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Effects of inhalation exposure of methacholine on intra-pleural pressure, airway resistance and compliance in conscious telemetered rats
Abstracts
collected using surgical monitoring equipment (Surgivet V6004). Bland and Altman statistical analysis of correlation was conducted (with regard to repeated measures on each animal) for minute volume, pO2 or pCO2; for PO2 and pulse oximetry values; and PCO2 and expired CO2. PC2O and expired CO2 were highly correlated (0.97). Pulse oximetry values did not show a significant correlation with P2O, suggesting that the monitoring equipment did not have adequate sensitivity for measuring rapid changes in blood oxygenation in this species. Statistically significant correlations of 0.82 and 0.77 were noted for minute volume and pO2 or pCO2, respectively, indicating that the assessment of minute volume could provide an adequate view of blood oxygenation when direct assessment is not possible. doi:10.1016/j.vascn.2012.08.134
Super-intervals: Application to respiratory safety pharmacology data in rats Simon Authiera, Margareta Someb, Sebastien Fourniera, Eric Troncyc
197
was given at three single doses to 4 male telemetered beagle dogs according to a cross-over design. Air was used as inhaled control. Respiratory recordings were performed before dosing, during dosing, at 20 min and 60 min following dosing. Data was collected continuously for 5 min except at dosing where the measurement is performed throughout the dose delivery (5–15 min). Heart rate and blood pressure were recorded by telemetry for 24 h. A significant increase in respiratory rate and minute volume was observed following inhalation of all three doses. Tidal volume was increased at the mid and high doses. A significant dose-related increase in heart rate and a dose-related decrease in mean arterial pressure were observed as well. Respiration is now measured routinely in safety pharmacology inhalation studies in telemetered dogs, enabling data collection from both the cardiovascular and respiratory systems when the drug is administered to the dog via the intended clinical route. Previously, the rat whole body plethysmography system with intravenous administration was used for respiratory assessment in inhalation projects. doi:10.1016/j.vascn.2012.08.136
a
CIToxLAB, Laval, Québec, Canada AstraZeneca R&D Södertälje, Safety Assessment, Södertälje, Sweden c Faculty of Veterinary Medicine, Université de Montréal, Québec, Canada b
Safety pharmacology was propelled by computerized monitoring technologies with high frequency data acquisition systems. Data reduction is a cornerstone of interpretation with impact on processing time and statistical analysis. The effects of various data reduction intervals on data dispersion and minimal detectable differences (MDD) were evaluated. Control data from head-out (HOP) and whole body (WBP) plethysmography in Sprague–Dawley (HOP) or Wistar Han (WBP) rats (n = 8/model) were evaluated for dispersion with interval durations from 10 s to 240 min. Optimal reduction in dispersion for respiratory rate (RR) was achieved with a 45-min interval for HOP compared to 1 min for tidal volume (TV). An optimal reduction of dispersion was attained with an averaging interval of 120 min for RR and 5 min for TV with WBP. These results are compatible with higher variability in RR compared to TV. With HOP, the MDD (α ≤ 0.05 and β = 0.8 two-sided) for group size of n = 8 was 9.2% (1-min interval) and 15.2% (180-min interval) for TV and RR, respectively. With the same group size, the MDD for WBP was 15.0% (5-min interval) and 16.9% (30-min interval) for TV and RR, respectively. The MDD for peak inspiratory and peak expiratory flows with HOP were 11.0% and 10.7% (180-min interval) while WBP revealed comparable MDD at 10.6% and 16.9% (120-min interval). The optimal interval for data reduction varies with the various parameters. The optimal data reduction interval should be sufficiently long to attenuate data dispersion but should avoid dilution of pharmacodynamic effects with unaltered data. doi:10.1016/j.vascn.2012.08.135
Respiratory assessment in safety pharmacology inhalation studies in telemetered dogs Margareta Some AstraZeneca R&D, Safety Pharmacology, Södertälje, Sweden At AstraZeneca R&D the in-house safety evaluation of inhaled compounds in the dog is performed using a custom-built system. The system delivers the drug by inhalation via a face mask with the actual individual dose calculated by measuring the breathing of each dog. It can also be used for detecting any drug-related effects on the breathing pattern. A novel compound for potential administration by inhalation
