The incidence of spontaneous arrhythmias in telemetered beagle dogs, Göttingen Minipigs and Cynomolgus non-human primates: A HESI consortium retrospective analysis.

Introduction: Characterization of the incidence of spontaneous arrhythmias to identify possible drug-related effects is often an important part of the analysis in safety pharmacology studies using telemetry.

Methods: A retrospective analysis in non-clinical species with and without telemetry transmitters was conducted. Electrocardiograms (24 h) from male and female beagle dogs (n = 131), Göttingen minipigs (n = 108) and cynomolgus non-human primates (NHP; n = 78) were analyzed.

Evaluation of levocetirizine in beagle dog and cynomolgus monkey telemetry assays: Defining the no QTc effect profile by timepoint and concentration-QTc analysis.

In prior clinical studies, levocetirizine (LEVO) has demonstrated no effect on ventricular repolarization (QTc intervals), therefore it is a relevant negative control to assess in nonclinical assays to define low proarrhythmic risk. LEVO was tested in beagle dog and cynomolgus monkey (nonhuman primate [NHP]) telemetry models to understand the nonclinical-clinical translation of this negative control. One oral dose of vehicle, LEVO (10 mg/kg/species) or moxifloxacin (MOXI; 30 mg/kg/dog; 80 mg/kg/NHP) was administered to instrumented animals (N = 8/species) using a cross-over dosing design; MOXI was the in-study positive control.

Evaluation of moxifloxacin in canine and non-human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration-QTc analysis.

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose-response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data.

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

Introduction: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP).

Methods: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays.

Results: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology.

Cardiovascular response to small-molecule APJ activation.

Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and has the potential to be a novel target to treat HF. Intravenous administration of apelin improves cardiac function acutely in patients with HF.

The West coast regional safety pharmacology society meeting update: Filling translational gaps in safety assessment.

The Safety Pharmacology Society (SPS) held a West Coast Regional Meeting in Foster City, CA on November 14, 2018 at the Gilead Sciences Inc. site. The meeting was attended by scientists from the pharmaceutical and biotechnology industry, contract research organizations (CROs) and academia.

A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium.

Introduction: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.

Decreased contractility and altered responses to inotropic agents in myocytes from tachypacing-induced heart failure canines.

Contractility measurements using primary isolated cardiac myocytes (CM) have commonly been used in understanding the physiology and pharmacology of cellular mechanics. In the majority of studies, CM from healthy animals were used, and fewer studies were performed with CM from diseased hearts. To better understand the translational value of contractility on the cellular level of a diseased animal model, myocytes were isolated from left ventricles of a tachypacing-induced heart failure (HF) canine model, and their contractility was measured by recording sarcomere shortening using an image-based IonOptix video system.

Bioelectronic block of paravertebral sympathetic nerves mitigates post-myocardial infarction ventricular arrhythmias.

Background: Autonomic dysfunction contributes to induction of ventricular tachyarrhythmia (VT).

Objective: To determine the efficacy of charge-balanced direct current (CBDC), applied to the T1-T2 segment of the paravertebral sympathetic chain, on VT inducibility post-myocardial infarction (MI).

Methods: In a porcine model, CBDC was applied in acute animals (n = 7) to optimize stimulation parameters for sympathetic blockade and in chronic MI animals (n = 7) to evaluate the potential for VTs.

Premature Ventricular Contraction Coupling Interval Variability Destabilizes Cardiac Neuronal and Electrophysiological Control: Insights From Simultaneous Cardioneural Mapping.

Background: Variability in premature ventricular contraction (PVC) coupling interval (CI) increases the risk of cardiomyopathy and sudden death. The autonomic nervous system regulates cardiac electrical and mechanical indices, and its dysregulation plays an important role in cardiac disease pathogenesis. The impact of PVCs on the intrinsic cardiac nervous system, a neural network on the heart, remains unknown.

Bioelectronic neuromodulation of the paravertebral cardiac efferent sympathetic outflow and its effect on ventricular electrical indices.

Background: Neuromodulation of the paravertebral ganglia by using symmetric voltage controlled kilohertz frequency alternating current (KHFAC) has the potential to be a reversible alternative to surgical intervention in patients with refractory ventricular arrhythmias. KHFAC creates scalable focal inhibition of action potential conduction.

Objective: The purpose of this article was to evaluate the efficacy of KHFAC when applied to the T1-T2 paravertebral chain to mitigate sympathetic outflow to the heart.

Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig.

Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15-20%) aortic constriction.

Sympathetic nerve stimulation, not circulating norepinephrine, modulates T-peak to T-end interval by increasing global dispersion of repolarization.

Background: T-peak to T-end interval (Tp-e) is an independent marker of sudden cardiac death. Modulation of Tp-e by sympathetic nerve activation and circulating norepinephrine is not well understood. The purpose of this study was to characterize endocardial and epicardial dispersion of repolarization (DOR) and its effects on Tp-e with sympathetic activation.

Comprehensive analysis of cardiac arrhythmias in telemetered cynomolgus monkeys over a 6 month period.

Introduction: Cardiac arrhythmia findings can be a challenge to interpret and difficult to attribute to background incidence or test article treatment. Thus, there is a growing need to better understand arrhythmia incidence in the experimental animal models used to assess the cardiovascular safety of new drugs. Currently, there is little information on the frequency of spontaneous cardiac arrhythmias in the cynomolgus monkey.

Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain.

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit.

BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart.

Drug-induced cardiac arrhythmia, specifically Torsades de pointes, is associated with QT/QTc interval prolongation, thus prolongation of the QT interval is considered as a biomarker for Torsades de pointes risk (N Engl J Med 350:1013-1022, 2004). Specific inhibition of human ether-a-go-go-related gene (hERG) potassium channels has been recognized as the main mechanism for QT prolongation (Cardiovasc Res 58:32-45, 2003). This mechanism has been demonstrated for a variety of small-molecule agents, which access the inner pore of the hERG channel preferentially from inside the cell.

Regulation of CCL2 and CCL3 expression in human brain endothelial cells by cytokines and lipopolysaccharide.

Background: Chemokines are emerging as important mediators of CNS inflammation capable of activating leukocyte integrins and directing the migration of leukocyte subsets to sites of antigenic challenge. In this study we investigated the expression, release and binding of CCL2 (MCP-1) and CCL3 (MIP-1alpha) in an in vitro model of the human blood-brain barrier.

Methods: The kinetics of expression and cytokine upregulation and release of the beta-chemokines CCL2 and CCL3 were studied by immunocytochemistry and enzyme-linked immunosorbent assay in primary cultures of human brain microvessel endothelial cells (HBMEC).

A comparison of three software platforms for automated ECG analysis.

Introduction: Current regulatory guidelines attempt to standardize the models used to assess the safety aspects of new test compounds. However, they do not address the means of deriving the critical data. With the increased data volume that is a result of more extensive safety scrutiny and continuous data assessment, especially in cardiovascular telemetry studies, there is a clear need to assess the automated ECG analysis tools currently available on the market.

Assessment of two external telemetry systems (PhysioJacket and JET) in beagle dogs with telemetry implants.

Introduction: Regulatory guidelines recommend the use of conscious, unrestrained animals for comprehensive cardiovascular safety assessment of a new therapeutic agent. Cardiovascular safety pharmacology studies normally use internal telemetry (surgical implants) in free-moving animals to monitor key ECG endpoints, like the QTc interval, but this technical approach is highly resource intensive. In toxicology studies, ECG recording is also typically performed under chemical or physical restraint, which has a number of disadvantages, e.