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Journal of Pharmacological and... 2023Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia....
Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities. The use of MLM relies on large libraries of training compounds for the quantitative structure-activity relationship (QSAR) modelling of hERG inhibition. The focus on inhibition omits potential effects of hERG channel agonist molecules and their associated QT shortening risk. It is instructive, therefore, to consider how known hERG agonists are handled by MLM. Here, two highly developed online computational tools for the prediction of hERG liability, Pred-hERG and HergSPred were probed for their ability to detect hERG activator drug molecules as hERG interactors. In total, 73 hERG blockers were tested with both computational tools giving overall good predictions for hERG blockers with reported ICs below Pred-hERG and HergSPred cut-off threshold for hERG inhibition. However, for compounds with reported ICs above this threshold such as disopyramide or sotalol discrepancies were observed. HergSPred identified all 20 hERG agonists selected as interacting with the hERG channel. Further studies are warranted to improve online MLM prediction of hERG related cardiotoxicity, by explicitly taking into account channel agonism as well as inhibition.
Topics: Humans; Potassium Channel Blockers; Ether-A-Go-Go Potassium Channels; Arrhythmias, Cardiac; Machine Learning; Internet
PubMed: 37468081
DOI: 10.1016/j.vascn.2023.107293 -
Heart (British Cardiac Society) Jan 2024Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by fibrofatty replacement of the ventricular myocardium due to specific mutations,... (Review)
Review
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by fibrofatty replacement of the ventricular myocardium due to specific mutations, leading to ventricular arrhythmias and sudden cardiac death. Treating this condition can be challenging due to progressive fibrosis, phenotypic variations and small patient cohorts limiting the feasibility of conducting meaningful clinical trials. Although widely used, the evidence base for anti-arrhythmic drugs is limited. Beta-blockers are theoretically sound, yet their efficacy in reducing arrhythmic risk is not robust. Additionally, the impact of sotalol and amiodarone is inconsistent with studies reporting contradictory results. Emerging evidence suggests that combining flecainide and bisoprolol may be efficacious.Radiofrequency ablation has shown some potential in disrupting ventricular tachycardia circuits, with combined endo and epicardial ablation yielding better results which could be considered at the index procedure. In addition, stereotactic radiotherapy may be a future option that can decrease arrhythmias beyond simple scar formation by altering levels of Nav1.5 channels, Connexin 43 and Wnt signalling, potentially modifying myocardial fibrosis.Future therapies, such as adenoviruses and GSk3b modulation, are still in early-stage research. While implantable cardioverter-defibrillator implantation is a key intervention for reducing arrhythmic death, the risks of inappropriate shocks and device complications must be carefully considered.
Topics: Humans; Arrhythmogenic Right Ventricular Dysplasia; Arrhythmias, Cardiac; Anti-Arrhythmia Agents; Death, Sudden, Cardiac; Sotalol; Tachycardia, Ventricular; Defibrillators, Implantable
PubMed: 37433658
DOI: 10.1136/heartjnl-2023-322612 -
Journal of Comparative Effectiveness... Aug 2023To evaluate the clinical and economic impact of antiarrhythmic drugs (AADs) compared with ablation both as individual treatments and as combination therapy without/with...
