JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties
| Autor: | Amanda C. Cotias, Katharinne Ingrid Moraes de Carvalho, Gina C. Couto, Camila R. Pão, Patrícia M.R. e Silva, Edna A. Anjos-Valotta, Josiane S. Neves, Robson Xavier Faria, Priscilla C. Olsen, Renato S.B. Cordeiro, Magda F. Serra, Marco A. Martins, Jorge Carlos Santos da Costa |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lung Contraction (grammar) Carbachol Lidocaine business.industry Inflammation Lymphocyte proliferation Pharmacology Eosinophil Bronchospasm 03 medical and health sciences 030104 developmental biology Anesthesiology and Pain Medicine medicine.anatomical_structure Anesthesia Medicine medicine.symptom business medicine.drug |
| Zdroj: | Anesthesiology. 124:109-120 |
| ISSN: | 0003-3022 |
| Popis: | 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 Ca2+; 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 × 104/μm2 (n = 6; P < 0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 104/μm2 (n = 7; P < 0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1. Conclusion These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm. |
| Databáze: | OpenAIRE |
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