Multiple hERG channel blocking pathways: implications for macromolecules.

Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents via binding to the channel's inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to 'unconventional' noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics.

Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone.

INTRODUCTION: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. METHODS: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). RESULTS: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. DISCUSSION: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single­lead ECGs collected from freely moving dogs and monkeys.

Torsades de pointes and myocardial infarction following reversal of supraventricular tachycardia with adenosine: a case report.

Adenosine is an antiarrhythmic drug that slows conduction through the atrioventricular node and acts as a coronary blood vessel dilator. This case report highlights two unusual life-threatening events following the use of adenosine to revert supraventricular tachycardia in a structurally normal heart: non-sustained polymorphic ventricular tachycardia and myocardial infarction. A 46-year-old woman presented to the emergency department with a two-hour history of palpitations and was diagnosed with supraventricular tachycardia. Vagal maneuvers were ineffective, and after intravenous adenosine administration, the patient presented with chest pain and hypotension. The rhythm degenerated into non-sustained polymorphic ventricular tachycardia and spontaneously reverted to sinus rhythm with ST elevation in lead aVR and ST depression in the inferior and anterolateral leads. The patient spontaneously recovered within a few minutes. Despite successful arrhythmia reversal, the patient was admitted to the intensive care unit because of an infarction without obstructive atherosclerosis. This report aims to alert emergency physicians about the potential complications associated with supraventricular tachycardia and its reversal with adenosine.

A real-world pharmacovigilance study of QT interval prolongation and Torsades de Pointes associated with CDK4/6 inhibitors in breast cancer patients: findings from the FDA adverse event reporting system.

BACKGROUND: The aim of this study was to evaluate the association between CDK4/6 inhibitors and QT interval prolongation (QTp) and Torsades de Pointes (TdP) in breast cancer patients. METHOD: The cases with breast cancer from 2015 to 2022 were extracted from the FDA adverse event database (FARES) and further divided into a CDK4/6 inhibitor group and a positive control group. The associations between CDK4/6 inhibitors and QTp and TdP adverse events were evaluated using the reporting odds ratio (ROR) and the information component (IC). RESULTS: A total of 172,266 breast cancer patients were included. A total of 234 QTp/TdP events occurred in the CDK4/6 inhibitor group. Disproportionality analysis revealed that ribociclib was related to QTp/TdP. The ROR was 10.10 (95% 8.56-11.92), and the IC was 2.84 (95% 2.28-3.32). Palbociclib and abemaciclib had no correlation with QTP/TDP events. CONCLUSION: Based on this real-world pharmacovigilance analysis, this study demonstrated a significant association between ribociclib and QTp/TdP events, which should attract clinical attention. The QT interval was monitored before and after medication. Attention should be given to adjusting the drugson time.

QT-Interval Prolongation, Torsades de Pointes, and Heart Failure With EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: Systematic Review.

A systematic literature review was conducted to determine the incidence and mortality of QT-interval prolongation (QTp), torsades de pointes (TdP), and heart failure (HF) in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR) TKIs. Of 296 identified publications, 95 met eligibility criteria and were abstracted for QTp/TdP and HF outcomes (QTp/TdP: 83 publications, including 5 case study publications; HF: 79 publications, including 6 case study publications [involving 8 patients]). QTp incidence ranged from 0% to 27.8% in observational studies and from 0% to 11% in clinical trials, with no deaths due to QTp. There were no TdP events or deaths due to TdP. The incidence of HF ranged from 0% to 8%, and HF mortality rates ranged from 0% to 4%. Patients receiving treatment with EGFR TKIs should be monitored for signs of QTp, TdP, and HF per prescribing information. Standardized definitions and methods to improve monitoring of QTp, TdP, and HF-related events are needed in patients with NSCLC.

Assessment of drug utilization and potentially inappropriate medications in hemodialysis patients with end-stage renal dysfunction: A study in a tertiary care hospital in Bahrain.

