Use of within-group designs to test anti-tussive drugs in conscious guinea-pigs.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Venkatasamy
R
R
Sackler Institute of Pulmonary Pharmacology, Pharmaceutical Science Division, School of Biomedical and Health Science, Kings College London, London SE1 1UL, United Kingdom.
McKenzie
A
A
Page
C P
CP
Walker
M J
MJ
Spina
D
D
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000779:Anesthetics, Local / Q000627:therapeutic use; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D002211:Capsaicin; D002908:Chronic Disease; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018592:Cross-Over Studies; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D008012:Lidocaine / Q000627:therapeutic use; D008297:Male; D015203:Reproducibility of Results; D012107:Research Design; D012996:Solutions; D013016:Sound; D013726:Terbutaline / Q000008:administration & dosage / Q000627:therapeutic use
D000318:Adrenergic beta-Agonists; D000779:Anesthetics, Local; D000996:Antitussive Agents; D012996:Solutions; D019343:Citric Acid; D008012:Lidocaine; D013726:Terbutaline; D002211:Capsaicin