Internodal conduction pathways: revisiting a century-long debate on their existence, morphology, and location in the context of 2023 best science.

Internodal conduction pathways are the communication apparatus of the cardiac conduction system conveying sinus node action potentials (APs) to the atrioventricular node and atrial working myocytes. In 1910, at the Deutschen Pathologischen Gesellschaft held in Erlangen, Charles Thörel related his discovery of an internodal bundle structured with Purkinje-like cells, which was rejected by the participants, who endorsed the then-leading doctrine that atrial contractile cardiomyocytes operate as internodal routes. Starting in 1963 and for five subsequent decades, two groups have revisited this issue.

Remembering the canonical discoverers of the core components of the mammalian cardiac conduction system: Keith and Flack, Aschoff and Tawara, His, and Purkinje.

The mammalian cardiac conduction system (CCS) is a multifaceted continuum of electrically distinct, interconnected constructs within the myocardial mass. The key components are the sinus node (SAN), the atrioventricular node (AVN), the His bundle (HB), and the Purkinje fiber network (PF), the latter serendipitously discovered by Jan Evangelista Purkinje in 1839 in the sheep ventricle. In 1893, Wilhelm His, Jr.

Nonclinical cardiovascular safety assessment of thioridazine: Impact of autonomic tone, body temperature, and choice of species.

Pending updates to ICH S7B/E14 guidelines will enable the substitution of human TQT studies with support from concomitant negative hERG and non-rodent CV studies. This retrospective analysis compared the effects of thioridazine (THD) (5-20 mg/kg) on heart rate (HR), blood pressure (BP), body temperature (Tc), and QT in the dog (n = 6), cynomolgus monkey (n = 4), and Goettingen minipig (n = 4) with data from previously completed studies employing crossover designs. As QT measurements are confounded by HR and Tc changes, QT effects were individually corrected for changes in HR (QTca) and Tc (QTcaT).

19th Annual Meeting of the Safety Pharmacology Society: regulatory and safety perspectives for advanced therapy medicinal products (cellular and gene therapy products).

This report summarizes and discusses talks delivered at an educational course offered during the 2019 Annual Meeting of the Safety Pharmacology Society on advanced therapy medicinal products (ATMPs) and cell gene therapeutic products (CGTPs). ATMPs and CGTPs comprise gene and cell therapy medicinal products, tissue-engineered products, or the incorporation of one of these products into a medical device. Cited examples of ATMPs are autologous CD34 cells encoding for the β-globin gene, CAR (chimeric antigen receptor)-T cell immunotherapy medicines, genome editing products, and engineered heart muscle patches constructed from induced human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for remuscularization of the failing human heart.

18 Annual Meeting of the Safety Pharmacology Society: drug safety assessment on gastrointestinal system functions.

: The 18 Annual Meeting of the Safety Pharmacology Society included a session dedicated to the assessment of drug safety on the gastrointestinal (GI) system.: GI anatomy, physiology, adverse effects (AEs) of chemical and biological therapies, and approaches to mitigate them.: GI AEs, albeit common and generally of minor intensity, may prolong clinical development time and reduce patient compliance.

18th world congress of basic and clinical pharmacology: thought-provoking lectures on drug safety issues.

: Pharmacology of the Future for Science, Drug Development and Therapeutics was the leitmotif which guided the presentations at the 18th World Congress of Basic and Clinical Pharmacology held in Kyoto in July 2018 (WPC2018).: Of the 380 invited lectures, this report reviews the opening presentation on immune checkpoint inhibitors and three talks dealing with drug safety issues (irreproducibility of nonclinical data, clinical Phase 1 catastrophes by TGN1214 and BIA-102,474-101 in healthy volunteers, and Phase I sentinel dosing to reduce risk to clinical study participants).: The nonclinical safety assessment of drug candidates preceding clinical investigations requires the adoption of more human predictable biological assays and a careful and critical analysis of all available knowledge on a candidate to ensure the safety of clinical trial participants.