BACKGROUND: Patients undergoing dialysis pose therapeutic challenges in terms of polypharmacy, administration of potentially inappropriate drugs, and drugs with the potential risk of toxicity. OBJECTIVE: This study evaluated the use of drugs, potentially inappropriate medicines (PIM), drugs with risk of Torsades de Pointes (TdP), and the complexity of the prescribed regimen using the medication regimen complexity index scale in patients undergoing hemodialysis. METHODS: A retrospective cohort study was carried out amongst patients receiving hemodialysis. Drugs were classified into one of four classes: (i) drugs used in managing renal complications, (ii) cardiovascular drugs, (iii) anti-diabetic drugs, (iv) drugs for symptomatic management, and (v) others. Drugs were considered as PIM according to the Can-SOLVE CKD working group from a network of Canadian nephrology health professionals. The study adhered to the CredibleMeds classification of drugs with known, possible, and conditional risk of TdP and the complexity of prescribed medicines was evaluated based on the pre-validated medication regimen complexity index scale based on form/route, frequency of dosing, and requirement of special instructions. RESULTS: Sixty-three participants were included in the study (49 males and 14 females) with the median (range) age of 45 (21-66) years. Cardiovascular drugs followed by drugs used for managing renal complications were the most common classes administered. Notably, 12 (19.1%) patients received one of the non-steroidal anti-inflammatory drugs, 21 (33.3%) received a proton pump inhibitor, three (4.8%) received pregabalin, two (3.2%) received opioid drugs, and one (1.6%) was administered celecoxib. Atorvastatin, furosemide, omeprazole, and allopurinol were the most common PIM drugs administered to the study participants followed by others. Drugs used for symptomatic management had significantly more PIM compared to other classes (p < 0.0001). Six (9.5%) patients received drugs with known TdP risk, one with possible TdP risk, and 61 with conditional risk. Median (range) medical regimen complexity index score was 26.5 (2-62.5). CONCLUSION: A huge burden of drug therapy was observed in the hemodialysis patients in terms of higher proportions of PIM, complex medical regimen, and prescription of drugs with risk of TdP. Implementation of clinical decision support tools enhancing rational prescription and identification of drugs with TdP risk, introducing antimicrobial stewardship, and stepwise deprescription of the drugs with the least benefit-risk ratio are warranted.

Prevalence of Medication Associated with QTc Prolongation Used Among Critically Ill Patients.

Background: Acquired prolonged corrected QT (QTc) interval can lead to life-threatening Torsade de Pointes (TdP) arrhythmia. Multiple risk factors including medications, comorbidities, and electrolyte imbalances contribute significantly to acquired manifestations of the QTc prolongation. Critically ill patients are particularly more vulnerable to TdP due to complex medical conditions, aging, and polypharmacy. Objective: This study aimed to assess the prevalence of TdP-associated medication prescribing, identify risk factors for QTc prolongation and TdP, and determine primary predictors of high TdP medication usage in critically ill patients in Jordan. Methods: We conducted a retrospective cross-sectional analysis of electronic medical records for patients from King Abdullah University Hospital who were admitted to Intensive Care Unit (ICU) between (July 2012-July 2022). We collected data on patients' demographics, clinical characteristics, comorbidities, laboratory results, and prescribed medications. Medications were categorized into three TdP risk levels according to CredibleMeds® assessment tool. Data were analyzed using descriptive statistics and a binary logistic regression model. Results: Of the 13,300 patients (58.2% male, median age 62 years). Prescribing prevalence for medications with known TdP risk was 19%, possible risk (24.7%), conditional risk (21.6%), and confirmed conditional risk (8.3%). Common comorbidities included hypertension (40.9%), diabetes (33.3%), and cancer (15.4%). Drugs with known TdP risk included citalopram, amiodarone, clarithromycin, and ciprofloxacin. A binary regression model revealed that as age increased, the odds of TdP associated medication prescribing decreased (OR = 0.989, p < 0.001), while patients on more than five medications had higher odds (OR = 4.281, p < 0.001). Conclusion: The study identified a notable prevalence of prescribing for medications with QTc prolongation/TdP risk in critically ill patients. Healthcare providers in the ICU should exercise caution to minimize the inadvertent prescription of TdP associated medications especially among older patients and those with polypharmacy.

First generation antipsychotic-associated serious adverse events in women: a retrospective analysis of a pharmacovigilance database.

BACKGROUND: Women have been under-represented in trials of antipsychotic medications. AIM: Our primary objective was to evaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to men through an analysis of the FDA Adverse Event Reporting System (FAERS). METHOD: We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men. RESULTS: A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71-0.87) for NMS, 0.83 (0.68-1.01) for TD, 1.21 (0.94-1.53) for TdP, 0.71 (0.51-0.98) for AG, and 0.91 (0.68-1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29-2.94) and death associated with reports of AG (ROR = 2.46, 1.15-5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26-2.21) for women relative to men for TdP. CONCLUSION: The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.

Torsade de pointes secondary to long QT syndrome after intragastric balloon placement. A rare but severe complication.

