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. The first group, led by Thomas James, defended the histological existence of uninsulated, high-speed cordlike internodal conduction tracts. Although not supported by robust experimental data, this hypothesis achieved the status of a physiological creed in the scientific community. The second group, led by Robert Anderson, systematically refuted this stance and adopted anisotropy as an innovative internodal conduction mechanism operating via spindle-shaped atrial contractile myocytes structured in anisotropic muscular bundles relaying sinoatrial node (SAN) APs to their atrial destinations at physiologically required (fit for purpose) velocities to enable electromechanical synchrony of atrial systoles. Modern imaging and electrophysiological techniques can now clearly visualize muscular internodal and interatrial tracts and SAN depolarization electrical waves, confirming the existence of atrial conduction paths consisting of anisotropically arranged contractile cardiomyocytes. Mastery of the current best-science anatomy and physiology of the human atria is required for electrophysiologists to safely perform atrial radiofrequency ablation interventions to restore sinus rhythm in patients distressed by supraventricular arrhythmias.NEW & NOTEWORTHY 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.

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. 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.

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. 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.

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

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.

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 ßA-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.

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

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.

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 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.

Simple-to-use, reference criteria for revealing drug-induced QT interval prolongation in conscious dogs.

Electrocardiogram (ECG) QT interval prolongation produced by drugs in certain animal models is currently believed to be predictive of cardiac proarrhythmic effects in humans. For this reason, nonclinical assessment of the effects of novel drugs on cardiac repolarization is a regulatory prerequisite for progressing such agents to clinical evaluation. The present investigation was carried out to develop reliable, simple-to-use reference criteria for identifying individual animals as responders to drugs that prolong the QT interval. ECG were recorded for 30 s at 0 (8 am), 2, 4, 6 and 24 h in 6 trained, conscious, beagle dogs during 5 control experimental sessions. QT intervals were measured and corrected for heart rate by applying the Van de Water algorithm (QTc). The maximal (QTc(max)) and minimal (QTc(min)) values of QTc observed in each of the five control recording sessions were noted. Two reference (R) criteria were used to designate an individual animal as a responder to drug treatment: 1) QTc(maxR) which was obtained by adding 10 ms to the largest value of QTc(max) observed during the five control recording sessions and 2) (QTc(max)-QTc(min))(maxR) which was obtained by increasing by 50% the largest of the (QTc(max)-QTc(min)) values [(QTc(max)-QTc(min))(max)] observed in the 5 control recording sessions. The sensitivity and reliability of these criteria were tested by determining QTc intervals before and 2, 4, 6 and 24 h after placebo or quinidine (200, 400 and 800 mg p.o. per animal). The reference values of QTc(maxR) and (QTc(max)-QTc(min))(maxR) for the various dogs ranged from 246 to 270 ms and from 15 to 19.5 ms, respectively. The number of dogs responding to treatment (T: quinidine at 200, 400 and 800 mg, p.o. per animal) with a QTc(maxT) and/or a (QTc(max)-QTc(min))(maxT) equal to or greater than the respective reference values was, respectively, 1/6, 3/6 and 5/6 dogs. Additionally, the number of responders correlated well with the concentration of free quinidine in the plasma. In conclusion, this investigation succeeded in establishing reliable, reference criteria for individual dogs despite the intrinsic daily variation of QTc interval. The application of these criteria allowed identifying individual animals responding to quinidine with delayed cardiac repolarization.

