This editorial prefaces the annual themed issue on those methods with application to safety pharmacology (SP) in the Journal of Pharmacological and Toxicological Methods (JPTM). Highlighted content is derived from the 2024 Safety Pharmacology Society (SPS) meeting held in San Diego, CA, USA. The meeting showcased 122 posters, many of which are reproduced as abstracts published in JPTM. The manuscripts predominantly reflect updates to core battery safety evaluation and data analysis methods and include areas of novel investigation within SP. The results from several surveys including an updated salary survey by the SPS, current industry practices on neurotoxicity by the ACT, SPS and STP and results on the need to revisit the ICH S7A guidance on safety and secondary pharmacology by EFPIA, JPMA, and PhRMA provide timely updates. Other manuscripts include in vitro assessment methods for sodium channel block using MEA arrays, and a comparison of the in vitro effects of positive control drugs on the hERG channel current using different testing procedures. In vivo cardiovascular manuscripts include an overview of surgical telemetry implantation methods, utility of automated blood sampling methods in SP studies, evaluation of the performance characteristics for common QTc data collection methods, and an evaluation of a clinically used wearable ECG device for use in SP studies. There is also an overview of the impact of respiratory SP and a comprehensive review and comparison of current practices regarding methodological approaches used to acquire CV data in repeat-dose non-rodent toxicology studies. The 21 years of consecutive themed issues on SP methods attends to the importance of methods evaluation and the contribution of SP to the process of methods evaluation.

Clinical success in prevention of sudden cardiac death has been poor. New approaches to prevention of ventricular fibrillation (VF), one of the main causes of sudden cardiac death, are clearly needed. In the present article we have reviewed some of our own data which support the notion that VF may be prevented by manipulation of chloride homeostasis. Our studies have revealed a novel approach to VF suppression via alteration of sarcolemmal membrane resistance.

The second salary survey of safety pharmacology professionals was conducted in late 2023. This electronic survey was distributed to all members of the Safety Pharmacology Society (SPS). Survey questions assessed demographic variables, professional background, employment type, and annual incomes. Of 463 active SPS members, 120 responses were received. A majority of the responses (56 %) were from North America, followed by Europe (35 %), then Asia-Pacific (9 %). The results of the 2023 salary survey highlight the continued growth in salaries in the field of safety pharmacology and may serve as a valuable resource for current and future safety pharmacologists.

OBJECTIVE:Ventricular arrhythmias are the primary arrhythmias that cause sudden cardiac death. We address the problem of classification between ventricular tachycardia (VT), ventricular fibrillation (VF) and non-ventricular rhythms (NVR). METHODS:To address the challenging problem of the discrimination between VT and VF, we develop similarity maps - a novel set of features designed to capture regularity within an ECG trace. These similarity maps are combined with features extracted through learnable Parzen band-pass filters and derivative features to discriminate between VT, VF, and NVR. To combine the benefits of these different features, we propose a hierarchical multi-stream ResNet34 architecture. RESULTS:Our empirical results demonstrate that the similarity maps significantly improve the accuracy of distinguishing between VT and VF. Overall, the proposed approach achieves an average class sensitivity of 89.68%, and individual class sensitivities of 81.46% for VT, 89.29% for VF, and 98.28% for NVR. CONCLUSION:The proposed method achieves a high accuracy of ventricular arrhythmia detection and classification. SIGNIFICANCE:Correct detection and classification of ventricular fibrillation and ventricular tachycardia are essential for effective intervention and for the development of new therapies and translational medicine.

Accurate differentiation between Ventricular Tachycardia (VT) and Ventricular Fibrillation (VF) is essential in the field of cardiology. Recent advancements in deep learning have facilitated automated arrhythmia recognition, surpassing traditional electrocardiogram (ECG) methods that depend on manual feature extraction. Building on our previous work, which emphasized the importance of identifying patterns of regularity, we have developed a model that merges Graph Convolutional Networks (GCN) with Long Short-Term Memory (LSTM) networks. This GCN-LSTM model employs a trainable weighted ϵ-neighborhood graph to capture the similarity among time series within ECG segments. This approach has demonstrated substantial improvement in the classification of VT, VF, and non-ventricular rhythms.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM. As in prior years, the manuscripts reflect various areas of innovation in SP including in silico modeling of stroke volume, cardiac output and systemic vascular resistance, computational approaches that compare drug-induced proarrhythmic sensitivity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), an evaluation of the utility of the corrected J-Tpeak and Tpeak-to-Tend parameters from the ECG as potential proarrhythmia biomarkers, and the applicability of nonclinical concentration-QTc (C-QTc) modeling of data derived from the conduct of the in vivo QTc study as a component of the core battery of safety pharmacology studies.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). We highlight here the content derived from the recent 2022 Safety Pharmacology Society (SPS) and Canadian Society of Pharmacology and Therapeutics (CSPT) joint meeting held in Montreal, Quebec, Canada. The meeting also generated 179 abstracts (reproduced in the current volume of JPTM). As in previous years the manuscripts reflect various areas of innovation in SP including a comparison of the sensitivity of cross-over and parallel study designs for QTc assessment, use of human-induced pluripotent stem cell (hi-PSC) neuronal cell preparations for use in neuropharmacological safety screening, and hiPSC derived cardiac myocytes in assessing inotropic adversity. With respect to the latter, we anticipate the emergence of a large data set of positive and negative controls that will test whether the imperative to miniaturize, humanize and create a high throughput process is offset by any loss of precision and accuracy.