To evaluate the clinical and economic impact of antiarrhythmic drugs (AADs) compared with ablation both as individual treatments and as combination therapy without/with considering the order of treatment among patients with atrial fibrillation (AFib). A budget impact model over a one-year time horizon was developed to assess the economic impact of AADs (amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol, and as a group) versus ablation across three scenarios: direct comparisons of individual treatments, non-temporal combinations, and temporal combinations. The economic analysis was conducted in accordance with CHEERS guidance as per current model objectives. Results are reported as costs per patient per year (PPPY). The impact of individual parameters was evaluated using one-way sensitivity analysis (OWSA). In direct comparisons, ablation had the highest annual medication/procedure cost ($29,432), followed by dofetilide ($7661), dronedarone ($6451), sotalol ($4552), propafenone ($3044), flecainide ($2563), and amiodarone ($2538). Flecainide had the highest costs for long-term clinical outcomes ($22,964), followed by dofetilide ($17,462), sotalol ($15,030), amiodarone ($12,450), dronedarone ($10,424), propafenone ($7678) and ablation ($9948). In the non-temporal scenario, total costs incurred for AADs (group) + ablation ($17,278) were lower compared with ablation alone ($39,380). In the temporal scenario, AADs (group) before ablation resulted in PPPY cost savings of ($22,858) compared with AADs (group) after ablation ($19,958). Key factors in OWSA were ablation costs, the proportion of patients having reablation, and withdrawal due to adverse events. Utilization of AADs as individual treatment or in combination with ablation demonstrated comparable clinical benefits along with costs savings in patients with AFib.
Topics: Humans; Atrial Fibrillation; Anti-Arrhythmia Agents; Dronedarone; Sotalol; Propafenone; Flecainide; Amiodarone
PubMed: 37387403
DOI: 10.57264/cer-2023-0065 -
Journal of Hazardous Materials Sep 2023Biological oxygen-dosed activated carbon (BODAC) filters in an Ultrapure water plant were demonstrated to have the potential to further treat secondary wastewater...
Biological oxygen-dosed activated carbon (BODAC) filters in an Ultrapure water plant were demonstrated to have the potential to further treat secondary wastewater treatment effluent. The BODAC filters were operated for 11 years without carbon regeneration or replacement, while still functioning as pre-treatment step to reverse osmosis (RO) membranes by actively removing organic micropollutants (OMPs) and foulants. In this study, the removal of nutrients and 13 OMPs from secondary wastewater treatment effluent was investigated for 2 years and simultaneously, the granules' characterization and microbial community analysis were conducted to gain insights behind the stable long-term operation of the BODAC filters. The results showed that the BODAC granules' surface area was reduced by ∼70 % of what is in virgin carbon granules and covered by biofilm and inorganic depositions. The BODAC filters reduced the concentration of soluble organics, mainly proteins, performed as an effective nitrification system, and almost completely removed manganese. During the 2 years of observation, the filters consistently removed some OMPs such as hydrochlorothiazide, metoprolol, sotalol, and trimethoprim by at least 70 %. Finally, through microbial community analysis, we found that nitrifying and manganese-oxidizing bacteria were detected in high relative abundance on BODAC granules, supporting BODAC performance in removing OMPs and manganese as well as converting nitrogenous species in the water.
Topics: Charcoal; Oxygen; Manganese; Water Pollutants, Chemical; Water Purification; Nutrients
PubMed: 37356180
DOI: 10.1016/j.jhazmat.2023.131882 -
Journal of Pharmacological Sciences Aug 2023We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant...
Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.
We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.
Topics: Dogs; Animals; Rats; Atrial Fibrillation; Torsades de Pointes; Isoflurane; Anti-Arrhythmia Agents
PubMed: 37344055
DOI: 10.1016/j.jphs.2023.05.003 -
Association of sotalol versus atenolol therapy with survival in dogs with severe subaortic stenosis.Journal of Veterinary Cardiology : the... Aug 2023Dogs with severe subaortic stenosis (SAS) are at risk of dying suddenly from fatal arrhythmias. Survival is not improved when treated with pure beta-adrenergic receptor...
INTRODUCTION/OBJECTIVES
Dogs with severe subaortic stenosis (SAS) are at risk of dying suddenly from fatal arrhythmias. Survival is not improved when treated with pure beta-adrenergic receptor (β)-blockers; however, the effect of other antiarrhythmic drugs on survival is unknown. Sotalol is both a β-blocker and a class III antiarrhythmic drug; the combination of these differing mechanisms may provide benefit to dogs with severe SAS. The primary objective of this study was to compare survival in dogs with severe SAS that were treated with either sotalol or atenolol. The secondary objective was to evaluate the effect of pressure gradient (PG), age, breed, and aortic regurgitation on survival.
