skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions

Abstract

Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100 mg/kg p.o.) or morphine (30 mg/kg i.p.) under varying conditions (100% air versus 5% CO{sub 2}-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used referencemore » agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations.« less

Authors:
; ;  [1];  [1]
  1. Porsolt and Partners Pharmacology, Z.A. des Suhards, 53940 Le Genest-Saint-Isle (France)
Publication Date:
OSTI Identifier:
21460207
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 247; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2010.06.012; PII: S0041-008X(10)00215-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIR; GUINEA PIGS; HEALTH HAZARDS; MICE; MORPHINE; OPTIMIZATION; PHARMACOLOGY; RATS; RESPIRATION; SAFETY; THEOPHYLLINE; ALKALOIDS; ANALGESICS; ANIMALS; AROMATICS; AZAARENES; CARDIOVASCULAR AGENTS; CENTRAL NERVOUS SYSTEM AGENTS; CENTRAL NERVOUS SYSTEM DEPRESSANTS; DIURETICS; DRUGS; FLUIDS; GASES; HAZARDS; HETEROCYCLIC COMPOUNDS; MAMMALS; NARCOTICS; OPIUM; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; PURINES; RODENTS; VASODILATORS; VERTEBRATES; XANTHINES

Citation Formats

Goineau, Sonia, Rompion, Sonia, Guillaume, Philippe, and Picard, Sandra. Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.06.012.
Goineau, Sonia, Rompion, Sonia, Guillaume, Philippe, & Picard, Sandra. Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions. United States. doi:10.1016/j.taap.2010.06.012.
Goineau, Sonia, Rompion, Sonia, Guillaume, Philippe, and Picard, Sandra. Wed . "Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions". United States. doi:10.1016/j.taap.2010.06.012.
@article{osti_21460207,
title = {Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions},
author = {Goineau, Sonia and Rompion, Sonia and Guillaume, Philippe and Picard, Sandra},
abstractNote = {Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100 mg/kg p.o.) or morphine (30 mg/kg i.p.) under varying conditions (100% air versus 5% CO{sub 2}-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used reference agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations.},
doi = {10.1016/j.taap.2010.06.012},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 247,
place = {United States},
year = {2010},
month = {9}
}