Validation of the normal, freely moving Göttingen minipig for pharmacological safety testing.

INTRODUCTION: The objective of this study was to use a newly established cardiovascular model using freely moving minipigs to document the hemodynamic and electrocardiographic effects of known pharmacological agents. The data generated are to serve as the basis of pharmacological drug safety evaluations using this new model. METHODS: 6 Göttingen minipigs were equipped with a radiotelemetry system (ITS). Following a recovery period, aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously recorded throughout an 8 h monitoring period following oral administration of one of the test agents or vehicle. Notocord HEM 4.2 software was used for data acquisition. One known hERG blocker (moxifloxacin (30, 100 or 300 mg/kg)) and one non-selective beta-adrenoreceptor antagonist (propranolol (3, 10 or 20 mg/kg)) were tested in the model using a cross-over study design in 6 pigs. RESULTS: We obtained high signal quality and found stable hemodynamic parameters with low intrinsic heart rates in the Göttingen minipig under resting, pre-treatment conditions. After oral dosing of moxifloxacin, a substantial, dose-dependent increase in the QT-interval duration could be shown, as anticipated for this agent. After propranolol administration, a decrease in HR and left ventricular dP/dt was detected as expected for a beta-adrenoceptor blocking agent. DISCUSSION: The present data demonstrate that using this model in conscious, chronically instrumented Göttingen minipigs, a cross-over study with six animals was sensitive enough to detect a dose-dependent QT prolongation when moxifloxacin was administered in oral doses leading to clinically relevant plasma drug concentrations. Additionally, we could demonstrate the expected propranolol-induced effects on heart rate and myocardial contractility, despite the low intrinsic resting heart rates in these minipigs. These data support the use of the Göttingen minipig as a sensitive cardiovascular and electrocardiographic model for the testing of new pharmaceutical agents.

Evaluation of cardiovascular and ECG parameters in the normal, freely moving Göttingen Minipig.

INTRODUCTION: The objective of this study was to evaluate the normal cardiovascular and ECG parameters in freely moving minipigs and to use these data as the basis of pharmacological drug safety evaluation. METHODS: 7 Göttingen Minipigs were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously monitored. Notocord HEM 4.2 software was used for data acquisition. Power calculations for the various parameters were done to assess appropriate sample sizes. RESULTS: We obtained excellent signal quality and found stable hemodynamic parameters with a low intrinsic heart rate in the Göttingen Minipig. After oral dosing of vehicle, the hemodynamic parameters returned quickly to baseline values indicating that the procedure was well tolerated. The heart rate dependency of the QT interval had to be corrected individually. A sufficient power could be achieved with a sample size of 4 due to the low variability of the parameters measured. DISCUSSION: These are, to our knowledge, the first data documenting the course of systemic arterial and ventricular hemodynamic parameters in the freely moving Göttingen Minipig over 24 h. As such, they may serve as a basis for future studies in which drug effects are studied in these animals.

The value added by measuring myocardial contractility 'in vivo' in safety pharmacological profiling of drug candidates.

INTRODUCTION: The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. METHODS: Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt-heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt-heart rate relationship. RESULTS: There was a clear LVdP/dt-HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship. DISCUSSION: Contractility of the myocardium is regulated by autonomic input activating primarily myocardial beta1-adrenoceptors, but it is also affected by the "force-frequency" relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.

Optimizing the experimental environment for dog telemetry studies.

INTRODUCTION: The objective of this study was to test the influence of housing conditions on hemodynamics during cardiovascular general pharmacological studies. Our goal was to optimize both the quality of the data through an optimization of the physiological conditions, as well as to ensure the dog's well-being in general pharmacological studies. METHODS: Two groups of four dogs were equipped with radiotelemetry transmitters and continuously monitored in two different housing models. Model I consisted of 4 cages, two on each site of a corridor. Model II consisted of 4 cages positioned in a row, where the bordering cages were not separated with a metal plate. The physiological status of the dogs in the different housing models was based on the frequency of vocalizations and the average resting heart rate, as well as video monitoring. RESULTS: The housing arrangement during the study had a remarkable effect on the hemodynamics measured. The hemodynamic parameters were best when the dogs were housed with their usual run mate. In this setting, they have impressively low average heart rates of about 60 bpm during the entire study, was associated with fewer vocalizations. DISCUSSION: This study demonstrated that the quality of the acquired cardiovascular data for conscious dogs is dependent on the pen configuration and group make-up during a study.

A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs.

INTRODUCTION: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device. METHODS: Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system. Administration by inhalation was achieved using a novel delivery device. The Respimat device is a propellant-free inhaler to deliver aerosols from solutions. The new system was evaluated using Formoterol with four dogs using a 4 x 4 Latin square design. Three doses of Formoterol (0.6, 1.2, and 2.4 microg/kg, dissolved in 60% ethanol) were administered by inhalation together with a vehicle (60% ethanol) treatment by applying three inhalations, each consisting of 10 microl solution. RESULTS: Formoterol increased HR, QRS-interval, QT-interval, and LVPdP/dtmax and dose-dependently decreased systolic and diastolic BP. This effect lasted up to 14 h. DISCUSSION: Drug administration by inhalation in the conscious labrador dog using the Respimat is a useful new model for safety pharmacology studies of new drug candidates that are intended to be given by inhalation in the clinic.