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. METHODS: Digital ECGs were collected for 18-21 h in telemetered dogs (n=7) and cynomolgus monkeys (n=7) employing epicardial ECG leads and analyzed by computerized algorithms. ECG intervals were determined employing beat-to-beat (1 ms BW) and 10 s logging rates (for 1, 10, 20, and 50 ms BW). Diurnal heart rate variability was defined as the beat-to-beat RR ratio (VR) where SA was defined as >+/-10% change in VR. RESULTS: Canine beat-to-beat QT-RR data were curvilinear and plateaued, with multiple RR values associated to any given QT for RR>or=900 ms. Cynomolgus QT-RR data collected as beat-to-beat or at a 10 s logging rate were linear for all RR intervals. During the day, SA comprised 62.9+/-2.4% and 11.4+/-6.1% of total beats in the dog and cynomolgus, respectively, with no diurnal/nocturnal differences in either species. QT interval changes varied with BW such that 5 ms resolution was maintained for BW

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.o.). Moxifloxacin plasma concentrations were determined 4 h postdose. ECG intervals were analyzed by computerized algorithms. Individual probabilistic QT rate-corrections (QTc) were derived from the slopes of predose log-transformed QT-RR data where each QT value was the mean of >250 beats/RR increment. The resulting QTc was used to determine the repolarization effects of moxifloxacin, expressed as the placebo-adjusted change in QTc (DeltaQTc), and as the integrated response from 0 to 12 h (AUC(0-->12)) postdose. RESULTS: No DeltaQTc effect was produced by 10 mg/kg moxifloxacin. However, moxifloxacin (50 mg/kg; 5.86+/-0.5 microg/mL C(max)) significantly prolonged the RR interval by 50 to 112 ms from 3.5 to 7.5 h postdose and DeltaQTc by >or=7.2 ms from 1.83 to 9.17 h, with a maximal DeltaQTc effect of +26.4 ms. No notable effects on either systemic blood pressure or body temperature occurred with either dose. DISCUSSION: Probabilistic QT rate-corrections appear to have eliminated the confounding effects of heart rate, provided for a stable QTc baseline, and enabled the demonstration of an exposure-dependent QTc prolongation by moxifloxacin. The duration and magnitude of the QTc effect paralleled moxifloxacin pharmacokinetics, and C(max) values were similar to those achieved clinically in thorough QT/QTc studies. Thus, novel probabilistic QT rate-corrections may offer highly robust assessments of repolarization risk in both nonclinical and clinical investigations.

Novel probabilistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys.

INTRODUCTION: QT intervals are not regulated on a beat-to-beat cadence, but are strongly influenced by the preceding heart rate history (hysteresis). ECG sampling, when performed over sufficiently long periods, results in the detection of ranges of different QT values for each discrete RR interval. Given the potential impact of QT hysteresis in QT interval rate-correction procedures, we hypothesized that, physiologically, the QT interval exists as a probabilistic variable where the exact value corresponding to any RR interval is precisely estimated from the associated QT population. METHODS: Digital ECGs were collected for 18-21 h in telemetered dogs (n=7) and cynomolgus monkeys (n=7) employing epicardial ECG leads for accurate T(end) detection, and analyzed by computerized algorithms. Descriptive statistics were calculated for raw QT values in 10 ms RR increments. Individual rate-corrected QT (QTc) formulae were derived from the slopes of log-transformed QT-RR data where each QT point was the mean of >250 beats/RR increment. The aptness of this QTc model was assessed by residual analysis. RESULTS: Beat-to-beat ECG analysis demonstrated that for all discrete cycle lengths, the associated raw QT intervals were normally distributed populations, spanning approximately 30-40 and 45-100 ms in the dog and cynomolgus monkey, respectively. In both species, QTc was stable (< or =5 ms variation) over all physiological RR intervals. DISCUSSION: The probabilistic treatment of raw QT interval populations natively associated to any RR interval provides hysteresis-free raw QT estimates which can be accurately modeled, allowing the derivation of a precise QTc value. Previous unawareness of the probabilistic nature of the QT interval explains the historical failure of numerous QT rate-correction formulae to correctly solve this scientific issue. Importantly, QT distribution analysis has the potential to provide, for the first time, a universal and sensitive method for QT heart rate-correction, providing a robust method for nonclinical and clinical cardiac safety investigations of repolarization delay.

15th 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. 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.

Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans.

