The Toxicologist - Society of Toxicology

fects of new compounds are equally important to anticipate. Current development
in technology now allows simultaneous evaluation of ECG, systemic pressure and
Left Ventricular Pressure (LVP), a good indicator of myocardial contractility. The
aim of this study is to validate a model of chronically instrumented non human primate
(NHP) for the assessment of inotropic effect in conjunction with the evaluation
of effect on blood pressure, heart rate (HR) and ECG. A positive
(Pimobendan) and two negative inotropic drugs (Verapamil and Propranolol) were
tested. Pimobendan induces a rapid increase in dP/dt Max and a decrease dP/dt
Min and the LV Ejection Time, two other important representative parameters of
contractility. Verapamil and Propranolol caused a short and rapid decrease of dP/dt
Max and a rise of dP/dt Min and LV ejection time. Modification of HR (approx
50% decrease) was noted only after administration of Propranolol. No effects on
blood pressure or ECG parameters were reported. In conclusion, whilst no effects
on systemic blood pressure, HR and ECG recording were observed, modifications
of contractility parameters such as dP/dt Max, dP/dt Min and LV Ejection Time
were detected after administration of Pimobendan and Verapamil. Therefore, evaluation
of inotropic parameters in safety pharmacology provides valuable information
for the detection of risk of contractility of new drugs.
601 COMBINED CARDIOVASCULAR AND RESPIRATION
ASSESSMENT IN THE CONSCIOUS GÖTTINGEN
MINI-PIG FOLLOWING INHALATION
ADMINISTRATION OF ALBUTEROL.
S. Purbrick, S. A. Moore, E. Peake, V. Milner, H. Brown, D. Butler, A.
French, K. Melliti, G. Peake, D. Cameron, K. Meecham and C. J. Hardy.
Respiratory Safety Assessment, Huntingdon Life Sciences, Huntingdon, United
Kingdom.
The minipig is increasingly being used as a species of choice for toxicological and
pharmacological studies. We have gained significant experience in using the telemetered
minipig in safety pharmacology studies, administering test compounds via
several different routes. In this study we assessed the cardiovascular and respiratory
effects of inhaled administration of the beta-2-adrenergic agonist, Albuterol
(Salbutamol) to provide a positive control. Telemetered Gottingen minipigs (ca. 22
kg) were acclimatised to custom designed facemasks over a period of 10 days on 8
separate occasions. Throughout the mask-wearing procedures, the minipigs were
acclimatised to harnesses that were fixed to poles on restraint tables. Initial duration
of mask attachment was 30 min, gradually increasing to 90 min by the end of acclimatisation.
In addition to wearing the mask, the minipigs were also acclimatised
to an initial airflow (7 L/min per minipig) for 15 min. To assess the impact of the
inhalation procedures, Albuterol was administered as a liquid droplet aerosol with
water used as the vehicle following completion of the acclimatisation process. The
0.35 mg/kg Albuterol delivered dose (mass median aerodynamic diameter of 1.7
μm) caused decreases in arterial blood pressures and concurrent heart rate increased
with a maximum change of approximately 136%, at 0.25 h, along with shortening
of the ECG lead II PR and QT interval (coinciding with the observed heart rate
changes). These changes in haemodynamics lasted for up to 18 h. The responses to
Albuterol were similar in magnitude to those observed previously in the beagle dog.
Albuterol caused an increase in tidal volume resulting in a respective increase in respiratory
minute volume (RMV) from approximately 4.0 L/min to 5.5 L/min and
continued for at least 90 min post dose. The pre-dose RMV value was noticeably
lower than that predicted by some published algorithms.
602 ECG RECORDING METHODS IN DOG TOXICOLOGY
STUDIES: WHAT IS THE REAL BENEFIT OF EXTERNAL
TELEMETRY ?
P. Lainee, J. Schofield, C. Draper, K. Elliott, C. Barnard and J. Valentin. Global
Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United
Kingdom.
Over the last years, ECG recording methods in non-rodent toxicology studies have
significantly changed. Standard ECG snapshot recordings (STD) with manual
readings have been replaced by computerised systems and more recently by continuous
acquisition using external telemetry (EXT). Initially technically challenging,
EXT is now used routinely to frontload electrophysiology assessments or combine
Safety Pharmacology (SP) and Toxicology study designs. 39 preclinical projects
were reviewed to compare the quality of data obtained with each method and evaluate
their potential to predict the adverse effects observed in SP telemetry studies.
Baseline dog data (STD: n=291, EXT: n=177) were analysed for statistical power,
i.e. to determine the threshold to obtain a statistical difference (p