The obesity pandemic is becoming one of the most prevalent diseases nowadays. There is a wide spectrum of treatment, ranging from hygienic-dietary measures to bariatric surgery. Endoscopic intragastric balloon placement is becoming increasingly more frequent, due to its technical simplicity, safety and short-term success(1). Although complications are rare some can be severe, so pre-endoscopic evaluation must be carried out carefully. A 43-year-old woman with a history of grade I obesity (BMI 32.7) had an Orbera® intragastric balloon implanted successfully. After the procedure she presented frequent nausea and vomiting, partially controlled with antiemetics. She attended the Emergency Department(ED) with a persistent emetic syndrome - oral intolerance and short-term loss of consciousness(syncope), for which she was admitted. Lab tests showed metabolic alkalosis with severe hypokalemia(K+ 1.8mmol/L), so fluid therapy was initiated for hydroelectrolytic replacement. During the patient's stay in the ED, two episodes of polymorphic ventricular tachychardia "Torsades de Pointes" (PVT-TDP) occurred, leading to cardiac arrest and requiring electrical cardioversion to restore sinus rhythm, in addition to a temporary pacemaker placement. Telemetry showed a corrected QT interval of >500ms, compatible with Long QT Syndrome(LQTS). Once the patient was hemodynamically stabilized a gastroscopy was performed. The intragastric balloon located in the fundus was removed using an extraction kit, puncturing and aspirating 500ml of saline solution, and extracting the collapsed balloon without any complications. The patient achieved an adequate oral intake afterwards, and no recurrence of emetic episodes were noticed. Previous ECGs revealed a prolonged QT interval and a genetic study confirmed a congenital type 1 LQTS. Treatment was initiated with beta-blockers and a bicameral automatic defibrillator was implanted in order to prevent recurrences. Intragastric balloon placement is generally a safe procedure, serious complications present in 0.70% of cases(2). It is essential to have a proper pre-endoscopic evaluation, including patient's medical history and comorbidities. Episodes of PVT-TDP may present precipitated by certain medications (eg. metoclopramide) or hydroelectrolytic imbalances (eg, hypokalemia)(3). A standardized evaluation of ECG before intragastric balloon placement may be useful to prevent these rare but serious complications.

ICH S7B In Vitro Assays Do Not Address Mechanisms of QTC Prolongation for Peptides and Proteins - Data in Support of Not Needing Dedicated QTC Studies.

Current cardiac safety testing focuses on detecting drug-induced QTC prolongation as a surrogate for risk of Torsade de Pointes. The nonclinical strategy, described in International Conference on Harmonization (ICH) S7B, includes in vitro assessment of hERG block or ventricular repolarization delay and in vivo QT prolongation. Several studies have reported predictive values of ICH S7B results for clinical QTC outcomes for small molecules; none has examined peptides and proteins other than monoclonal antibodies. To address this knowledge gap, information for peptides and proteins submitted to the US Food and Drug Administration (FDA) was collected. Results of hERG assays, ventricular repolarization assays, and in vivo QT assessment were compared with clinical QTC study outcomes. The results show that 14% clinical QTC studies for approved and investigational products failed to exclude 10-ms QTC prolongation. Clinical QTC prolongation for these molecules lacked concentration-dependence which is expected for hERG block-mediated mechanism or QTC prolongation could not be excluded due to characterization in the clinical study. The hERG and ventricular repolarization assays do not identify clinical QTC prolongation potential for peptides and proteins. Lack of alignment between hERG and ventricular repolarization assay results and clinical QTC outcomes suggests that the mechanisms of QTC prolongation by some peptides and proteins are unrelated to direct cardiac ion channel block. Similar to large targeted proteins and monoclonal antibodies, peptides and proteins regardless of size have a low likelihood of direct cardiac ion channel interactions. This characteristic supports waiving the requirement for thorough QT assessment for products comprised of naturally occurring amino acids unless proarrhythmia potential is suggested by nonclinical or clinical data.

Taquicardia ventricular polimórfica tipo torsadess de pointes secundaria a estimulación por marcapasos / Polymorphic ventricular taquicardia "torsades de pointes" associated to abnormal pacemaker stimulation

La taquicardia ventricular polimórfica se origina en los ventrículos, cuyos complejos QRS son de morfología, amplitud y dirección variable, con frecuencias que oscilan entre 200 y 250 lpm, pudiendo ser autolimitadas o degenerar en una fibrilación ventricular. La TdP es un tipo de taquicardia ventricular polimórfica caracterizada por complejos con un eje eléctrico que gira alrededor de la línea isoeléctrica y que está asociada a QT largo. Se presenta el caso de una paciente portadora de marcapaso que presenta episodios de taquicardia ventricular polimórfica, con una morfología típica de TdP, sin documentación de QT prolongado previo ni actual, generada por la estimulación ventricular sobre onda T, de forma accidental por desplazamiento del electrodo auricular a Ventrículo Derecho (VD).