ANIMALS
Forty-three client-owned dogs.
MATERIALS AND METHODS
Retrospective cohort study. Medical records of dogs diagnosed with severe SAS (PG ≥ 80 mmHg) between 2003 and 2020 were reviewed.
RESULTS
No statistical difference was identified in survival time between dogs treated with sotalol (n=14) and those treated with atenolol (n=29) when evaluating all-cause mortality (p=0.172) or cardiac-related mortality (p=0.157). Of the dogs that died suddenly, survival time was significantly shorter in dogs treated with sotalol compared to those treated with atenolol (p=0.046). Multivariable analysis showed that PG (p=0.002) and treatment with sotalol (p=0.050) negatively influenced survival in the dogs that died suddenly.
CONCLUSIONS
Sotalol did not have a significant effect on survival overall but may increase the risk of sudden death in dogs with severe SAS compared to atenolol.
Topics: Dogs; Animals; Sotalol; Atenolol; Constriction, Pathologic; Retrospective Studies; Anti-Arrhythmia Agents; Adrenergic beta-Antagonists; Aortic Stenosis, Subvalvular; Dog Diseases
PubMed: 37307692
DOI: 10.1016/j.jvc.2023.05.003 -
Journal of Cardiovascular Pharmacology Aug 2023According to the American Heart Association, approximately 6 million adults have been afflicted with heart failure in the United States in 2020 and are more likely to... (Review)
Review
According to the American Heart Association, approximately 6 million adults have been afflicted with heart failure in the United States in 2020 and are more likely to have sudden cardiac death accounting for approximately 50% of the cause of mortality. Sotalol is a nonselective β-adrenergic receptor antagonist with class III antiarrhythmic properties that has been mostly used for atrial fibrillation treatment and suppressing recurrent ventricular tachyarrhythmias. The use of sotalol in patients with left ventricular dysfunction is not recommended by the American College of Cardiology or American Heart Association because studies are inconclusive with conflicting results regarding safety. This article aims to review the mechanism of action of sotalol, the β-blocking effects on heart failure, and provide an overview of clinical trials on sotalol use and its effects in patients with heart failure. Small- and large-scale clinical trials have been controversial and inconclusive about the use of sotalol in heart failure. Sotalol has been shown to reduce defibrillation energy requirements and reduce shocks from implantable cardioverter-defibrillators. Torsades de Pointes is the most life-threatening arrhythmia that has been documented with sotalol use and occurs more commonly in women and heart failure patients. Thus far, mortality benefits have not been demonstrated with sotalol use and larger multicenter studies are required going forward.
Topics: Humans; Female; Sotalol; Anti-Arrhythmia Agents; Adrenergic beta-Antagonists; Heart Failure; Atrial Fibrillation
PubMed: 37229640
DOI: 10.1097/FJC.0000000000001439 -
PharmacoEconomics Aug 2023Atrial fibrillation (AF) remains the most common form of cardiac arrhythmia. Management of AF aims to reduce the risk of stroke, heart failure and premature mortality...
BACKGROUND
Atrial fibrillation (AF) remains the most common form of cardiac arrhythmia. Management of AF aims to reduce the risk of stroke, heart failure and premature mortality via rate or rhythm control. This study aimed to review the literature on the cost effectiveness of treatment strategies to manage AF among adults living in low-, middle- and high-income countries.
METHODS
We searched MEDLINE (OvidSp), Embase, Web of Science, Cochrane Library, EconLit and Google Scholar for relevant studies between September 2022 and November 2022. The search strategy involved medical subject headings or related text words. Data management and selection was performed using EndNote library. The titles and abstracts were screened followed by eligibility assessment of full texts. Selection, assessment of the risk of bias within the studies, and data extraction were conducted by two independent reviewers. The cost-effectiveness results were synthesised narratively. The analysis was performed using Microsoft Excel 365. The incremental cost effectiveness ratio for each study was adjusted to 2021 USD values.
