Venkatasamy R, McKenzie A, Page C P, Walker M J, Spina D
Sackler Institute of Pulmonary Pharmacology, Pharmaceutical Science Division, School of Biomedical and Health Science, Kings College London, London SE1 1UL, United Kingdom.
J Pharmacol Toxicol Methods. 2010 Mar-Apr;61(2):157-62. doi: 10.1016/j.vascn.2010.02.015. Epub 2010 Mar 1.
Cough is a common medical problem for which there are few effective drug treatments. A limited understanding of the mechanisms of induction and maintenance of cough and a paucity of suitable animal models frustrate drug discovery efforts to find novel anti-tussives. As in humans, guinea-pigs evoke a cough reflex upon exposure to tussive agents such as citric acid and capsaicin; both of which have been widely used to assess novel anti-tussive drugs. However, the potential for using within-group designs in drug development has received little attention and such designs may offer a way of assisting the drug discovery effort in the area of cough as well as other areas.
Cough can be monitored in conscious guinea-pigs by placing animals in a Perspex chamber, in which air is continually exchanged by use of negative pressure and drug delivery of aerosols to the chamber can be accurately timed. Cough in response to a tussive agent (e.g. 0.2-0.4M citric acid; 10-30 microM capsaicin) is detected by the simultaneous microphonic recording of audible signals characteristic of the cough response as well as by positive pressure changes in the chamber generated by a cough dependent rapid expiration of air from the lungs. Both the sound and pressure signals are recorded using an online analyzer, whilst the number of coughs can be analyzed off-line. The number of coughs over a 15 min period is used to quantitate tussive events.
Reproducible cough can be detected in animals using cross-over designs that lend themselves to drug studies. Both the time and concentration dependence of anti-tussive drug action can be evaluated in the same animal. Furthermore, the effect of different anti-tussive drugs can be evaluated thereby reducing between group error and thereby improving the sensitivity of the test.
Repeated measures design improves the precision with which to evaluate anti-tussive drugs in preclinical models and could be used to make the drug discovery process more efficient.
咳嗽是一个常见的医学问题，有效的药物治疗方法却很少。对咳嗽诱发和维持机制的了解有限，以及缺乏合适的动物模型，阻碍了寻找新型镇咳药的药物研发工作。与人类一样，豚鼠在接触柠檬酸和辣椒素等镇咳剂时会引发咳嗽反射；这两种物质都已被广泛用于评估新型镇咳药。然而，在药物研发中使用组内设计的潜力很少受到关注，这种设计可能为咳嗽及其他领域的药物研发工作提供一种帮助。
可通过将清醒的豚鼠置于有机玻璃箱中来监测咳嗽，在该箱中通过负压持续交换空气，并且可以精确设定向箱内递送气雾剂药物的时间。通过同时对咳嗽反应特征性的可听信号进行微音器记录以及通过肺部咳嗽依赖性快速呼气在箱内产生的正压变化来检测对镇咳剂（例如0.2 - 0.4M柠檬酸；10 - 30微摩尔辣椒素）的咳嗽反应。声音和压力信号均使用在线分析仪记录，而咳嗽次数可离线分析。15分钟内的咳嗽次数用于定量镇咳事件。
使用适用于药物研究的交叉设计可在动物中检测到可重复的咳嗽。可以在同一只动物中评估镇咳药作用的时间和浓度依赖性。此外，可以评估不同镇咳药的效果，从而减少组间误差并提高测试的灵敏度。
重复测量设计提高了在临床前模型中评估镇咳药的精度，可用于提高药物研发过程的效率。
