Respiratory safety pharmacology: concurrent validation of volume, rate, time, flow and ratio variables in conscious male Sprague-Dawley rats.
This study compares basic respiratory variables (rate, tidal and minute volumes) with time-, flow- and ratio-derived parameters obtained using head-out plethysmography in rats following administration of reference drugs (isotonic saline, 2.0 mL/kg, IV; albuterol, 400 μg/kg, inhalation; methacholine, 136 μg/kg, IV; and remifentanil, 14 μg/kg, IV) to identify respiratory variables with superior sensitivity. Paired t-tests by block-period, and analysis of covariance (ANCOVA) with baseline as covariate and a posteriori pair-wise comparisons using Dunnett's test were used. Variations in respiratory parameters observed over time justify the use of a control group in any respiratory safety pharmacology study for inter-groups comparison. Handling-, and slumbering-, induced perturbations were minimal. The system was sensitive and specific to detect changes in respiratory variables related to pharmacologically-induced bronchodilation, bronchoconstriction and central respiratory depression. The standard variables (respiratory rate, tidal and minute volumes) confirmed to be the cornerstone of respiratory safety pharmacology to detect pharmacological changes. Flow-derived parameters appeared as highly valuable complement for interpretation of respiratory response, whereas time- and ratio-derived parameters presented limited added value during interpretation.
Legaspi
Margarita
M
Biology Experimental Center, INRS, 531 Boulevard des Prairies, Laval, QC, Canada H7V 1B7.
Authier
Simon
S
Gauvin
Dominique
D
Moreau
Maxim
M
Beauchamp
Guy
G
Chaurand
Fernando
F
Troncy
Eric
E
D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D007320:Inspiratory Capacity / Q000187:drug effects; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D010991:Plethysmography; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077208:Remifentanil; D015203:Reproducibility of Results; D012119:Respiration / Q000187:drug effects*; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000139:chemically induced; D056152:Respiratory Rate / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects*; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013990:Tidal Volume / Q000187:drug effects
D010880:Piperidines; D016210:Methacholine Chloride; D012965:Sodium Chloride; D000077208:Remifentanil; D000420:Albuterol