Rat cardiovascular telemetry: Marginal distribution applied to positive control drugs.

Cardiovascular effects are considered frequent during drug safety testing. This investigation aimed to characterize the pharmacological response of the conscious telemetered rat in vivo model to known cardiovascular active agents. These effects were analyzed using statistical analysis and cloud representation with marginal distribution curves for the contractility index and heart rate as to assess the effect relationship between cardiac variables. Arterial blood pressure, left ventricular pressure, electrocardiogram and body temperature were monitored. The application of data cloud with marginal distribution curves to heart rate and contractility index provided an interesting tactic during the interpretation of drug-induced changes particularly during selective time resolution (i.e. marginal distribution curves restricted to Tmax). Taken together, the present data suggests that marginal distribution curves can be a valuable interpretation strategy when using the rat cardiovascular telemetry model to detect drug-induced cardiovascular effects. Marginal distribution curves could also be considered during the interpretation of other inter-dependent parameters in safety pharmacology studies.

Evaluation of a novel ECG lead placement method in telemetered freely moving cynomolgus monkeys: assessment of an intravascular biopotential lead.

INTRODUCTION: ECG is considered as a critical biomarker of cardiac safety pharmacology. ECG signal quality is essential for accurate interval quantification and automated arrhythmia detection. METHODS: We evaluated ECG signal quality over a 6 month period from 15 cynomolgus monkeys with radiotelemetry transmitters using biopotential leads where the negative lead was inserted in the jugular vein and advanced to the superior vena cava (intravascular lead) and the positive lead was placed on the diaphragm at the apex of the heart (diaphragmatic lead). Signal noise and signal-to-noise ratio from this implantation methodology were compared with signals obtained from animals with subcutaneous ECG lead. Macroscopic pathology and histopathology associated with the intravascular lead were evaluated at 6 months post-implantation in six monkeys. RESULTS: The ECG morphology obtained with the intravascular/diaphragmatic lead placement was comparable to conventional subcutaneous ECG (emulating Lead II) but presented higher amplitudes (P-wave +50.0%; R-wave +30.0%). Signal noise showed a circadian cycle of changes in magnitude for subcutaneous ECG leads that was not observed with this method. The intravascular/diaphragmatic lead placement presented a higher signal-to-noise ratio than subcutaneous ECG leads. No macroscopic abnormality was observed to be associated with the intravascular lead. Mild thickening of the intima/subintima with mild intimal proliferation of the cranial vena cava surrounding the intravascular lead were noted at histopathological examination. DISCUSSION: The intravascular/diaphragmatic ECG lead placement in cynomolgus monkeys provided reduced signal noise and elevated P-QRS-T amplitudes. The intravascular lead was well tolerated and appeared suitable for chronically instrumented cardiovascular safety pharmacology studies. Further assessments would be warranted to evaluate the potential of this methodology in other species.

Cardiovascular and respiratory safety pharmacology in Göttingen minipigs: Pharmacological characterization.

INTRODUCTION: Similarities between pigs and humans support the relevance of Göttingen minipigs for regulatory safety pharmacology. The minipig is the species of choice for cardiovascular safety pharmacology when pivotal repeat toxicology studies are conducted in this species. METHODS: 4 male Göttingen minipigs with cardiovascular telemetry transmitters received intravenous saline, esmolol (0.5, 1, 2, 4 and 8mg/kg), medetomidine (0.04mg/kg), remifentanil (0.5, 1, 2, 4, 8 and 16µg/kg) and dopamine (2, 8, 10, 20, 30 and 50µg/kg/min) and oral sotalol (3 and 10mg/kg). Respiratory monitoring was conducted in 3 male and 3 female Göttingen minipigs receiving intravenous saline and methacholine (0, 3.4, 13.5 and 68µg/kg). RESULTS: Heart rate (HR) corrected QT was optimal with a method based on analysis of covariance (QTca) followed by Fridericia's standard formula. Esmolol induced a decrease in HR. Medetomidine was associated with an initial hypertension with bradycardia followed by sustained hypotension, bradycadia and prolonged QTc. Remifentanil induced a dose-dependent QTc shortening with an increase in arterial pressures. Sotalol caused a decrease in HR and systolic arterial pressure with an increase in PR and QTc intervals. Dopamine induced an increase in arterial and pulse pressures. Methacholine increased tidal volume, respiratory rate and minute volume. DISCUSSION: The results suggest that the minipig is a valid alternative to other non-rodent species for cardiovascular and respiratory safety pharmacology studies when this species is justified.