Orthostatic hypotension can be investigated in conscious dogs as part of standard telemetry studies
1
measured by an oesophageal catheter in anaesthetised rats (32 Sprague Dawley). Surgical placement of the pressure-sensitive catheter was successful in 60% of rats as confirmed by a strong, physiological signal and high-resolution computerised tomography or histology. MCh dose dependently increased resistance in 2 teleme- tered rats. No apparent pharmacological response was observed in the other dosed rats due to large pressure signal variability. Baseline resistance approximately doubled in all anaesthetised rats (n=32) given 10 μg/kg/min MCh. Variability in the telemetry signal was associated with the posture adopted by the rat or the degree of movement within the HOP chamber, especially during dosing. Despite widespread consultation, extensive evaluation of habituation protocols and confirmation of catheter tip placement, we were not able to obtain reliable broncoconstrictor responses. Given the challenges associated with setting up this model, we would favour assessment of bronchoconstriction in anaesthetised rats. doi:10.1016/j.vascn.2010.11.018 Poster Number: 15 Board Number: 15 The use of whole body plethysmography to evaluate drug-induced changes in respiratory disorders: Sleep apneas, cough and bronchospasm Eric Delpy, Fabrice Infanti, Mathilde Loiseau, Christophe Drieu La Rochelle Biotrial Pharmacology, Rennes, France Whole body plethysmography (WBP) is widely used in safety pharmacology to investigate in conscious animals potential undesir- able pharmacodynamic effects of a substance on respiratory function. Proper characterisation of a breathing pattern includes measure- ments of respiratory rate, tidal and minute volume, inspiratory and expiratory times and peak flows. The aim of this study is to show that WBP could also be used to study drug-induced changes in respiratory disorders such as apneas, cough or bronchospasm. Spontaneous and post-sight sleep apneas were investigated in rats. Apneas were recorded from 30 min post dosing (time required for rats to fall asleep) and over 5 hours. In saline-treated animals, the number of apneas with a duration of more than 2.5 s was 34±3 and the total duration was 117±12 s. Diazepam (5 mg/kg, i.p.) decreased both the number (-20%) and the duration (-38%) of apneas. Cough was investigated in guinea-pigs and was induced by a 10-min citric acid inhalation. The number of coughs was counted by a trained experimenter based on characteristic animal posture, sound pro- duced and respiratory signal. The number of coughs in saline-treated animals was 25±2. Baclofen (0.1, 0.3 and 1 mg/kg s.c.) and codeine (10, 30 and 100 mg/kg p.o.) dose-dependently decreased the number of coughs. Bronchospasm was investigated both in ovalbumin- sensitised and non-sensitised guinea-pigs; bronchoconstriction was evaluated by the calculation of enhanced pause (Penh). In sensitised animals, ovalbumin (1-100 μg/kg i.v.) dose-dependently increased Penh. In non-sensitised animals, histamine (0.3-30 μg/kg i.v.) dose- dependently increased Penh and this effect was inhibited by mepyramine. These results show that WBP is appropriate to evaluate the effects of new chemical entities on respiratory disorders such as sleep apneas, cough and bronchospasm. doi:10.1016/j.vascn.2010.11.019 Poster Number: 16 Board Number: 16 Orthostatic hypotension can be investigated in conscious dogs as part of standard telemetry studies Nicola Smith, Matt Skinner, Pierre Lainee, Jackie Moors, Stewart Brown, Amy Deaville, Jean-Pierre Valentin AstraZeneca R&D, Macclesfield, Cheshire, United Kingdom Despite being a common cardiovascular adverse event in Phase 1 clinical trials, orthostatic hypotension (OH) is not routinely investi- gated during standard preclinical studies. The aim of this work was to validate a dog tilt model designed to assess OH. Four to six dogs implanted with DSI telemetry transmitters were orally dosed on separate occasions with Prazosin (0.01, 0.03 and 0.1 mg/kg), Captopril (3, 30 and 100mg/kg), Verapamil (1, 5 and 15 mg/kg), Atenolol (1, 3 and 10 mg/kg) or vehicle. Heart Rate and systolic blood pressure (SBP) were recorded while the dogs were exposed to a 1-minute head-up postural change of approximately 90° to induce OH at set timepoints pre and post-dose. Under control conditions, orthostatic tilt elicited an increase in SBP maintained for the duration of the tilt and an initial transient tachycardia. Prazosin and Captopril caused a decrease in the tilt-evoked increase in SBP (-75% and –30% vs vehicle, respectively), and increased tachycardia (27% and 57% vs vehicle, respectively). Verapamil caused an increase in the tilt-evoked tachycardia (176% vs vehicle) with minimal effect on the SBP response. Atenolol caused a decrease in tilt-evoked tachycardia (-69% vs vehicle) without affecting the SBP response. (% Values show max. change). Results correlate with the potency for these reference