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A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming stages of drug development. In this study, we screened the PRESTWICK CHEMICAL LIBRARY composed of 1,520 approved drugs in an infected cell-based assay. The robustness of the screen was assessed by the identification of drugs that already demonstrated in vitro antiviral effect against SARS-CoV-2. Thereby, 90 compounds were identified as positive hits from the screen and were grouped according to their chemical composition and their known therapeutic effect. Then EC50 and CC50 were determined for a subset of 15 compounds from a panel of 23 selected drugs covering the different groups. Eleven compounds such as macrolides antibiotics, proton pump inhibitors, antiarrhythmic agents or CNS drugs emerged showing antiviral potency with 2 < EC50 ≤ 20 µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study provides information for the selection of drugs to be further validated in vivo. Disclaimer: This study corresponds to the early stages of antiviral development and the results do not support by themselves the use of the selected drugs to treat SARS-CoV-2 infection.

Cardiac arrhythmias remain a common cause of death and disability. Antiarrhythmic drugs (AADs) and antiarrhythmic agents remain a cornerstone of current cardiac arrhythmia management, despite moderate efficacy and the potential for significant adverse proarrhythmic effects. Due to conceptual, regulatory and financial considerations, the number of novel antiarrhythmic targets and agents in the development pipeline has decreased substantially during the last few decades. However, several promising candidates remain and there are exciting developments in repurposing and reformulating already existing drugs for indications related to cardiac arrhythmias. This review discusses the key conceptual considerations for the development of new antiarrhythmic agents, summarizes new compounds and formulations currently in clinical development for rhythm control of atrial fibrillation, and highlights the potential for drug repurposing. Finally, future directions in AAD development are discussed. Together with an ever-increasing understanding of the molecular mechanisms underlying cardiac arrhythmias, these components support a cautiously optimistic outlook towards improved pharmacological treatment opportunities for patients suffering from cardiac arrhythmias.

In this trial, patients with symptomatic paroxysmal atrial fibrillation were assigned to either radiofrequency ablation or antiarrhythmic drug therapy as first-line treatment. There was no significant difference between the groups in the cumulative burden of AF over a 2-year period. Radiofrequency catheter ablation has emerged as an effective therapy for patients with paroxysmal atrial fibrillation who have recurrent episodes of arrhythmia despite antiarrhythmic drug therapy. 1 – 8 It has been suggested that pulmonary-vein isolation can also be used as first-line treatment in selected patients with paroxysmal atrial fibrillation, 6 and there are physiological reasons to assume that ablation as first-line therapy might be more effective than later intervention. Irreversible structural changes such as fibrosis and myolysis are commonly detected in the atria when atrial fibrillation has become persistent, 9 , 10 and extensive atrial fibrosis detected by magnetic resonance imaging predicts a poor outcome . . .

Based on recent findings, an increased late sodium current (I ) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is I and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased I in heart diseases, and also discusses how the upregulated I can play a role in the generation of cardiac arrhythmias. The last part of the article is about I inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.

Voltage-gated sodium channel Na V 1.5 is essential for cardiac excitability, mediating the rapid depolarization phase of the cardiac action potential (AP) and ensuring proper electrical conduction in the heart. Dysfunction of Na V 1.5 is implicated in life-threatening arrhythmias, making it a critical therapeutic target. Acting as a Na V 1.5 open-state blocker, quinidine demonstrates efficacy in arrhythmia treatment, but its low specificity restricts its clinical application. Here, we report an optopharmacological strategy that enables a precise and optical control of Na V 1.5 function by means of photoswitchable quinidine derivatives. Through systematic structural optimization, we identify azo-Q2a as a high-performance photoswitchable inhibitor, exhibiting low activity in the dark or under 480 nm light irradiation ( trans isomer), while approximately 7-fold higher efficacy is observed under 365 nm light irradiation ( cis isomer). Of note, azo-Q2a demonstrates exceptional selectivity for Na V 1.5 over cardiac ion channels and other Na V 1 subtypes, minimizing potential off-target effects. Furthermore, by solving the cryo-EM structure of the Na V 1.5 in complex with the cis -active isomer azo-Q2a (3.0 Å resolution), we reveal the essential binding site that is responsible for the optical control of Na V 1.5. Finally, azo-Q2a also attenuates the heart rate of living zebrafish larvae with light, showing its potential in cardiac-related research and treatment. Our work not only establishes azo-Q2a as a robust photoswitchable inhibitor for Na V 1.5 but also provides a structural blueprint for the rational design of next-generation optopharmacological antiarrhythmic agents. This study presents azo-Q2a, a quinidine-derived photo-switchable molecule that enables optical control of Na V 1.5. It exhibits selectivity, and its binding mode is revealed by cryo-EM, offering a potential strategy for managing heart arrhythmia.