Effects of inhalation exposure of methacholine on intra-pleural pressure, airway resistance and compliance in conscious telemetered rats Rachel Armstrong, Sarah Donington, Simon Moore, Peter Davies, Stephen Jordan, Ken Meecham Huntingdon Life Sciences Ltd, Alconbury, Cambs, United Kingdom Lung airflow disorders can be evaluated in animal models by measuring total pulmonary resistance or compliance during tidal breathing or mechanical ventilation. Airway resistance and compliance are commonly measured in anaesthetised animals due to the need for direct measurement of pleural pressure. However, anaesthetised preparations alone are not suitable for assessment of drug-induced changes in ventilation or chronic measurements of airflow obstruction. Assessment of intra-pleural pressure in conscious animals enables dynamic measurements of airflow resistance and compliance in spontaneously breathing animals using a pressure-sensitive catheter inserted into the oesophageal wall connected to a telemetry device. Murphy et al. developed this technique over 10 years ago but the success of this technique in Contract Research Organisations has been limited. The purpose of this study was to therefore evaluate the potential effect of methacholine on intra-pleural pressure (IPP), dynamic compliance and resistance, in conscious restrained telemetered rats. This was a validation study to assess the suitability of techniques and procedures developed to measure respiratory parameters. Eight male Sprague Dawley rats were implanted with DSITM telemetry transmitters with the pressure catheter inserted into the serosal layer of the oesophageal wall and advanced into the thoracic cavity. Animals were then habituated to head out plethysmographs over 5 consecutive days. Pre-dose basal levels of resistance, compliance and other respiratory parameters were recorded for up to 45 min and animals received vehicle and increasing doses of methacholine via nose only inhalation exposure. The data suggested that a good pressure signal was achieved in telemetered rats at the time of surgery and during habituation to the plethysmographs. Dose-dependent increases in resistance and decreases in compliance were observed, following methacholine exposure demonstrating the validity of the system. The respiratory data obtained suggests that this model has the potential to be used on respiratory safety pharmacology and toxicology studies. doi:10.1016/j.vascn.2012.08.137
collected using surgical monitoring equipment (Surgivet V6004). Bland and Altman statistical analysis of correlation was conducted (with regard to repeated measures on each animal) for minute volume, pO2 or pCO2; for PO2 and pulse oximetry values; and PCO2 and expired CO2. PC2O and expired CO2 were highly correlated (0.97). Pulse oximetry values did not show a significant correlation with P2O, suggesting that the monitoring equipment did not have adequate sensitivity for measuring rapid changes in blood oxygenation in this species. Statistically significant correlations of 0.82 and 0.77 were noted for minute volume and pO2 or pCO2, respectively, indicating that the assessment of minute volume could provide an adequate view of blood oxygenation when direct assessment is not possible. doi:10.1016/j.vascn.2012.08.134
Super-intervals: Application to respiratory safety pharmacology data in rats Simon Authiera, Margareta Someb, Sebastien Fourniera, Eric Troncyc
197
was given at three single doses to 4 male telemetered beagle dogs according to a cross-over design. Air was used as inhaled control. Respiratory recordings were performed before dosing, during dosing, at 20 min and 60 min following dosing. Data was collected continuously for 5 min except at dosing where the measurement is performed throughout the dose delivery (5–15 min). Heart rate and blood pressure were recorded by telemetry for 24 h. A significant increase in respiratory rate and minute volume was observed following inhalation of all three doses. Tidal volume was increased at the mid and high doses. A significant dose-related increase in heart rate and a dose-related decrease in mean arterial pressure were observed as well. Respiration is now measured routinely in safety pharmacology inhalation studies in telemetered dogs, enabling data collection from both the cardiovascular and respiratory systems when the drug is administered to the dog via the intended clinical route. Previously, the rat whole body plethysmography system with intravenous administration was used for respiratory assessment in inhalation projects. doi:10.1016/j.vascn.2012.08.136
a
CIToxLAB, Laval, Québec, Canada AstraZeneca R&D Södertälje, Safety Assessment, Södertälje, Sweden c Faculty of Veterinary Medicine, Université de Montréal, Québec, Canada b
