Activity in Group-Housed Home Cages of Mice as a Novel Preclinical Biomarker in Oncology Studies.

Background: Improving experimental conditions in preclinical animal research is a major challenge, both scientifically and ethically. Automated digital ventilated cages (DVC) offer the advantage of continuous monitoring of animal activity in their home-cage. The potential utility of this technology remains understudied and deserves investigation in the field of oncology.

Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction.

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined.

Detecting drug-induced prolongation of the QRS complex: new insights for cardiac safety assessment.

Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I(Na)) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I(Na), this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation.

Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic).

The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds.

Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds.

Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines.

Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure-activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure-activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows.