This report reexamines disparate historical views on internodal pathway existence and nature. The conflicting research, ongoing since 1963, regarding these issues, is appraised. The discovery of myocytes anisotropically structured in atrial bundles relaying sinoatrial node (SAN) action potentials (APs) to atrioventricular node (AVN) and atrial wall destinations is emphasized, since it is still a relatively unfamiliar subject in physiology teaching. Modern imaging technologies can now visualize internodal pathways as muscular bundles displaying SAN electrical waves traversing the atrial walls.

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). THD-induced hemodynamic changes seen in humans were most accurately reflected in the monkey and, to a lesser extent, the dog, but not in the minipig. The minipig was most sensitive to THD QTc effects. When QTca was adjusted for THD-associated Tc decreases in minipigs and monkeys, the minipig revealed a lessened but pronounced QTcaT increase (48 ms). In the monkey, a persistent QTca increase was reduced to only a transient (0.5-3 h) QTcaT increase (20 ms). The dog's lack of THD QTca effects triggered co-administration of atenolol (AT) to attenuate THD-induced HR increases in the dog and monkey. THD + AT revealed peak QTcaT increases of 32 ms in the dog and 40 ms in the monkey, suggesting potential autonomic nervous system (ANS) interference in detecting repolarization changes. These results highlight critical species-specific differences in the outcome of parallel safety investigations. Species selection for nonclinical safety studies should consider the potential impact of Tc and ANS effects to avoid false-negative or overly positive outcomes.

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. described a ventricular muscular tract conveying SAN-generated action potentials from the AVN (discovered by Sunao Tawara and Karl Albert Aschoff in 1906) to the PF. In 1906, Keith and Flack completed these explorations by localizing the SAN, the primum movens of CCS, which functions as a biologic oscillator emitting cadenced impulses that travel via the Bachmann bundle to the atrial myocytes and, via internodal pathways, to the AVN. Here these impulses are briefly delayed, enabling atrial systole before continuing via the AVN and the high-speed His-Purkinje conduction axis to signal ventricular contraction. The CCS canonical discoverers (Keith and Flack, Aschoff and Tawara, His, and Purkinje), historical controversies, fundamental notions of anatomy, physiology, and pathology, and therapeutic interventions pertaining to the CCS are the main themes of this review. Any scientist mentioned or unmentioned in this report who contributed directly or indirectly, with correct or inaccurate hypotheses, to the characterization of the CCS deserves our deepest gratitude for the long and painstaking hours spent microscopically scrutinizing heart specimens from multiple mammalian species, including humans.NEW & NOTEWORTHY This report presents the first comprehensive summary of the factors enabling the discovery of the cardiac conduction system (CCS). Biographical highlights and achievements of the CCS canonical discoverers, hypotheses concerning mechanisms underlying sinus node (SAN) automaticity, use of eponyms to denominate a discovery, famous controversies, possible reproachable behavior (e.g., intellectual support for eugenics in post-World War I Germany) by two of the discoverers, and examples of historical mentor-pupil relationships are discussed.

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 βA-T87Q-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 (hiPSC-CMs) for remuscularization of the failing human heart. The nonclinical assessment of efficacy and safety of ATMPs for undertaking human clinical trials requires innovative, product-specific strategies. In order to succeed in gaining marketing approval for these novel medicines, sponsors should establish well-defined collaborative relationships with the appropriate regulatory authorities.

Introduction: 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).Areas covered: 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).Expert opinion: 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.

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

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 in vitro 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. This report reviews the fundamental tenets, key components (chip plate, biomaterials, cell differentiation approaches, and monitoring sensors) and issues concerning OOC systems (engineered top-down and bottom-up strategies for tissue/organ assembly, public aids to OOC development, regulatory validation, advantages, limitations, prospective and perspective of OOCs, ethics). Examples of OOC platforms (cancer-, lung-, blood-brain barrier-, heart-, intestine-, kidney-, liver-, pharmacokinetics-, placenta and vessel-on-chip) and their importance for drug research and development are presented. Expert opinion: OOC device-generated bioconstructs hold great promise as experimental human tissue and organ platforms for generating human-pertinent knowledge on drug candidates for clinical assessment and reducing reliance on animal models. MPS technologies currently enable ready-to-assemble tissue patches and, hopefully, in coming decades, full-size, patient-personalized organs for regenerative medical interventions.

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. In 1823, Purkinje became a Physiology and Pathology professor at the Prussian Medical University in Breslau, where he innovated the traditional teaching methods of physiology. Purkinje's contributions to physiology were manifold: accurate descriptions of various visual phenomena (e.g., Purkinje-Sanson images, Purkinje phenomenon), discovery of the terminal network of the cardiac conduction system (Purkinje fibers), identification of cerebellar neuronal bodies (Purkinje cells), formulation of the vertigo law (Purkinje's law), discovery of criteria to classify human fingerprints, etc. In 1850, Purkinje accepted and held until his death the Physiology chair at Prague Medical Faculty. During this period, he succeeded in introducing the Czech idiom (in addition to long-established German and Latin) as a Medical Faculty teaching language. Additionally, as a zealous Czech patriot, he actively contributed to the naissance and consolidation of a national Czech identity conscience. Purkinje was a trend-setting scientist who, throughout his career, worked to pave the way for the renovation of physiology from a speculative discipline, ancilla of anatomy, into a factual, autonomous science committed to the discovery of mechanisms governing in-life functions.

