title: Effect of econazole and benzydamine on sensory neurons in culture.
abstract: 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 Ca2+by stimulating Ca2+entry and release from the endoplasmic reticulum. Ca2+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.
authors.affiliation: Institute of Molecular and Cell Biology, Miguel Hernandez University, Alicante, Spain. aferrer@umh.es.
authors.forename: S
authors.initials: S
authors.lastname: Mathivanan
authors.affiliation: Institute of Molecular and Cell Biology, Miguel Hernandez University, Alicante, Spain.
authors.forename: R
authors.initials: R
authors.lastname: de la Torre-Martinez
authors.affiliation: Institute of Molecular and Cell Biology, Miguel Hernandez University, Alicante, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Wolf
authors.affiliation: Angelini Research Center, Angelini S.p.A., S. Palomba-Pomezia (Rome), Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mangano
authors.affiliation: Angelini Research Center, Angelini S.p.A., S. Palomba-Pomezia (Rome), Italy.
authors.forename: L
authors.initials: L
authors.lastname: Polenzani
authors.affiliation: Angelini Research Center, Angelini S.p.A., S. Palomba-Pomezia (Rome), Italy.
authors.forename: C
authors.initials: C
authors.lastname: Milanese
authors.affiliation: Institute of Molecular and Cell Biology, Miguel Hernandez University, Alicante, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001591:Benzydamine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004464:Econazole / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D016207:Cytokines; D050051:Transient Receptor Potential Channels; D001591:Benzydamine; D004464:Econazole; D002118:Calcium