Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone.

Introduction: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval.

Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP).

Introduction: Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics.

Intravenous solid tip ECG lead placement in telemetry implanted dogs: Part 2: High quality telemetry signals yield high sensitivity to drug-induced changes.

Introduction: Dogs are commonly used in cardiovascular drug safety assessment, and implanted telemetry models include subcutaneous or epicardial electrocardiogram (ECG) electrode placements. The purpose of this study was to determine the sensitivity of a canine telemetry model with intravenous ECG lead placement: the negative ECG lead (solid tip) inserted into the jugular vein and the positive lead sutured to the diaphragm. Reference drugs were administered to test the sensitivity to drug-induced changes.

Left thoracotomy surgical approach for chronic instrumentation in dogs and monkeys providing high-quality electrocardiogram signals.

Introduction: Assessment of cardiovascular parameters, including the electrocardiogram (ECG) is required by the regulatory guidelines. In safety pharmacology studies, this is typically done using chronically implanted radiotelemetry devices in non-rodent species.

Methods: We compared ECG signal quality from ten male beagle dogs and 10 male cynomolgus monkeys with telemetry transmitters implanted using two surgical approaches: i) epicardial ECG lead placement via single incision, left side thoracotomy or ii) subcutaneous ECG lead placement via laparotomy.

Kinetics of selected di-n-butyl phthalate metabolites and fetal testosterone following repeated and single administration in pregnant rats.

Human exposure to phthalic acid diesters occurs through a variety of pathways as a result of their widespread use in consumer products and plastics. Repeated doses of di-n-butyl phthalate (DBP) from gestation day (GD) 12 to 19 disrupt testosterone synthesis and male sexual development in the fetal rat. Currently little is known about the disposition of DBP metabolites, such as monobutyl phthalate (MBP) and its glucuronide conjugate (MBP-G), during gestation after repeated exposure to DBP.

Tissue exposures to free and glucuronidated monobutylyphthalate in the pregnant and fetal rat following exposure to di-n-butylphthalate: evaluation with a PBPK model.

Human exposure to phthalic acid diesters occurs through a variety of pathways as a result of their widespread use in plastics. Repeated doses of di-n-butylphthalate (DBP) from gestation day (GD) 12 to 19 disrupt testosterone synthesis and male sexual development in the fetal rat. To gain a better understanding of the relationship of the target tissue (testes) dose to observed developmental effects, the pharmacokinetics of monobutyl phthalate (MBP) and its glucuronide (MBP-G) were examined in pregnant and fetal rats following single and repeated administration of DBP from GD 12-19.

Pharmacokinetics of monobutylphthalate, the active metabolite of di-n-butylphthalate, in pregnant rats.

Di-n-butylphthalate (DBP) is a phthalic acid ester used as a plasticizer and solvent. DBP is a developmental toxicant in rats and mice, with adverse effects arising from the monoester metabolite monobutyl phthalate (MBP). The objective of this study was to evaluate the pharmacokinetics of MBP and monobutyl phthalate glucuronide (MBP-G) in pregnant rats following intravenous (i.

Kinetics of adsorption of beta-amyloid peptide Abeta(1-40) to lipid bilayers.

The Alzheimer's disease-related peptide beta-amyloid (Abeta) is toxic to neurons. The toxicity of the peptide appears to require conversion of the monomeric form to an aggregated fibrillar species. The interaction of Abeta with cell membranes has attracted interest as one plausible mechanism by which the peptide exerts its toxic activity.