中枢和外周作用 GABA 激动剂对健康人体咳嗽反射的影响。

Effect of centrally and peripherally acting GABA agonism on the healthy human cough reflex.

机构信息

Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK; North Manchester General Hospital, Pennie Acute NHS Trust, UK, Department of Respiratory Medicine.

Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.

出版信息

Pulm Pharmacol Ther. 2021 Dec;71:102079. doi: 10.1016/j.pupt.2021.102079. Epub 2021 Sep 24.

DOI:10.1016/j.pupt.2021.102079

PMID:34571095

Abstract

BACKGROUND

Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABA receptors in both the peripheral and central nervous systems inhibit cough.

OBJECTIVE

To compare the effect of central and peripherally acting GABA agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers.

METHODS

We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50).

RESULTS

Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 μM (95%CI 24.4-91.7) vs 37.6 μM (95%CI 19.2-73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 μM (95%CI 37.2-151.8), p = 0.002).

CONCLUSION

This data suggests the anti-tussive actions of GABA agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.

摘要

背景

目前尚无有效的止咳治疗药物。了解介导动物模型咳嗽反射的神经元机制如何转化为人类机制，对于开发有效的治疗方法非常重要。临床前研究表明，外周和中枢神经系统中 GABA 受体的激活可抑制咳嗽。

目的

比较中枢和外周作用的 GABA 激动剂（lesogaberan 和 baclofen）对健康志愿者咳嗽反射的影响。

方法

我们在健康对照者中进行了一项单中心、双盲、双模拟、三交叉试验，比较了 lesogaberan（120mgMR）、baclofen（40mg）和安慰剂单次剂量的作用。在每次研究日的筛查和给药后 2 小时，通过吸入辣椒素来评估咳嗽反应。主要终点是任何辣椒素浓度下引起的最大咳嗽次数（Emax），次要终点是引起 50%最大反应的浓度（ED50）。

结果

15 名参与者入组研究（中位年龄 29（IQR 25-44）岁；7 名女性，平均 BMI 24.6（±3.0）。与安慰剂相比，lesogaberan 治疗使 Emax 略有但具有统计学意义的增加[平均 13.4 次咳嗽（95%CI 10.1-17.9）vs. 11.8 次咳嗽（8.8-15.9），p=0.04]，但对 ED50 无影响[几何均数 47.4μM（95%CI 24.4-91.7）vs 37.6μM（95%CI 19.2-73.5），p=0.37]。相比之下，baclofen 对 Emax 无显著影响（11.1，95%CI 8.1-15.4）（p=0.23），但与安慰剂相比，ED50 显著增加（几何均数 75.2μM（95%CI 37.2-151.8），p=0.002）。