Human organotypic bioconstructs from organ-on-chip devices for human-predictive biological insights on drug candidates.

Introduction: Historically, drug development and marketing failures have been experienced by pharma organizations largely from insufficient human-predictability of biological data.

Areas Covered: Organs-on-chips (OOCs) are emerging, cutting edge microphysiology systems for production of microengineered three-dimensional, miniature organotypic constructs obtained by cultivating small amounts of human primary, or induced pluripotent stem, cells in native-like microhabitats. These preparations circumvent experimental limitations inherent to animal assays and two-dimensional monolayers, the mainstay core biological assays of traditional drug research.

Reminiscing about Jan Evangelista Purkinje: a pioneer of modern experimental physiology.

This article reminisces about the life and key scientific achievements of Jan Evangelista Purkinje (1787-1869), a versatile 19th century Czech pioneer of modern experimental physiology. In 1804, after completing senior high school, Purkinje joined the Piarist monk order, but, after a 3-yr novitiate, he gave up the religious calling "to deal more freely with science." In 1818, he earned a Medical Doctor degree from Prague University by defending a dissertation on intraocular phenomena observed in oneself.

15 Annual Meeting of the Safety Pharmacology Society: Focus on traditional sensory systems.

Introduction: This report summarizes and comments key talks on the five traditional senses (ear, vestibular system, vision, taste, olfaction, and touch) which were delivered during the 2015 Annual Meeting of the Safety Pharmacology (SP) Society.

Areas Covered: The functional observational battery (FOB) can detect major candidate drug liabilities only on ear, touch and vision. Anatomy, physiology, pharmacology, and pathology notions on each sensory system introduce speaker talks.

Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation.

Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use.

Topics Covered: Key talks delivered at the 'CiPA on my mind' session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.

The prospective IQ-CSRC trial: A prototype early clinical proarrhythmia assessment investigation for replacing the ICH E14 thorough QTc (TQT) study.

Introduction: Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA).

Topics: The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT). Designed in accordance with the results of a simulation study by the FDA QT Interdisciplinary Review Team (IRT), it succeeded in correctly categorizing 5/5 established QTc-prolonging agents free of notable heart rate effects (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and the QTc-negative drug, levocetirizine.

14th Annual Meeting of the Safety Pharmacology Society: Threading through peripheral and central nervous system presentations.

The 2014 Annual Meeting of the Safety Pharmacology Society discussed pathophysiological mechanisms and novel investigational approaches to assess drug safety. The plenary keynote reviewed past, present, and future research on Alzheimer's disease. Polysomnography tools can uncover drug-induced sleep disturbances.

CiPA: Ongoing testing, future qualification procedures, and pending issues.

Introduction: The comprehensive in vitro proarrhythmia assay (CiPA) is a nonclinical, mechanism-based paradigm for assessing drug proarrhythmic liability.

Topics Covered: The first CiPA assay determines effects on cloned human cardiac ion channels. The second investigates whether the latter study-generated metrics engender proarrhythmic markers on a computationally reconstructed human ventricular action potential.

Telemetric assessment of social and single housing: Evaluation of electrocardiographic intervals in jacketed cynomolgus monkeys.

Introduction: Proactive efforts to socially house laboratory animals are a contemporary, important focus for enhancing animal welfare. Jacketing cynomolgus monkeys has been traditionally considered an exclusionary criterion for social housing based on unsubstantiated concerns that study conduct or telemetry equipment might be compromised. Our objective was to evaluate the effects of jacketing naïve, adolescent cynomolgus monkeys in different single and social housing types based on parallel comparisons of heart rate.

Comprehensive in vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: a visionary 21st century initiative.

Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the 2005 regulatory strategy recommended by the International Conference of Harmonization S7B guideline.

Areas Covered: CiPA consists of three components. The first assay evaluates candidate drug effects on key cardiac ion channels.

Comparative TQT analysis with three fully-automated platforms: comparison to core laboratory semi-automated results.