Safety pharmacology was propelled by computerized monitoring technologies with high frequency data acquisition systems. Data reduction is a cornerstone of interpretation with impact on processing time and statistical analysis. The effects of various data reduction intervals on data dispersion and minimal detectable differences (MDD) were evaluated. Control data from head-out (HOP) and whole body (WBP) plethysmography in Sprague–Dawley (HOP) or Wistar Han (WBP) rats (n = 8/model) were evaluated for dispersion with interval durations from 10 s to 240 min. Optimal reduction in dispersion for respiratory rate (RR) was achieved with a 45-min interval for HOP compared to 1 min for tidal volume (TV). An optimal reduction of dispersion was attained with an averaging interval of 120 min for RR and 5 min for TV with WBP. These results are compatible with higher variability in RR compared to TV. With HOP, the MDD (α ≤ 0.05 and β = 0.8 two-sided) for group size of n = 8 was 9.2% (1-min interval) and 15.2% (180-min interval) for TV and RR, respectively. With the same group size, the MDD for WBP was 15.0% (5-min interval) and 16.9% (30-min interval) for TV and RR, respectively. The MDD for peak inspiratory and peak expiratory flows with HOP were 11.0% and 10.7% (180-min interval) while WBP revealed comparable MDD at 10.6% and 16.9% (120-min interval). The optimal interval for data reduction varies with the various parameters. The optimal data reduction interval should be sufficiently long to attenuate data dispersion but should avoid dilution of pharmacodynamic effects with unaltered data. doi:10.1016/j.vascn.2012.08.135
Respiratory assessment in safety pharmacology inhalation studies in telemetered dogs Margareta Some AstraZeneca R&D, Safety Pharmacology, Södertälje, Sweden At AstraZeneca R&D the in-house safety evaluation of inhaled compounds in the dog is performed using a custom-built system. The system delivers the drug by inhalation via a face mask with the actual individual dose calculated by measuring the breathing of each dog. It can also be used for detecting any drug-related effects on the breathing pattern. A novel compound for potential administration by inhalation
Effects of inhalation exposure of methacholine on intra-pleural pressure, airway resistance and compliance in conscious telemetered rats Rachel Armstrong, Sarah Donington, Simon Moore, Peter Davies, Stephen Jordan, Ken Meecham Huntingdon Life Sciences Ltd, Alconbury, Cambs, United Kingdom Lung airflow disorders can be evaluated in animal models by measuring total pulmonary resistance or compliance during tidal breathing or mechanical ventilation. Airway resistance and compliance are commonly measured in anaesthetised animals due to the need for direct measurement of pleural pressure. However, anaesthetised preparations alone are not suitable for assessment of drug-induced changes in ventilation or chronic measurements of airflow obstruction. Assessment of intra-pleural pressure in conscious animals enables dynamic measurements of airflow resistance and compliance in spontaneously breathing animals using a pressure-sensitive catheter inserted into the oesophageal wall connected to a telemetry device. Murphy et al. developed this technique over 10 years ago but the success of this technique in Contract Research Organisations has been limited. The purpose of this study was to therefore evaluate the potential effect of methacholine on intra-pleural pressure (IPP), dynamic compliance and resistance, in conscious restrained telemetered rats. This was a validation study to assess the suitability of techniques and procedures developed to measure respiratory parameters. Eight male Sprague Dawley rats were implanted with DSITM telemetry transmitters with the pressure catheter inserted into the serosal layer of the oesophageal wall and advanced into the thoracic cavity. Animals were then habituated to head out plethysmographs over 5 consecutive days. Pre-dose basal levels of resistance, compliance and other respiratory parameters were recorded for up to 45 min and animals received vehicle and increasing doses of methacholine via nose only inhalation exposure. The data suggested that a good pressure signal was achieved in telemetered rats at the time of surgery and during habituation to the plethysmographs. Dose-dependent increases in resistance and decreases in compliance were observed, following methacholine exposure demonstrating the validity of the system. The respiratory data obtained suggests that this model has the potential to be used on respiratory safety pharmacology and toxicology studies. doi:10.1016/j.vascn.2012.08.137