Polymorphic ventricular tachycardia is a tachycardia originating in the ventricles, where the QRS complexes have variable morphology, amplitude, and direction, with frequencies ranging between 200 and 250 bpm; it may be self-limited or degenerate into ventricular fibrillation. Torsades de Pointes (TdP) is a type of polymorphic ventricular tachycardia characterized by complexes with an electrical axis that rotates around the isoelectric line and that is associated with long QT interval. We present the case of a patient with a pacemaker who presents episodes of polymorphic ventricular tachycardia, with a typical morphology of TdP, without documentation of previous or current prolonged QT, generated by ventricular stimulation on the T wave, accidentally due to displacement of the atrial electrode to the Right Ventricle (RV).

Prolonged Exposure to Remdesivir Inhibits the Human Ether-A-Go-Go-Related Gene Potassium Current.

ABSTRACT: Remdesivir, approved for the treatment of COVID-19, has been associated with heart-rate corrected QT interval (QTc) prolongation and torsade de pointes in case reports. However, data are conflicting regarding the ability of remdesivir to inhibit the human ether-a-go-go-related gene (hERG) -related current. The objective of this study was to investigate the effects remdesivir and its primary metabolite, GS-441524, on hERG-related currents. Human embryonic kidney 293 cells stably expressing hERG were treated with various concentrations of remdesivir and GS-441524. The effects of acute and prolonged exposure on hERG-related current were assessed using whole-cell configuration of voltage-clamp protocols. Acute exposure to remdesivir and GS-441524 had no effect on hERG currents and the half-activation voltage (V 1/2 ). Prolonged treatment with 100 nM and 1 µM remdesivir significantly reduced peak tail currents and hERG current density. The propensity for remdesivir to prolong QTc intervals and induce torsade de pointes in predisposed patients warrants further investigation.

Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation.

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

Pharmacological Risk Assessment Among Older Patients with Polypharmacy Using the Clinical Decision Support System Janusmed Risk Profile: A Cross-Sectional Register Study.

BACKGROUND: Polypharmacy in older people is steadily increasing and a combination of many medicines may result in adverse effects, especially if the medicines interact pharmacodynamically. Examples are additive or synergistic effects increasing the risk of falls, haemorrhage, serotonin syndrome and torsade de pointes. The clinical decision support system Janusmed Risk Profile has been developed to find such risks based on a patients' medication list. OBJECTIVES: The main aim of this retrospective register-based study was to study what pharmacodynamic risks older patients (aged 65 years or older) on polypharmacy (defined as using five or more medicines) are exposed to. Second, we studied if the introduction of the Janusmed Risk Profile in the main electronic health record system in Region Stockholm influenced the proportion of patients prescribed combinations that increase the risk for the nine adverse-effect categories defined (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonin syndrome). METHODS: Data on all prescription medicines to individuals aged 65 years or older, and with at least five concomitant medicines were retrieved and analysed for the risk categories in the Janusmed Risk Profile. The proportions of patients with a high/moderate risk during a 4-month period before (period 1) and after (period 2) the introduction were compared. RESULTS: A total of 127,719 patients in period 1 (November 2016-February 2017), and 131,458 patients in period 2 (November 2017-February 2018) were included in the study. The proportion of patients with a high or moderate risk for each of the nine properties (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonergic effects) were 10.9, 34.7, 32.8, 33.6, 17.2, 0.7, 15.4, 0.5 and 2.4%, respectively, in period 1 and 10.4, 35.5, 32.8, 33.3, 10.8, 0.71, 14.9, 0.5 and 2.3% in period 2. The changes for sedation and QT prolongation were statistically significant, with the most pronounced decrease for QT prolongation from 17.2 to 10.8% (p < 0.001). When analysing patients at a high risk, the decrease was significant for haemorrhage, orthostatism, QT prolongation and sedation. CONCLUSIONS: Older people are exposed to combinations of medications that increase the risk for potentially severe adverse effects. Prescribers seem to respond especially to warnings for QT prolongation, presented in the Janusmed Risk Profile implemented in the electronic health record system.

Contribution of cytokine-mediated prolongation of QTc interval to the multi-hit theory of Torsade de Pointes.

BACKGROUND: Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine). METHODS: Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate IKr inhibition at varying IL-6 and quetiapine concentrations. RESULTS: IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p = .0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD90:179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p = .0357). When hypokalemia was introduced, the APD90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p = .2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p = .2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate IKr inhibition. CONCLUSIONS: Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting.

