JM25-1，一种兼具气道松弛和抗炎特性的利多卡因类似物：对新型支气管痉挛治疗的启示。

JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties: Implications for New Bronchospasm Therapy.

机构信息

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.

出版信息

Anesthesiology. 2016 Jan;124(1):109-20. doi: 10.1097/ALN.0000000000000919.

DOI:10.1097/ALN.0000000000000919

PMID:26669988

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.

CONCLUSION

These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.

摘要

背景

吸入性利多卡因在动物模型和患者中拮抗支气管痉挛，但不良反应限制了其疗效。本研究评估了类似物 JM25-1 的抗支气管痉挛潜力，探讨了其在体外的机制及其在动物模型中的转化。

方法

在 GH3 细胞、大鼠气管环、小鼠淋巴细胞和人嗜酸性粒细胞系统中评估 JM25-1 的有效性，分别评估钠电流、收缩、增殖和存活的变化。在卵清蛋白致敏的小鼠中研究肺功能和炎症变化。

结果

JM25-1 的疗效高于利多卡因，抑制乙酰胆碱诱导和钙诱导的气管收缩（在 1 mM 时最大效应抑制率 [%]：67 ± 10 [JM25-1] 与 41 ± 11 [利多卡因] [P < 0.001] 用于乙酰胆碱；100 ± 3 [JM25-1] 与 36 ± 26 [利多卡因] [P < 0.001] 用于 Ca；均数 ± 标准差；n = 9 各），但钠电流较低（50%抑制浓度 = 151.5，n = 8 与 0.2 mM；n = 5；P < 0.001）。JM25-1 还抑制嗜酸性粒细胞存活（死亡细胞 [%]：65 ± 6；n = 4；P < 0.001 在 1 mM 时）和淋巴细胞增殖（S + G2 期细胞 [%]：94 ± 10；n = 6；P < 0.001）在 0.6 mM 时。雾化 JM25-1（1%）将肺嗜酸性粒细胞数量从 13.2 ± 2.4 降至 1.7 ± 0.7 × 10/μm（n = 6；P < 0.001）和中性粒细胞从 1.9 ± 0.4 降至 0.2 ± 0.1 × 10/μm（n = 7；P < 0.001）。其他参数，包括气道高反应性、细胞因子、黏液和细胞外基质沉积，也对雾化 JM25-1 敏感。