| Popis: |
Introduction A number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. As some drugs may not cause changes in core battery parameters such as tidal volume (V t ), respiratory rate (RR) or minute ventilation (MV), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. The present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (R rs ) and conventional respiratory parameters (V t , RR, MV) in conscious Beagle dogs and cynomolgus monkeys. Methods An Airwave Oscillometry system ( tremoFlo ; THORASYS Inc., Montreal, Canada) was used to concomitantly assess R rs and conventional respiratory parameters before and after intravenous treatment with a bronchoactive agent. Respiratory mechanics measurements were performed by applying a short ( i.e. 16 s) single high frequency (19 Hz) waveform at the subject's airway opening via a face mask. During measurements, pressure and flow signals were recorded. After collection of baseline measurements, methacholine was administered intravenously to Beagle dogs ( n = 6) and cynomolgus monkeys ( n = 4) at 8 and 68 μg/kg, respectively. Results In dogs, methacholine induced significant increases in V t , RR and MV while in monkeys, it only augmented RR. A significant increase in R rs was observed after methacholine administration in both species with mean percentage peak increases from baseline of 88 (53)% for dogs and 28 (16)% for cynomolgus monkeys. Conclusion Airwave Oscillometry appears to be a promising non-invasive methodology to enable respiratory mechanics measurements in conscious large animals, a valuable refinement in respiratory safety pharmacology. |
Full Text from ScienceDirect