dc.creator | Carvalho, Katharinne Ingrid Moraes | |
dc.creator | Coutinho, Diego de Sá | |
dc.creator | Joca, Humberto Cavalcante | |
dc.creator | Miranda, Artur Santos | |
dc.creator | Cruz, Jader dos Santos | |
dc.creator | Silva, Emerson Teixeira | |
dc.creator | Souza, Marcus Vinícius Nora | |
dc.creator | Faria, Robson Xavier | |
dc.creator | Silva, Patricia Machado Rodrigues e | |
dc.creator | Costa, Jorge Carlos Santos | |
dc.creator | Martins, Marco Aurélio | |
dc.date | 2021-01-13T18:29:21Z | |
dc.date | 2021-01-13T18:29:21Z | |
dc.date | 2020 | |
dc.date.accessioned | 2023-09-26T20:42:37Z | |
dc.date.available | 2023-09-26T20:42:37Z | |
dc.identifier | CARVALHO, Katharine Ingrid Moraes et al. Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity. Frontiers in Pharmacology, v. 11, Article 1159, p. 1-12, July 2020. | |
dc.identifier | 1663-9812 | |
dc.identifier | https://www.arca.fiocruz.br/handle/icict/45670 | |
dc.identifier | 10.3389/fphar.2020.01159 | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/8862452 | |
dc.description | Local anesthetics (LAs), such as lidocaine and mexiletine, inhibit bronchoconstriction in asthmatics, but adverse effects limit their use for this specific clinical application. In this study, we describe the anti-spasmodic properties of the mexiletine analog 2-(2- aminopropoxy)-3,5-dimethyl, 4-Br-benzene (JME-173), which was synthesized and screened for inducing reduced activity on Na+ channels. The effectiveness of JME-173 was assessed using rat tracheal rings, a GH3 cell line and mouse cardiomyocytes to access changes in smooth muscle contraction, and Na+, and Ca++ionic currents, respectively. Bronchospasm and airway hyper-reactivity (AHR) were studied using whole-body barometric plethysmography in A/J mice. We observed that the potency of JME-173 was 653-fold lower than mexiletine in inhibiting Na+ currents, but 12-fold higher in inhibiting L-type Ca++ currents. JME-173 was also more potent than mexiletine in inhibiting tracheal contraction by carbachol, allergen, extracellular Ca++, or sodium orthovanadate provocations. The effect of JME-173 on carbachol-induced tracheal contraction remained unaltered under conditions of de-epithelized rings, b2-receptor blockade or adenylate cyclase inhibition. When orally administered, JME-173 and theophylline inhibited methacholine-induced bronchospasm at time points of 1 and 3 h post-treatment, while only JME-173 remained active for at least 6 h. In addition, JME-173 also inhibited AHR in a mouse model of lipopolysaccharide (LPS)-induced lung inflammation. Thus, the mexiletine analog JME-173 shows highly attenuated activity on Na+ channels and optimized anti-spasmodic properties, in a mechanism that is at least in part mediated by regulation of Ca++ inflow toward the cytosol. Thus, JME-173 is a promising alternative for the treatment of clinical conditions marked by lifethreatening bronchoconstriction. | |
dc.format | application/pdf | |
dc.language | eng | |
dc.publisher | Frontiers Media | |
dc.rights | open access | |
dc.subject | Anestésico local | |
dc.subject | Hiper-reatividade das vias aéreas | |
dc.subject | Asma | |
dc.subject | Broncodilatador | |
dc.subject | Fronteiras anti-inflamatórias | |
dc.subject | Local anesthetic | |
dc.subject | Airway hyper-reactivity | |
dc.subject | Asthma | |
dc.subject | Bronchodilator | |
dc.subject | Anti-inflammatory Frontiers | |
dc.title | Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity | |
dc.type | Article | |