title: JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties: Implications for New Bronchospasm Therapy.
abstract: BACKGROUND
  Inhaled lidocaine antagonized bronchospasm in animal models and patients, but adverse effects limited its efficacy. This study evaluated the antibronchospasm potential of the analog JM25-1, exploring in vitro mechanisms and translation to an animal model.
  
  
  METHODS
  The effectiveness of JM25-1 was assessed in GH3 cells, rat tracheal rings, mouse lymphocytes, and human eosinophil systems in vitro, assessing changes in Na current, contraction, proliferation, and survival, respectively. Lung function and inflammatory changes were studied in ovalbumin-sensitized mice.
  
  
  RESULTS
  The efficacy of JM25-1 was higher than lidocaine in inhibiting carbachol-induced and calcium-induced tracheal contractions (maximum effect inhibition at 1 mM [%]: 67 ± 10 [JM25-1] vs. 41 ± 11 [lidocaine] [P < 0.001] for carbachol; 100 ± 3 [JM25-1] vs. 36 ± 26 [lidocaine] [P < 0.001] for Ca; mean ± SD; n = 9 each) but lower in Na current (50% inhibitory concentration = 151.5, n = 8 vs. 0.2 mM; n = 5; P < 0.001). JM25-1 also inhibited eosinophil survival (dead cells [%]: 65 ± 6; n = 4; P < 0.001 at 1 mM) and lymphocyte proliferation (cells in phase S + G2 [%]: 94 ± 10; n = 6; P < 0.001) at 0.6 mM. Aerosolized JM25-1 (1%) decreased lung eosinophil numbers from 13.2 ± 2.4 to 1.7 ± 0.7 × 10/μm (n = 6; P < 0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 10/μm (n = 7; P < 0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1.
  
  
  CONCLUSIONS
  These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.
authors.affiliation: From the Laboratory of Inflammation (M.F.S., G.C.C., A.C.C., C.R.P., K.I.M.d.C., E.A.A.-V., J.C.S.C., R.S.B.C., P.M.R.S., M.A.M.) and Laboratory of Cellular Communication (R.X.F.), Oswaldo Cruz Institute, Rio de Janeiro, Brazil; and Institute of Biomedical Sciences (J.S.N.) and Laboratory of Clinical Bacteriology and Immunology (P.C.O.), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Magda F
authors.initials: MF
authors.lastname: Serra
authors.forename: Josiane S
authors.initials: JS
authors.lastname: Neves
authors.forename: Gina C
authors.initials: GC
authors.lastname: Couto
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Cotias
authors.forename: Camila R
authors.initials: CR
authors.lastname: Pão
authors.forename: Priscilla C
authors.initials: PC
authors.lastname: Olsen
authors.forename: Katharinne I Moraes
authors.initials: KI
authors.lastname: de Carvalho
authors.forename: Edna A
authors.initials: EA
authors.lastname: Anjos-Valotta
authors.forename: Robson X
authors.initials: RX
authors.lastname: Faria
authors.forename: Jorge C S
authors.initials: JC
authors.lastname: Costa
authors.forename: Renato S B
authors.initials: RS
authors.lastname: Cordeiro
authors.forename: Patricia M R
authors.initials: PM
authors.lastname: Silva
authors.forename: Marco A
authors.initials: MA
authors.lastname: Martins
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001986:Bronchial Spasm; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D014132:Trachea / Q000187:drug effects* / Q000503:physiopathology*
chemical_list: D000779:Anesthetics, Local; D000893:Anti-Inflammatory Agents; C000606759:JM25-1 compound; D008012:Lidocaine