compounds to induce OH in man and demonstrate that the dog tilt is sensitive enough to identify potential OH inducers. These tests can be included in the ICH S7A/B telemetry designs to refine CV preclinical assessments prior to the first clinical trials. doi:10.1016/j.vascn.2010.11.020 Poster Number: 17 Board Number: 17 Using the conscious telemetered rat for early in vivo ECG safety studies: QT interval measurement and correction Oladipupo Adeyemi, Sonia Roberts, Jolie Harris, Mark Dewhurst Pfizer Global Research & Development, Sandwich, United Kingdom The QT interval of the ECG represents the time from the start of ventricular depolarisation to the end of repolarisation. QT varies inversely with heart rate (HR) in dogs, primates and man; however, this relationship was previously reported to be absent in rats1. In addition, the lack of IKr-channel function in repolarisation in rats, has limited the interest in ECG measurements from this species. The aim of this study was to investigate further the utility of QT interval measurements in conscious telemetered rats. QT was measured from the Q-point to the end of the ST-complex in untreated male Sprague-Dawley rats (n=7, 450-650 g) over 23 hrs. QT was inversely correlated to HR (r2 = 0.87), and directly correlated to RR (r2= 0.89). QTc was calculated using the slope of the linear regression line to correct to a HR of 350 bpm. Other methods of correction (Bazett and Fridericia) were also investigated; however, these did not correct for changes in HR over the range studied. The ECG effects of two compounds, PF-x and cisapride (3, 10 and 30 mg/kg p.o.) were Abstracts e6
-
Upload
nicola-smith -
Category
Documents
-
view
212 -
download
0
Transcript of Orthostatic hypotension can be investigated in conscious dogs as part of standard telemetry studies
measured by an oesophageal catheter in anaesthetised rats (32Sprague Dawley). Surgical placement of the pressure-sensitivecatheter was successful in 60% of rats as confirmed by a strong,physiological signal and high-resolution computerised tomography orhistology. MCh dose dependently increased resistance in 2 teleme-tered rats. No apparent pharmacological response was observed inthe other dosed rats due to large pressure signal variability. Baselineresistance approximately doubled in all anaesthetised rats (n=32)given 10 μg/kg/min MCh. Variability in the telemetry signal wasassociated with the posture adopted by the rat or the degree ofmovement within the HOP chamber, especially during dosing.Despite widespread consultation, extensive evaluation of habituationprotocols and confirmation of catheter tip placement, we were notable to obtain reliable broncoconstrictor responses. Given thechallenges associated with setting up this model, we would favourassessment of bronchoconstriction in anaesthetised rats.
doi:10.1016/j.vascn.2010.11.018
Poster Number: 15Board Number: 15
The use of whole body plethysmography to evaluate drug-inducedchanges in respiratory disorders: Sleep apneas, coughand bronchospasmEric Delpy, Fabrice Infanti, Mathilde Loiseau,Christophe Drieu La Rochelle
Biotrial Pharmacology, Rennes, France
Whole body plethysmography (WBP) is widely used in safetypharmacology to investigate in conscious animals potential undesir-able pharmacodynamic effects of a substance on respiratory function.Proper characterisation of a breathing pattern includes measure-ments of respiratory rate, tidal and minute volume, inspiratory andexpiratory times and peak flows. The aim of this study is to show thatWBP could also be used to study drug-induced changes in respiratorydisorders such as apneas, cough or bronchospasm. Spontaneousand post-sight sleep apneas were investigated in rats. Apneas wererecorded from 30 min post dosing (time required for rats to fallasleep) and over 5 hours. In saline-treated animals, the number ofapneas with a duration of more than 2.5 s was 34±3 and the totalduration was 117±12 s. Diazepam (5 mg/kg, i.p.) decreased boththe number (-20%) and the duration (-38%) of apneas. Cough wasinvestigated in guinea-pigs and was induced by a 10-min citricacid inhalation. The number of coughs was counted by a trainedexperimenter based on characteristic animal posture, sound pro-duced and respiratory signal. The number of coughs in saline-treatedanimals was 25±2. Baclofen (0.1, 0.3 and 1 mg/kg s.c.) and codeine(10, 30 and 100 mg/kg p.o.) dose-dependently decreased the numberof coughs. Bronchospasm was investigated both in ovalbumin-sensitised and non-sensitised guinea-pigs; bronchoconstriction wasevaluated by the calculation of enhanced pause (Penh). In sensitisedanimals, ovalbumin (1-100 μg/kg i.v.) dose-dependently increasedPenh. In non-sensitised animals, histamine (0.3-30 μg/kg i.v.) dose-dependently increased Penh and this effect was inhibited bymepyramine. These results show that WBP is appropriate to evaluatethe effects of new chemical entities on respiratory disorders such assleep apneas, cough and bronchospasm.
