Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point
Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point
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DOI：
10.1016/j.jaci.2013.04.042
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发表时间：
2013-10-01
影响因子：
14.2
通讯作者：
Smith, Jaclyn A.
中科院分区：
文献类型：
--
作者：
Hilton, Emma C. Y.;Baverel, Paul G.;Smith, Jaclyn A.
背景：吸入性辣椒素可引起人类咳嗽，被广泛用于咳嗽和止咳治疗的研究。然而，传统的终点C2和C5（分别引起至少2次或5次咳嗽的辣椒素浓度）在健康和疾病之间显示出广泛的重叠，因此可能不能最好地反映临床相关机制。目的：我们试图研究不同疾病组的辣椒素剂量反应。方法：比较慢性咳嗽患者（CC, n = 20）、哮喘患者（n = 18）和健康志愿者（HVs, n = 20）的两种新型辣椒素咳嗽刺激。在试验1中，辣椒素的剂量增加一倍（0.48-1000 mmol/L，每剂量吸入4次），而在试验2中，剂量的顺序随机化。一个非线性混合效应模型按疾病组和性别比较剂量-反应参数。各项参数也与客观咳嗽频率相关。结果：该模型根据辣椒素浓度引起的最大咳嗽反应（E-max）和辣椒素剂量引起的半最大反应（ED50）对受试者进行分类。hv和哮喘患者在这两个参数上均无统计学差异，因此合并分析（平均ED50, 38.6 mmol/L[相对SE， 28%]；平均Emax， 4.5咳嗽[相对SE， 11%]）。与HVs/哮喘患者相比，CC患者ED50值较低（14.7 mmol/L[相对SE， 28%], P = 0.008）， Emax值较高（8.6次咳嗽[相对SE， 11%], P < 0.0001）。Emax值与24小时咳嗽频率高度相关（r = 0.71, P < 0.001），无论疾病组如何，女性受试者的Emax值比男性受试者高37% （P < 0.001）。结论：非线性混合效应模型表明，最大辣椒素咳嗽反应可以更好地区分健康和疾病，并预测自发咳嗽频率，因此为CC的机制提供了重要的见解。
Background: Inhaled capsaicin elicits cough reproducibly in human subjects and is widely used in the study of cough and antitussive therapies. However, the traditional end points C2 and C5 (the concentrations of capsaicin inducing at least 2 or 5 coughs, respectively) display extensive overlap between health and disease and therefore might not best reflect clinically relevant mechanisms.Objectives: We sought to investigate capsaicin dose responses in different disease groups.Methods: Two novel capsaicin cough challenges were compared in patients with chronic cough (CC; n = 20), asthmatic patients (n = 18), and healthy volunteers (HVs; n = 20). Increasing doubling doses of capsaicin (0.48-1000 mmol/L, 4 inhalations per dose) were administered in challenge 1, whereas the order of the doses was randomized in challenge 2. A nonlinear mixed-effects model compared dose-response parameters by disease group and sex. Parameters were also correlated with objective cough frequency.Results: The model classified subjects based on maximum cough response evoked by any concentration of capsaicin (E-max) and the capsaicin dose inducing half-maximal response (ED50). HVs and asthmatic patients were not statistically different for either parameter and therefore combined for analysis (mean ED50, 38.6 mmol/L [relative SE, 28%]; mean Emax, 4.5 coughs [ relative SE, 11%]). Compared with HVs/asthmatic patients, patients with CC had lower ED50 values (14.7 mmol/L [ relative SE, 28%], P = .008) and higher Emax values (8.6 coughs [relative SE, 11%], P < .0001). Emax values highly correlated with 24-hour cough frequency (r = 0.71, P < .001) and were 37% higher in female compared with male subjects, regardless of disease group (P < .001).Conclusions: Nonlinear mixed-effects modeling demonstrates that maximal capsaicin cough responses better discriminate health from disease and predict spontaneous cough frequency and therefore provide important insights into the mechanisms underlying CC.