INTRODUCTION: Assessment of respiratory safety is one of the most important requirements for new chemical entity (ICH Guideline S7A). The aim of the present study was to compare and validate respiratory safety pharmacology models in conscious rats, to find out the most appropriate method for detection of drug-induced adverse effects on respiratory function in preclinical safety studies. METHODS: Head out plethysmography and whole body plethysmography methods were used to monitor typical parameters of ventilatory function like respiratory rate (RR), tidal volume (TV), minute volume (MV) and mid expiratory flow (EF50). The effects of respiratory stimulant theophylline (100mg/kg) and respiratory depressant chlordiazepoxide (100mg/kg) were evaluated in both models. Propranolol (60mg/kg) was also used to compare head out and whole body plethysmography because of its bronchoconstrictor effects on airway function. RESULTS: Theophylline caused a significant increase in TV, EF50 and MV in both whole body and head out plethysmography. In whole body plethysmography, theophylline significantly increased RR, but this increase was not observed in head out plethysmography. Chlordiazepoxide significantly decreased RR, TV, EF50 and MV in head out plethysmography, but it significantly reduced only TV in whole body plethysmography. A significant reduction in TV was observed with propranolol in both whole body and head out plethysmography. DISCUSSION: We conclude that ventilatory function can be accurately assessed using head out plethysmography compared to whole body plethysmography. Our experimental results of EF50 from non-invasive methods suggest that reliable assessment of airway function demand additional invasive methods.
INTRODUCTION: Assessment of respiratory safety is one of the most important requirements for new chemical entity (ICH Guideline S7A). The aim of the present study was to compare and validate respiratory safety pharmacology models in conscious rats, to find out the most appropriate method for detection of drug-induced adverse effects on respiratory function in preclinical safety studies. METHODS: Head out plethysmography and whole body plethysmography methods were used to monitor typical parameters of ventilatory function like respiratory rate (RR), tidal volume (TV), minute volume (MV) and mid expiratory flow (EF50). The effects of respiratory stimulant theophylline (100mg/kg) and respiratory depressant chlordiazepoxide (100mg/kg) were evaluated in both models. Propranolol (60mg/kg) was also used to compare head out and whole body plethysmography because of its bronchoconstrictor effects on airway function. RESULTS:Theophylline caused a significant increase in TV, EF50 and MV in both whole body and head out plethysmography. In whole body plethysmography, theophylline significantly increased RR, but this increase was not observed in head out plethysmography. Chlordiazepoxide significantly decreased RR, TV, EF50 and MV in head out plethysmography, but it significantly reduced only TV in whole body plethysmography. A significant reduction in TV was observed with propranolol in both whole body and head out plethysmography. DISCUSSION: We conclude that ventilatory function can be accurately assessed using head out plethysmography compared to whole body plethysmography. Our experimental results of EF50 from non-invasive methods suggest that reliable assessment of airway function demand additional invasive methods.
Authors: James J Lynch; Emilie Rossignol; Joerg J Moehrle; Terry R Van Vleet; Kennan C Marsh; Toufan Parman; Jon Mirsalis; Sean E Ottinger; Jason A Segreti; Mohan Rao; Scott W Mittelstadt Journal: J Pharmacol Toxicol Methods Date: 2019-05-11 Impact factor: 1.950
Authors: Morgan L Crowley; Luis F Restrepo; Lea R Gamez-Jimenez; Avi Patel; Tobias Braun; Victoria L C Pallares; Nicholas P Ho; Morgan E Reeves; Christopher R McCurdy; Lance R McMahon; Takato Hiranita Journal: J Pharmacol Toxicol Methods Date: 2021-07-07 Impact factor: 2.285