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.

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.

Investigational drugs for treating agitation in persons with dementia.

Introduction: Agitation is common and distressing in persons with dementia, but safe, effective treatments remain elusive. In this review, the authors describe investigational compounds in ongoing or recently completed clinical trials for this indication and provide an opinion on how they may meet current therapeutic needs.

Areas Covered: Phase II and phase III clinical trials for agitation in persons with dementia were searched in US and EU clinical trial registries and in the medical literature for the period January 2013-February 2016 EXPERT OPINION: The authors searches identified 24 recent clinical trials investigating new treatments for agitation in persons with dementia.

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.

14th Annual Meeting of the Safety Pharmacology Society: threading through scientific sessions for originality and novelty.

Introduction: The Annual Meeting of the Safety Pharmacology (SP) Society is a yearly event designed to keep attendees abreast of how to best identify and mitigate organ function liabilities of candidate drugs selected for clinical assessment.

Areas Covered: Heart rate (HR) and blood pressure (BP) effects of candidate drugs in dogs/monkeys have satisfactory human translation. Mechanism-designed assays offer opportunities for innovative approaches to identify chemotherapeutic-induced peripheral neuropathy (PN).

13th Annual Meeting of the Safety Pharmacology Society: focus on novel technologies and safety pharmacology frontiers.

Introduction: The 13th Annual Meeting of the Safety Pharmacology (SP) Society discussed novel therapeutic areas, recent regulatory developments, emerging biology technologies and non-pharmaceutical dairy products that may need SP evaluations for ensuring their human safety.

Areas Covered: The meeting honored Willem Einthoven, the father of electrocardiography. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is an under-discussion proposal for replacing the International Conference on Hamonization (ICH) S7B guideline strategy.

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.

Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy.

Introduction: The rhythmic opening and tightly closing of cardiac valve leaflets are cardiac cyclic events imposing to blood a unidirectional course along the vascular tree. Drugs with 5-HT2B agonism properties can seriously compromise this biological function critical for hemodynamic efficiency as their intrinsic pro-fibrotic effects can, with time, make valvular coaptation blood regurgitant.

Topics Covered: Cardiac valve anatomy, physiology and pathology as well as 5-HT2B receptor properties (coupling, effects mediated, biased agonism) are briefly exposed.

2012 Annual Meeting of the Safety Pharmacology Society: spotlight on targeted oncology medicines.

Introduction: The 12th Annual Meeting of the Safety Pharmacology (SP) Society (SPS) covered various subjects among which safety issues concerning oncolytic drugs are reviewed and discussed in details.

Areas Covered: The challenges faced by a medical oncologist during the development of new anticancer medicines were the focus of the keynote address. Romidepsin, a drug initially abandoned because of serious cardiotoxicity in dogs, was successfully rescued for clinical evaluation by tailoring the dose regimen to mitigate cardiac toxicity risks.

2011 Annual Meeting of the Safety Pharmacology Society: an overview.

The keynote address of 2011 Annual Meeting of the Safety Pharmacology Society examined the known and the still to be known on drug-induced nephrotoxicity. The nominee of the Distinguished Service Award Lecture gave an account of his career achievements particularly on the domain of chronically instrumented animals for assessing cardiovascular safety. The value of Safety Pharmacology resides in the benefits delivered to Pharma organizations, regulators, payers and patients.

10th annual meeting of the Safety Pharmacology Society: an overview.

The 10th annual meeting of the Safety Pharmacology (SP) Society covered numerous topics of educational and practical research interest. Biopolymers - the theme of the keynote address - were presented as essential components of medical devices, diagnostic tools, biosensors, human tissue engineering and pharmaceutical formulations for optimized drug delivery. Toxicology and SP investigators - the topic of the Distinguished Service Award Lecture - were encouraged to collaborate in the development of SP technologies and protocols applicable to toxicology studies.

Safety Pharmacology Society: 9th Annual Meeting.

The keynote presentation of the Safety Pharmacology (SP) Society 9th Annual Meeting addressed the urgency, for pharmaceutical organizations, to implement strategies for effectively communicating drug risks to all concerned stakeholders and, in particular, the general public. The application of chronobiology to SP investigational protocols can improve the search of drug-induced adverse effects. The Distinguished Service Award Lecture reviewed a life-long journey through trials and tribulations in the quest of the ever-distant scientific truth.

Exploratory safety pharmacology: a new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations.

The primary objective of Safety Pharmacology is to ensure the safety of medicines on physiological functions in order to protect humans against adverse drug reactions. Safety Pharmacology became a major non-clinical discipline in 2000 when the International Conference on Harmonization approved the S7A guideline. This regulatory document requires pharmaceutical companies to undertake Safety Pharmacology assessment under Good Laboratory Practice (GLP) in order to guarantee the absence of unmanageable risks on vital organ function for compounds to be tested on humans.

Safety Pharmacology Society: 8th annual meeting.

Of the numerous topics discussed during the eighth annual meeting of the Safety Pharmacology (SP) Society the author identified the following key topics: i) the impact of hERG (human ether-à-go-go related gene) channel data on drug development, ii) safety evaluation of biological products, iii) opportunities and expectations from SP, iv) human stem cell derived cardiomyocytes for safety assessment, v) role of cellular calcium pathways in drug-induced arrhythmias, vi) collaboration initiatives for finding solutions to cardiac repolarisation and other recognised SP risks, vii) Pharma and FDA perspectives on ICH S7B guideline, viii) joint PhRMA-FDA dialogue on drug abuse potential assessment, ix) frontloading SP strategies for mitigating non-clinical and clinical attrition; and x) approaches to measure non-clinical assay predictability for human outcome. The establishment of consortia to accelerate the solution of critical SP issues and the implementation of Frontloading SP or Exploratory SP strategies for an early selection of safe clinical candidates are promising avenues for consolidating SP as an indispensable drug development discipline and for transforming established regulatory SP investigations into a risk-known exercise.

Drug discovery paradigms: past, present, future - a centennial symposium of the American Society for Pharmacology and Experimental Therapeutics.

Background: The American Society for Pharmacology and Experimental Therapeutics (ASPET) celebrated its centennial during the April 2008 Experimental Biology meeting held in San Diego, CA, USA.

Objectives: This report summarizes a centennial symposium on past, present and future paradigms in drug discovery. The John Langley (1905) concept of 'receptive substances' initiated a cascade of cardinal discoveries for pharmacology.