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al., 2015; Curtis et al., 2018). This update clarifies and simplifies the requirements on design and analysis for BJP manuscripts. This editorial also details updated requirements following an audit and discussion on best practice by the BJP editorial board. Explanations for the requirements are provided in the previous articles. Here, we address new issues that have arisen in the course of handling manuscripts and emphasise three aspects of design that continue to present the greatest challenge to authors: randomisation, blinded analysis and balance of group sizes.

Background and Purpose Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine. Experimental Approach The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg center dot kg(-1) i.v., whereas lidocaine reduced it even at 1 mg center dot kg(-1). In adult rat ventricular myocytes, OCT2013 had no effect on Ca2+ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity.

Positive inotropic drugs cause an increase in the force of contraction of ventricular heart muscle (myocardium). Heart failure has several possible causes and becomes symptomatic when inotropy becomes insufficient for cardiac output (the volume of blood ejected per unit time; CO) to meet the needs of the body. Positive inotropes were once the only option for treatment of heart failure, with the first-in-class, digitalis, evoking a dramatic improvement in the circulation leading to reversal of pulmonary and peripheral oedema. In the mid and late 20th century other positive inotropes emerged, first the β-adrenoceptor agonists (e.g., dobutamine) and later the phosphodiesterase (PDE) inhibitors. All have been superseded for long term treatment of heart failure by drugs acting outside the heart (discussed elsewhere in this volume) owing to lack of long term benefit (especially on survival) and adverse effects including proarrhythmia (increased appearance of cardiac arrhythmias) and adverse remodeling (heart enlargement). Some of this adversity is attributable to the increase in ventricular myocyte intracellular calcium ([Ca2+i]) seen with all positive inotropes. Despite recent interest in drugs with Ca2+ sensitizer activity (the ability to facilitate binding to the contractile protein, troponin C) long term treatment now focuses on alleviation of adverse remodeling.

Ventricular arrhythmias are the primary arrhythmias that cause sudden cardiac death. In current clinical and preclinical research, the discovery of new therapies and their translation is hampered by the lack of consistency in diagnostic criteria for distinguishing between ventricular tachycardia (VT) and ventricular fibrillation (VF). This study develops a new set of features, similarity maps, for discrimination between VT and VF using deep neural network architectures. The similarity maps are designed to capture the similarity and the regularity within an ECG trace. Our experiments show that the similarity maps lead to a substantial improvement in distinguishing VT and VF.

This chapter considers mechanisms of torsades de pointes (TdP) linked to delayed ventricular repolarization. Major ionic conductances contributing to action potential repolarization are summarized. The key role of IKr as an anti-target in drug-induced long QT syndrome (diLQTS) is considered, as is more recent evidence implicating late Na current (INa,L) enhancement as an additional mechanism by which chronic drug exposure can prolong ventricular action potentials. Factors influencing repolarization reserve, heterogeneity (dispersion) of repolarization and formation of early afterdepolarizations (EADs) are described. Evidence for TdP triggers and maintenance mechanisms from models of congenital LQTS variants 1–3 is discussed. Models of and issues pertaining to evaluation of TdP in diLQTS are then considered, including the use of surrogate measures as exemplified by the TRiAD model. Across the different forms of LQTS considered, EADs are strongly implicated as trigger events for TdP, whilst dispersion of repolarization is a likely maintenance substrate.

