Biomedical subjects

Michael Markert

Publications and source records attributed to Michael Markert.

3 recordsLinked to original sources

PubMed2006

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.

Animals↗

PubMedDate not supplied

Developing a strategy for the nonclinical assessment of proarrhythmic risk of pharmaceuticals due to prolonged ventricular repolarization.

The aspects for developing a strategy for the preclinical testing of drug candidates for proarrhythmic potential are presented. The rationale for such a strategy reflects primarily the needs for efficient and scientifically based drug development and also attempts to anticipate the possible outcomes of the currently ongoing regulatory activity (ICH S7b and E14). Whereas a wealth of new data have emerged over the past few years, demonstrating the utility of test systems for detecting drug effects on myocardial repolarization, the current regulatory trend appears to not use such data for the clinical trial design or risk assessment. Nevertheless, certain types of preclinical tests are highly recommended for optimizing drug development, despite their still questionable regulatory acceptance. This includes (1) testing for blockade of I(Kr) or hERG-mediated potassium current in heterologous cell systems, (2) measurement of effects on the myocardial action potential in vitro; and (3) assessment of effects on the ECG in a well-conducted in vivo study. Due to their requirement for little compound, the first two in vitro tests lend themselves for early safety testing of drug candidates still in the lead optimization phase of drug discovery; together, they form a useful and predictive in vitro assessment. This strategy is not new but reflects what was initially suggested by the Committee for Proprietary Medicinal Products (CPMP) some years ago. However, the validation of such a strategy and its utility in drug development is now well established and recommended, independent from future regulatory requirements.

Action Potentials↗

PubMedDate not supplied

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.

Administration, Inhalation↗