RESULTS
Fifty studies were included in the analysis after selection and risk of bias assessment. In high-income countries, apixaban was predominantly cost effective for stroke prevention in patients at low and moderate risk of stroke, while left atrial appendage closure (LAAC) was cost effective in patients at high risk of stroke. Propranolol was the cost-effective choice for rate control, while catheter ablation and the convergent procedure were cost-effective strategies in patients with paroxysmal and persistent AF, respectively. Among the anti-arrhythmic drugs, sotalol was the cost-effective strategy for rhythm control. In middle-income countries, apixaban was the cost-effective choice for stroke prevention in patients at low and moderate risk of stroke while high-dose edoxaban was cost effective in patients at high risk of stroke. Radiofrequency catheter ablation was the cost-effective option in rhythm control. No data were available for low-income countries.
CONCLUSION
This systematic review has shown that there are several cost-effective strategies to manage AF in different resource settings. However, the decision to use any strategy should be guided by objective clinical and economic evidence supported by sound clinical judgement.
REGISTRATION
CRD42022360590.
Topics: Adult; Humans; Atrial Fibrillation; Cost-Effectiveness Analysis; Developed Countries; Cost-Benefit Analysis; Stroke
PubMed: 37204698
DOI: 10.1007/s40273-023-01276-5 -
Ultrasound in Obstetrics & Gynecology :... Oct 2023While in-utero treatment of sustained fetal supraventricular arrhythmia (SVA) is standard practice in the previable and preterm fetus, data are limited on best practice...
OBJECTIVE
While in-utero treatment of sustained fetal supraventricular arrhythmia (SVA) is standard practice in the previable and preterm fetus, data are limited on best practice for late preterm (34 + 0 to 36 + 6 weeks), early term (37 + 0 to 38 + 6 weeks) and term (> 39 weeks) fetuses with SVA. We reviewed the delivery and postnatal outcomes of fetuses at ≥ 35 weeks of gestation undergoing treatment rather than immediate delivery.
METHODS
This was a retrospective case series of fetuses presenting at ≥ 35 weeks of gestation with sustained SVA and treated transplacentally at six institutions between 2012 and 2022. Data were collected on gestational age at presentation and delivery, SVA diagnosis (short ventriculoatrial (VA) tachycardia, long VA tachycardia or atrial flutter), type of antiarrhythmic medication used, interval between treatment and conversion to sinus rhythm and postnatal SVA recurrence.
RESULTS
Overall, 37 fetuses presented at a median gestational age of 35.7 (range, 35.0-39.7) weeks with short VA tachycardia (n = 20), long VA tachycardia (n = 7) or atrial flutter (n = 10). Four (11%) fetuses were hydropic. In-utero treatment led to restoration of sinus rhythm in 35 (95%) fetuses at a median of 2 (range, 1-17) days; this included three of the four fetuses with hydrops. Antiarrhythmic medications included flecainide (n = 11), digoxin (n = 7), sotalol (n = 11) and dual therapy (n = 8). Neonates were liveborn at 36-41 weeks via spontaneous vaginal delivery (23/37 (62%)) or Cesarean delivery (14/37 (38%)). Cesarean delivery was indicated for fetal SVA in two fetuses, atrial ectopy or sinus bradycardia in three fetuses and obstetric reasons in nine fetuses that were in sinus rhythm at the time of delivery. Twenty-one (57%) cases were treated for recurrent SVA after birth.
CONCLUSION
In-utero treatment of the near term and term (≥ 35-week) SVA fetus is highly successful even in the presence of hydrops, with the majority of cases delivered vaginally closer to term, thereby avoiding unnecessary Cesarean section. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Anti-Arrhythmia Agents; Atrial Flutter; Cesarean Section; Digoxin; Edema; Fetal Diseases; Fetus; Hydrops Fetalis; Retrospective Studies; Tachycardia; Tachycardia, Supraventricular
PubMed: 37128167
DOI: 10.1002/uog.26239