The atypic antipsychotic clozapine inhibits multiple cardiac ion channels.

Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/KV11.1 potassium channels, a pharmacological property associated with increased risk of potentially fatal Torsades de Pointes (TdP) and sudden cardiac death (SCD). Yet, the long-standing clinical practice of clozapine does not show a consistent association with increased incidence of TdP, although SCD is considerably higher among schizophrenic patients than in the general population. Here, we have established the inhibitory profile of clozapine at the seven cardiac ion currents proposed by the ongoing comprehensive in vitro pro-arrhythmia (CiPA) initiative to better predict new drug cardio-safety risk. We found that clozapine inhibited all CiPA currents tested with the following rank order of potency: KV11.1 > NaV1.5 (late current) ≈ CaV1.2 ≈ NaV1.5 (peak current) ≈ KV7.1 > KV4.3 > Kir2.1 (outward current). Half-maximal inhibitory concentrations (IC50) at the repolarizing KV11.1 and KV7.1 channels, and at the depolarizing CaV1.2 and NaV1.5 channels fell within a narrow half-log 3-10 µM concentration range, suggesting that mutual compensation could explain the satisfactory arrhythmogenic cardio-safety profile of clozapine. Although the IC50 values determined herein using an automated patch-clamp (APC) technique are at the higher end of clozapine plasmatic concentrations at target therapeutic doses, this effective antipsychotic appears prone to distribute preferentially into the cardiac tissue, which supports the clinical relevance of our in vitro pharmacological findings.

Cardiac Arrest Following Torsades de Pointes Caused by Hypokalemia and Catecholamines in a Patient with Congenital Long QT Syndrome Type 1 After Surgical Aortic Valve Replacement: A Case Report.

BACKGROUND Prevention of lethal arrhythmias in congenital long QT syndrome type 1 (LQT1) requires avoidance of sympathoexcitation, drugs that prolong QT, and electrolyte abnormalities. However, it is often difficult to avoid all these risks in the perioperative period of open heart surgery. Herein, we report hypokalemia-induced cardiac arrest in a postoperative cardiac patient with LQT1 on catecholamine. CASE REPORT A 79-year-old woman underwent surgical aortic valve replacement for severe aortic stenosis. Although the initial plan was not to use catecholamine, catecholamine was used in the Postoperative Intensive Care Unit with attention to QT interval and electrolytes due to heart failure caused by postoperative bleeding. Serum potassium levels were controlled above 4.5 mEq/L, and no arrhythmic events occurred. On postoperative day 4, the patient was started on insulin owing to hyperglycemia. Cardiac arrest occurred after the first insulin dose; the implantable cardioverter defibrillator was activated, and the patient's own heartbeat resumed. Subsequent examination revealed that a marked decrease in serum potassium level had occurred after insulin administration. The electrocardiogram showed obvious QT prolongation and ventricular fibrillation following R on T. Thereafter, under strict potassium management, there was no recurrence of cardiac arrest events. CONCLUSIONS A patient with LQT1 who underwent open heart surgery developed ventricular fibrillation after Torsades de Pointes, probably due to hypokalemia after insulin administration in addition to catecholamine. It is important to check serum potassium levels to avoid the onset of Torsades de Pointes in patients with long QT syndrome. In addition, the impact of insulin administration was reaffirmed.

Determination of five positive control drugs in hERG external solution (buffer) by LC-MS/MS to support in vitro hERG assay as recommended by ICH S7B.

ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated with clinical QTC prolongation as well as the rare, but potentially fatal ventricular tachyarrhythmia Torsade de Pointes (TdP). During recording, drug concentrations perfused to the cells can deviate from nominal concentrations due to molecule-specific properties (such as non-specific binding), thereby introducing error when assessing drug potency. To account for this potential source of error, both the original ICH S7B and the newly released ICH E14/S7B Q&As guidelines call for verifying drug solutions' concentrations. Dofetilide, cisapride, terfenadine, sotalol and E-4031 are hERG blockers commonly used as positive controls to illustrate hERG assay sensitivity. The first four compounds are also clinical drugs associated with high TdP risk; therefore, their safety margins may be useful comparators to better understand an investigational product's TdP risk. Having analytical methods to quantify these five compounds in the hERG external solution that will be used for patch clamp recordings is important from a regulatory science research perspective. However, a literature search revealed no analytical methods or stability information for these molecules in the high salt, serum-free matrix that constitutes the hERG external solution. This study was conducted to develop and validate LC-MS/MS methods to quantify these 5 molecules in hERG external solution. The bioanalytical methods for these positive controls were validated as per the FDA's bioanalytical method validation guidance along with various stabilities.