Background And Purpose: Technological advances in machine-read QT measurement now enable detailed and precise cardiac repolarization assessments. This study assessed the applicability of three state-of-art ECG measurement applications to provide reliable continuous analyses from data obtained in a positive thorough QT study previously characterized with sparse semi-automated measurements performed by an ECG core laboratory.

Methods: Continuous RR, QT, QTc measurements, and individual QT/RR relationships and their associated intra- and inter-subject variability were derived in parallel with BioQT, Ponemah PRO, and WinAtrec analysis software.

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

Introduction: In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic.

Pharmaceutical toxicology: designing studies to reduce animal use, while maximizing human translation.

Evaluation of the safety of new chemicals and pharmaceuticals requires the combination of information from various sources (e.g. in vitro, in silico and in vivo) to provide an assessment of risk to human health and the environment.

Pattern recognition analysis of digital ECGs: decreased QT measurement error and improved precision compared to semi-automated methods.

Background And Purpose: Machine-read QT measurements employing T-wave detection algorithms (ALG) are not accepted by regulatory agencies for the primary analysis of thorough QT (TQT) studies. Newly developed pattern recognition software (PRO) which matches ECG waveforms to user-defined templates may improve this situation.

Methods: We compared RR, QT, QTc, QT variability, T-end measurement errors, and individual QT rate correction factors and their associated coefficients of determination (R(2)) following ALG and PRO analysis.

Characterization of the human QT interval: novel distribution-based assessment of the repolarization effects of moxifloxacin.

The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer.

Comparison of telemetry and high-definition oscillometry for blood pressure measurements in conscious dogs: effects of torcetrapib.

This study compared torcetrapib-induced blood pressure (BP) changes simultaneously obtained by high-definition oscillometry (HDO) and telemetry. Male beagles (n = 6) received single oral doses of vehicle or torcetrapib at 10 or 30 mg/kg; BP were acquired simultaneously by HDO and telemetry from 2 h before dosage until 7 h afterward. Systolic, diastolic, and mean arterial pressures (MAP) and heart rate were compared by using Altman-Bland agreement analysis.

Sensitivity of common marmosets to detect drug-induced QT interval prolongation: moxifloxacin case study.

Introduction: Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization studies, but it has not been characterized in common marmosets which are uniquely suited to studies in early-stage development due to their small size and minimal test article requirements. The purpose of this study was to evaluate the sensitivity of the common marmoset to detect moxifloxacin-associated QT interval prolongation.

Methods: Eight telemetered common marmosets were monitored for 24 h following oral administration of moxifloxacin by gavage at 0, 10, 30, and 100 mg/kg using a Latin square design.

Application of probabilistic analysis for precisely correcting the QT interval for heart rate in telemetered common marmosets.

Introduction: QT intervals are strongly influenced by preceeding heart rate history and are also characterized by rate-independent variability, leading to difficulty in precise rate-correction of the raw QT interval. The present study elucidates a novel analytical method that effectively addresses this problematic phenomenon in telemetered common marmosets.

Methods: ECGs were collected from telemetered common marmosets (male and female) and analyzed by computerized algorithms.

Analysis of the nonclinical telemetered ECG: impact of logging rate and RR bin width in the dog and cynomolgus monkey.

Introduction: Species-dependent ECG differences may affect QT interval analysis. Among these are the range of QT and RR values, heart rate variability, and respiratory sinus arrhythmia (SA). Importantly, the effects of data logging rates and RR bin width (BW) on QT analysis have not been characterized in dogs and nonhuman primates.

Application of a probabilistic method for the determination of drug-induced QT prolongation in telemetered cynomolgus monkeys: effects of moxifloxacin.

Introduction: Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization safety studies, but it has not been characterized in the cynomolgus monkey. This important experimental animal species exhibits pronounced heart rate variability, complicating the temporal evaluation of QT interval data.

Methods: Digitized epicardial ECGs and aortic blood pressures were collected for 20 h in telemetered cynomolgus monkeys (n=6) following the administration of either vehicle or moxifloxacin (10 or 50 mg/kg, p.