Abstract Introduction The Comprehensive in vitro Proarrhythmia Assay (C i PA) 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 ‘C i PA 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.g. , biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of C i PA core assays are critically examined. Discussion In order to advance the C i PA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by C i PA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure.

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.Discussion: The positive results obtained with the IQ-CSRC study require additional confirmation with threshold QTc-positive and negative drugs and established QTc prolongers producing both increases and decreases in heart rate. In the future, similar studies should also adopt and validate innovative proarrhythmic metrics, in addition to, or instead of, the traditional proarrhythmic surrogate of QTc, to assess the proarrhythmic safety of candidate drugs. (C) 2016 Elsevier Inc. All rights reserved.

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. Techniques for evaluating drug effects on hearing functions are reviewed. Nonclinical approaches to assess vestibular toxicity leading to balance deficits are presented. Retinal explants studied with multielectrode arrays allow the identification of drug liability sites on the retina. Routinely performed Safety Pharmacology assays are not powered to address candidate drug-induced disturbances on taste and smell. This weakness needs correction since unintended pharmacological impairment of these sensorial functions may have serious health consequences. Neuropathy produced by chemotherapeutic agents may cause multiple sensorial perception distortions. CONCLUSIONS:Safety Pharmacology studies should ensure the safety of any candidate drug on the five sensorial systems.

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. FDA examiners currently assess proconvulsive liabilities on a case-by-case basis due to the lack of official guidance. In contrast, abuse liability potential is determined according to established paradigms. The FDA guideline on opioid deterrent formulations was discussed. The mechanisms and treatments of obstructive sleep apnea (OSA) and diabetes-induced neuropathic pain were reviewed. There were salient points arising from the CNS presentations but from a pharmacological point of view we note in particular that safety pharmacology should move to routinely apply polysomnographic technologies to determine whether candidate drugs exert deleterious effects on sleep quality and architecture that may markedly decrease quality of life and impair cognitive functions, including alertness and reaction time.

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. The third evaluates conclusions from, and searches possibly missed effects by in silico analysis, in human stem cell-derived cardiomyocytes (hSC-CMs). CiPA ad hoc Expert-Working Groups have proposed patch clamp protocols for seven cardiac ion channels, a modified O'Hara-Rudy model for in silico analysis, detailed procedures for field (MEA) and action potential (VSD) measurements in hSC-CMs, and 29 reference drugs for CiPA assay testing and validation. DISCUSSION:CiPA adoption as drug development tool for identifying electrophysiological mechanisms conferring proarrhythmic liability to candidate drugs is a complex, multi-functional task requiring significant time, reflection, and efforts to be fully achieved.

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 naive, adolescent cynomolgus monkeys in different single and social housing types based on parallel comparisons of heart rate.Methods: Eight naive cynomolgus monkeys were randomized into pairs and ECG data were collected for 24 h from each animal in each housing condition using a crossover design. Caging paradigms consisted of standard individual, standard pair, quaternary pair (4 linked cages), and European-style pair housing in non-sequential order varied by pair to control for possible time bias. Dosing and blood collection procedures were performed to characterize any effects of housing on ECG data during study conduct.Results: There was no increase in the incidence of equipment damage in pair vs. individually housed animals. Further, animals in all 4 housing paradigms showed similar acclimation assessed as heart rate (mean 139-154 beats per minute), and maintained similar diurnal rhythms, with an expected slowing of the heart rate at night (aggregate lights out HR 110 +/- 4 bpm compared to daytime 146 +/- 7 bpm).Discussion: This study demonstrates the effects of different social access and housing types on the study-naive cynomolgus monkeys during jacketed cardiovascular telemetry data collection in a repeat-dose toxicology study design. There were no discernible effects of social housing on baseline ECG parameters collected via jacketed telemetry, and all animals maintained expected diurnal rhythms in all housing settings tested. These data demonstrate that cynomolgus monkeys can be socially housed during data collection as a standard practice, consistent with global efforts to improve study animal welfare. (C) 2015 Elsevier Inc. All rights reserved.

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. Then, simulations test whether the channel dataset yields proarrhythmic markers on a computationally reconstructed human ventricular cardiomyocyte action potential. Finally, the relevance of in silico conclusions is verified by determining the electrical activity of human stem cell-derived ventricular cardiomyocytes. Expert opinion: The CiPA initiative is intended to move safety pharmacology from a predominantly traditional pharmacodynamics approach to in silico and in vitro drug toxicity assessment. In practice, CiPA assays will have to be compliant with regulatory safety pharmacology tenets. The latter will necessitate international consensus on assay protocols, method standardization and validation and, thus, is likely to involve protracted discussions to achieve agreement. As such, full CiPA implementation by July 2015, as currently envisaged, to supplant E14 guidance for a thorough QT/QTc interval study as prerequisite for noncardiac drug marketing approval, appears to be difficult. Nevertheless, safety stakeholders should do their best to validate and implement the CiPA initiative in the shortest possible time.