doi:10.1016/j.vascn.2010.11.019
Poster Number: 16Board Number: 16
Orthostatic hypotension can be investigated in conscious dogs aspart of standard telemetry studiesNicola Smith, Matt Skinner, Pierre Lainee, Jackie Moors,Stewart Brown, Amy Deaville, Jean-Pierre Valentin
AstraZeneca R&D, Macclesfield, Cheshire, United Kingdom
Despite being a common cardiovascular adverse event in Phase 1clinical trials, orthostatic hypotension (OH) is not routinely investi-gated during standard preclinical studies. The aim of this work was tovalidate a dog tilt model designed to assess OH. Four to six dogsimplanted with DSI telemetry transmitters were orally dosed onseparate occasions with Prazosin (0.01, 0.03 and 0.1 mg/kg), Captopril(3, 30 and 100 mg/kg), Verapamil (1, 5 and 15 mg/kg), Atenolol (1, 3and 10 mg/kg) or vehicle. Heart Rate and systolic blood pressure(SBP) were recorded while the dogs were exposed to a 1-minutehead-up postural change of approximately 90° to induce OH at settimepoints pre and post-dose. Under control conditions, orthostatictilt elicited an increase in SBP maintained for the duration of the tiltand an initial transient tachycardia. Prazosin and Captopril causeda decrease in the tilt-evoked increase in SBP (-75% and –30% vsvehicle, respectively), and increased tachycardia (27% and 57% vsvehicle, respectively). Verapamil caused an increase in the tilt-evokedtachycardia (176% vs vehicle) with minimal effect on the SBPresponse. Atenolol caused a decrease in tilt-evoked tachycardia(-69% vs vehicle) without affecting the SBP response. (% Valuesshow max. change). Results correlate with the potency for thesereference compounds to induce OH in man and demonstrate thatthe dog tilt is sensitive enough to identify potential OH inducers.These tests can be included in the ICH S7A/B telemetry designs torefine CV preclinical assessments prior to the first clinical trials.
doi:10.1016/j.vascn.2010.11.020
Poster Number: 17Board Number: 17
Using the conscious telemetered rat for early in vivo ECG safetystudies: QT interval measurement and correctionOladipupo Adeyemi, Sonia Roberts, Jolie Harris, Mark Dewhurst
Pfizer Global Research & Development, Sandwich, United Kingdom
The QT interval of the ECG represents the time from the start ofventricular depolarisation to the end of repolarisation. QT variesinversely with heart rate (HR) in dogs, primates and man; however,this relationship was previously reported to be absent in rats1. Inaddition, the lack of IKr-channel function in repolarisation in rats,has limited the interest in ECG measurements from this species. Theaim of this study was to investigate further the utility of QT intervalmeasurements in conscious telemetered rats. QT was measuredfrom the Q-point to the end of the ST-complex in untreated maleSprague-Dawley rats (n=7, 450-650 g) over 23 hrs. QT was inverselycorrelated to HR (r2=0.87), and directly correlated to RR (r2=0.89).QTc was calculated using the slope of the linear regression line tocorrect to a HR of 350 bpm. Other methods of correction (Bazett andFridericia) were also investigated; however, these did not correctfor changes in HR over the range studied. The ECG effects of twocompounds, PF-x and cisapride (3, 10 and 30 mg/kg p.o.) were
Abstractse6