An automation-ready workflow enables scalable production and analysis of human pluripotent stem cell–derived 3D cardiac microtissues.The platform supports reproducible, cost-efficient, high-throughput drug screening using calcium transients and voltage signals as functional readouts.Cardiomyocytes from a genetic disease human pluripotent stem cell line, combined with a pharmacological trigger, reliably reproduce an arrhythmic phenotype in the 3D model.Screening more than 2000 compounds confirmed the assay’s ability to identify candidate antiarrhythmic agents.The platform’s advanced technology readiness level supports its use in pharmaceutical testing and regulatory evaluation. Current cardiac cell models for drug screening often face a trade-off between cellular maturity and throughput. 3D human-induced pluripotent stem cell (hiPSC)–based heart models typically exhibit adult-like features, but their use often requires large cell numbers or complex equipment. In this study, we developed cost-effective methods to scale the production of stem cell–derived cardiac microtissues (cMTs) containing three cardiac cell types and assess calcium transients and action potential metrics for high-throughput screening (HTS). Automating the procedure revealed reproducible drug responsiveness and predictive accuracy in a reference compound screen. Furthermore, an arrhythmic phenotype was reliably triggered in cMTs containing cardiomyocytes with an RYR2 mutation. Screening a library of more than 2000 compounds demonstrated the suitability of the assay for identifying potential antiarrhythmic agents. Our findings underscore the scalability of cMTs and their utility in disease modeling and HTS. The advanced technology readiness level of cMTs supports their regulatory uptake and acceptance within the pharmaceutical industry. [Display omitted] 3D cardiac microtissues derived from human pluripotent stem cells offer a physiologically relevant alternative to conventional 2D cultures for cardiac safety and efficacy testing. In this study, we developed a cost-effective, automated platform for high-throughput generation and functional screening of cardiac microtissues. The system enables operator-independent assessment of compound effects on cardiac function using fluorescence-based calcium and voltage assays. With robust detection of both inotropic and arrhythmogenic phenotypes, as well as successful screening of a greater than 2000-compound library, the platform has transitioned from proof-of-concept to a working prototype evaluated under industry-relevant laboratory screening conditions, reaching Technology Readiness Level five. Despite these advances, some challenges remain for full-scale industrial implementation. While the model supports multiplexed readouts, integrating additional end points, such as force measurement or metabolic activity, would further enhance translational relevance but does introduce complexity in assay standardization and data interpretation. In addition, although the system supports the use of patient- and mutation-specific hPSC lines, modeling disease phenotypes remains variable, particularly for conditions with subtle functional changes. To enable broader adoption, standardized criteria for disease phenotype expression and response thresholds will be essential. From a policy standpoint, this work aligns with initiatives such as the FDA Modernization Act 2.0 and the adoption of the ICH S7B/E14 Q&As, both of which promote validated, human-relevant in vitro systems as alternatives to animal testing. Continued alignment with these frameworks, alongside interlaboratory validation, will be critical to transitioning cMTs from research tools to modular, cost-effective, and regulatory-accepted platforms for high-throughput cardiac safety and efficacy assessment. This work establishes scalable, automated methods for producing and screening 3D human stem cell–derived heart tissues. High-throughput screening of more than 2000 compounds shows that this model can predict drug effects on heart rhythm and contractility, paving the way for its use in drug safety and discovery pipelines.

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α1-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α1- but not α2-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α1-adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs.

To ensure safety and efficacy, most Aconitum herbs should be processed before clinical application. The processing methods include boiling, steaming, and sand frying. Among these methods, the transformation pathways of diterpenoid alkaloids in the process of sand frying are more complicated. Therefore, crassicauline A, a natural product with two ester bonds, was chosen as the experimental object. Consequently, a known alkaloid, together with three new alkaloids, was derived from crassicauline A. Meanwhile, the cardiotoxicity of converted products was reduced compared with their parent compound. Interestingly, some diterpenoid alkaloids have similar structures but opposite effects, such as arrhythmia and antiarrhythmic. Considering the converted products are structural analogues of crassicauline A, herein, the antiarrhythmic activity of the transformed products was further investigated. In a rat aconitine-induced arrhythmia assay, the three transformed products, which could dose-dependently delay the ventricular premature beat (VPB) incubation period, reduce the incidence of ventricular tachycardia (VT), combined with the increasing arrhythmia inhibition rate, exhibited prominent antiarrhythmic activities. Our experiments speculated that there might be at least two transformation pathways of crassicauline A during sand frying. The structure-activity data established in this paper constructs the critical pharmacophore of diterpenoid alkaloids as antiarrhythmic agents, which could be helpful in searching for the potential drugs that are equal or more active and with lower toxicity, than currently clinical used antiarrhythmic drugs.

Aim： This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. Methods： Human ether-a-go-go related gene （hERG）, KCNQ and Kvl.2 channels were expressed in CHO cells. The delayed rectifier potassium current （IK） was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-IO0 Rapid Solution Changer. Results： Both DC031050 and dofetilide potently inhibited hERG currents with IC5o values of 2.3＋1.0 and 17.9±1.2 nmol/L, respectively DC031050 inhibited the IK current with an IC50 value of 2.7±1.5 pmol/L, which was 〉1000 times the concentration required to inhibit hERG current. DC031050 at 3 pmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of IK, or the rate of IK from inactivation. Intracellular application of DC031050 （5 pmol/L） was insufficient to inhibit IK. DC031050 up to 10 pmol/L had no effects on KCNQ2 and Kvl.2 channel currents. Conclusion： DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.

The FDA recently approved labeling changes advising against the use of azithromycin in patients with known cardiovascular risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of class IA or class III antiarrhythmic agents. In 2011, approximately 40.3 million people in the United States (roughly one eighth of the population) received an outpatient prescription for the macrolide azithromycin, according to IMS Health. During that year, we at the Food and Drug Administration (FDA) reviewed the labels of azithromycin and other approved macrolide antibacterials in view of cardiovascular risks that had become evident from published studies and reports emerging through postmarketing surveillance. On the basis of its review, the FDA approved revisions to azithromycin product labels regarding risks of QT-interval prolongation and the associated ventricular arrhythmia torsades de pointes. The revised labels advise against using . . .