BACKGROUND: The issue of drug-induced QT interval prolongation and torsades de pointes represents a major concern for pharmaceutical development. In this investigation, we examined the value of the isolated rabbit Purkinje fibre as an in vitro action potential (AP) assay to predict the potential of drugs to induce these undesirable adverse effects. METHODS: First, we categorised the proarrhythmic risk of 26 medicinal products based on proportional reporting ratios for these two adverse events recorded in a US FDA database (Spontaneous Reporting System/Adverse Event Reporting System). Second, we measured drug effects on AP in rabbit Purkinje fibres. Finally, the results of the two analyses were compared to evaluate the predictive value of the in vitro assay. RESULTS: Analysis of the clinical data classified the drugs into 14 positive, 7 negative and 5 questionable for proarrhythmic risk. Based on in vitro electrophysiological profiles, the drugs were grouped into four categories: (i) profile 1 drugs prolong repolarisation without slowing depolarisation; (ii) profile 2 drugs prolong repolarisation and also slow depolarisation; (iii) profile 3 drugs shorten repolarisation; and (iv) profile 4 drugs are without effects. All 14 clinical-positive drugs fell into profiles 1 or 2 (prolongers) with low safety margins (except probucol, which showed no effect, probably because of its low solubility). Clinical-negative drugs belonged mostly to profiles 3 or 4 (non-prolongers) [except clemastine and amlodipine, which were prolongers but had large safety margins]. Clinical-questionable drugs either did not prolong or prolonged slightly but produced additional electrophysiological effects opposing prolongation. CONCLUSION: The rabbit Purkinje fibre is a valuable assay for evaluating the proarrhythmic liability of pharmaceuticals as it can reveal complex electrophysiological profiles that modulate repolarisation delay.

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. 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.

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. Candidate drugs in phase III development included the antipsychotic brexpiprazole, the antidepressant citalopram, the novel compound AVP-786 (deuterated-dextromethorphan/quinidine combination) and the cannabinoid nabilone. Of the compounds in phase II clinical trials, ELND005 (scyllo-inositol) is intended to progress into phase III development, based on evidence from a subgroup analysis and biomarker data. After many years without an FDA/EMA (Food and Drug Administration/European Medicines Agency) approved medication to treat agitation in persons with dementia, we may see the arrival of the first approved drug in the near future.

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.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined. DISCUSSION: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA 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.

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). SP has a large array of methodologies to determine safety on eye functions. Video-tracking analysis of zebrafish swimming behavior accurately profiles drugs for high-level brain function liabilities. Available in vitro and in vivo assays can identify, and determine physiological and pharmacological mechanisms of, candidate drug-induced emesis. Ad hoc Working Groups have already finalized protocols for testing the comprehensive in vitro arrhythmia assay (CiPA), an innovative paradigm for assessing mechanisms conferring candidate drug proarrhythmic liabilities. EXPERT OPINION: The good concordance of non-clinical and clinical Phase I BP and HR effects of candidate drugs support the use of dog/monkey models for clinical outcome. Drug liabilities (e.g., PN, nausea, vomiting, etc.) affecting non-vital organs/systems require the same degree of SP attention given to vital functions as they can dramatically reduce patient quality of life.

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. 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.

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. 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.

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. Drugs targeting epigenetic mechanisms (e.g., histone deacetylase inhibitors) have the potential to produce proarrhythmic safety liabilities by dysregulating the synthesis of cardiac ion channel proteins as well as the intracellular machinery, moving them to sarcolemmal residence. Novel frontiers of regulatory SP investigations are functional food and probiotic (microorganisms) preparations. EXPERT OPINION: The CiPA initiative is a unique opportunity for concerned stakeholders to drive SP into the adoption of 21st century safety assessment platforms, which, for discovering and mitigating mechanisms conferring safety risks to drugs, apply chiefly in silico and in vitro rather than traditional in vivo pharmacodynamics assays. The SP evaluation of functional foods and probiotics needs the development of product-tailored investigational approaches.