Mathivanan S, de la Torre-Martinez R, Wolf C, Mangano G, Polenzani L, Milanese C, Ferrer-Montiel A
Institute of Molecular and Cell Biology, Miguel Hernandez University, Alicante, Spain.
Angelini Research Center, Angelini S.p.A., S. Palomba-Pomezia (Rome), Italy.
J Physiol Pharmacol. 2016 Dec;67(6):851-858.
Econazole is an anti-mycotic agent widely used for the treatment of cutaneous fungal infections, and for the therapy of vaginal candidiasis. Topical application of this azole is generally safe, although some patients have complained of mild burning sensation/cutaneous irritation and itching, especially when administered intravaginally. The underlying mechanisms responsible of these adverse effects are poorly understood, though they suggest excitation of cutaneous nociceptor terminals. We report that exposure of primary cultures of rat nociceptors to econazole augments neuronal excitability. This effect appears mediated by increments in the intracellular Ca by stimulating Ca entry and release from the endoplasmic reticulum. Ca entry was not due to activation of thermo transient receptor potential (TRP) channels, suggesting a different ion channel targeted by the azole. Noteworthy, econazole-evoked responses were potentiated by a pro-inflammatory agent, which resulted in an increase in neuronal excitability. Econazole-elicited action potential firing was significantly abolished by the inflammatory cytokine inhibiting drug benzydamine via blockade of voltage-gated Na (Nav) channels. Collectively, our results indicate that the burning sensation of econazole is due at least in part to modulation of nociceptor excitability, and such sensation is increased in the presence of pro-inflammatory stimuli and blocked by benzydamine. These findings imply that a combination of the azole with benzydamine has the potential to reduce significantly the unpleasant symptoms related to infection and to the adverse effects of topical econazole formulations.
益康唑是一种广泛用于治疗皮肤真菌感染和阴道念珠菌病的抗真菌剂。这种唑类药物的局部应用通常是安全的，尽管一些患者抱怨有轻微的烧灼感/皮肤刺激和瘙痒，尤其是经阴道给药时。虽然这些不良反应的潜在机制尚不清楚，但提示皮肤伤害性感受器终末受到了刺激。我们报告，大鼠伤害性感受器的原代培养物暴露于益康唑会增强神经元兴奋性。这种效应似乎是通过刺激内质网钙的内流和释放导致细胞内钙增加介导的。钙内流并非由于热敏感瞬时受体电位（TRP）通道的激活，提示该唑类药物作用于不同的离子通道。值得注意的是，促炎剂可增强益康唑诱发的反应，导致神经元兴奋性增加。益康唑诱发的动作电位发放可被炎性细胞因子抑制药物苄达明通过阻断电压门控钠（Nav）通道而显著消除。总的来说，我们的结果表明，益康唑的烧灼感至少部分是由于伤害性感受器兴奋性的调节，并且在存在促炎刺激时这种感觉会增强，而苄达明可阻断这种感觉。这些发现意味着唑类药物与苄达明联合使用有可能显著减轻与感染相关的不适症状以及局部益康唑制剂的不良反应。
