Comparative safety respiratory pharmacology : validation of a head-out plethysmograph – pneumotachometer testing device in male Sprague–Dawley rats, Beagle dogs and Cynomolgus monkeys
The aim of this study was to evaluate the performance qualifications of the FlexiWare® system in conscious Sprague-Dawley rats, Cynomolgus monkeys, as well as awake and anesthetized Beagle dogs following the administration of pharmacological substances with known effects on the respiratory system. The pharmacological substances included albuterol administered by inhalation; methacholine and remifentanil, both administered intravenously. A preparation of saline solution administered intravenously was used as control. Respiratory monitoring included: respiratory rate (RR), tidal volume (TV), minute ventilation (MV), in rats, dogs and monkeys. Additional time-, flow-, and ratio-derived variables were used in the rat model. Those variables included inspiratory (IT) and expiratory (ET) times, time to peak expiratory flow, peak inspiratory and expiratory flows, mid-tidal expiratory flow (EF50), inspiratory:expiratory (I:E) and inspiratory to total breath (I:TB) ratios. The results of this study have proven that the FlexiWare® was a reliable method and should be considered in the core battery recommended in safety pharmacology studies (ICH 2000) to assess the broncho-dilative, -constrictive, and central depressant effects of drugs on the respiratory system of the common laboratory animal specie. The animals appeared to adapt well to the restraint unit. The variables evaluated, particularly RR, TV and MV, were adequate and allowed to characterize the response of the animals following the administration of the pharmacological substances. They are judiciously completed with flowderived variables. The addition of within-breath time parameters was not primordial to detect drug effects but offered complementary tools to interpret physiological changes. However the evaluation period should be limited to the first 2 hours post treatment. These studies represent a performance qualifications evaluation of the system and have originally demonstrated the precision (sensitivity and specificity) as well as repeatability for different variables and on different specie of interest.
Rats Singes Safety Respiratory Pharmacology Rats Monkeys Dogs