诱导的TRPA1激活的潜在致敏作用。对羟基苯甲酸丁酯、对羟基苯甲酸丙酯、对羟基苯甲酸乙酯、溴硝醇、对羟基苯甲酸甲酯、苯乙醇和苯酚在用于保存的浓度下，在转染的HEK293t细胞中诱导了TRPA1依赖性钙内流。其他防腐剂在所用浓度范围内增加了钙含量，但在未转染的对照中增加程度相似。5-羟色胺、组胺和前列腺素增强了苯乙醇、溴硝醇、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯和对羟基苯甲酸丁酯的TRPA1激活。对用于肠胃外给药的常见防腐剂进行系统筛选，结果鉴定出几种具有显著TRPA1通道激活作用的防腐剂。添加促炎介质可增强这种激活作用。这使得可以选择一种不会激活TRPA1的防腐剂，特别是在可能具有促炎作用的药物的情况下。