The 2021 Annual Safety Pharmacology (SP) Society (SPS) meeting was held virtually October 4-8, 2021 due to the continuing COVID-19 global pandemic. This themed issue of J Pharmacol Toxicol Methods comprises articles arising from the meeting. As in previous years the manuscripts reflect various areas of innovation in SP including a perspective on aging and its impact on drug attrition during safety assessments, an integrated assessment of respiratory, cardiovascular and animal activity of in vivo nonclinical studies, development of a dynamic QT-rate correction method in primates, evaluation of the "comprehensive in vitro proarrhythmia assay" (CiPA) ion channel protocol to the automated patch clamp, and best practices regarding the conduct of hERG electrophysiology studies and an analysis of secondary pharmacology assays by the FDA. The meeting also generated 85 abstracts (reproduced in the current volume of J Pharmacol Toxicol Methods). It appears that the validation of methods remains a challenge in SP. Nevertheless, the continued efforts to mine approaches to detection of proarrhythmia liability remains a baffling obsession given the ability of Industry to completely prevent drugs entering into clinical study only to be found to have proarrhythmic properties, with no reports of such for at least ten years. Perhaps it is time to move on from CiPA and find genuine problems to solve?

This editorial summarizes the content of the current themed issue of J Pharmacol Toxicol Methods derived from the 2020 Annual Safety Pharmacology Society (SPS) meeting that was held virtually September 14-17, 2020 due to the ongoing COVID-19 global pandemic. A selection of articles arising from the virtual meeting is summarized. Like previous years they continue to reflect current areas of innovation in SP including new methodologies to predict human safety, best practices for IKr current measurement, and best practice considerations for the conduct of in vivo nonclinical QT studies. The meeting included scientific content from 94 abstracts (reproduced in the current volume of J Pharmacol Toxicol Methods). This continued innovation reflects a rubric in SP that identifies problems, seeks solutions and, importantly, validates the solutions.

Introduction: Pre-clinically, safety risk assessment of a drug is primarily tested in vivo using functional evaluation of adult animals while the mechanistic etiology of drug-induced CNS adverse effects is often uncharacterized. In vitro electrophysiology may provide a better understanding of drug effects without additional animal use. However, in vitro protocols are typically designed for using embryonic or juvenile animals. Methods: We examined whether brain tissue isolated from adult rats (3-5 months old) and adult non-human primates (NHPs) (2-8 years old) can generate qualitatively equivalent readouts for electrophysiology to characterize AMPAR synaptic and single channel currents. We used a known positive AMPAR allosteric modulator (LY451395) to template a response profile and provide proof-of-concept data to assess responses of these native AMPARs in a drug context. Results: Brain slices from adult animals provided a support to measure AMPAR-driven excitatory post-synaptic currents (EPSCs), and can be dissociated into primary neuronal cultures for AMPAR single channel characterization. Additionally, similarities and differences in AMPAR basal kinetics and responses to LY451395 were seen between the two animal species. Discussion: Glutamatergic synaptic activity and AMPAR biophysical properties in adult animals may be used to characterize test-article-mediated alterations in CNS responses. The use of older animals opens the possibility for in vivo test-article administration, either acutely or repeatedly, before in vitro electrophysiological assessment in order to reveal cumulative or delayed-onset effects, adding versatility to safety pharmacology assessment of the CNS.

This editorial summarizes the content of the current themed issue of J Pharm Tox Methods derived from the 2019 Annual Safety Pharmacology Society (SPS) meeting held in Barcelona, Spain, and reflects on 20 years of innovation in the elaboration of methods for evaluating adversity, particularly during the nonclinical research phase. Given the success of safety pharmacology (SP) in the last 20 years, we propose that the rubric for SP method invention and validation be examined in more detail to explore whether it may have wider relevance to the drug discovery process. Articles arising from the Barcelona meeting are summarized here. They reflect current areas of controversy and innovation in SP. Not for the first time in recent years, the suitability of the No Observable Adverse Effect Level (NOAEL) as a variable in SP was considered in an article derived from a survey of SPS members. It was found from the survey and concluded from the analysis that the NOAEL is not necessary for assessing the safety of a New Chemical Entity (NCE). The meeting included scientific content from more than 190 abstracts (reproduced in the current volume of J Pharm Tox Methods). The impact of the INSPIRE program on the educational endeavor of SP, cardiovascular SP with regard to hERG and advances in CiPA and stem cells assays, the use of the echocardiogram in SP, the applicability of deep learning methods in SP and toxicology studies, the role of biomarkers in renal SP studies, and advances in CNS SP are highlighted in this issue of the Journal. This continued innovation reflects a rubric in SP that identifies problems, seeks solutions and, importantly, validates the solutions. If there is a lesson to be learned from the 20 years of annual SP methods themed issues it is that drug discovery efforts may benefit from a more rigorous validation process for discovery methods, using positive and negative controls for validation, as is done in SP method validation.