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Current Protocols Feb 2024In vitro electrophysiological safety studies have become an integral part of the drug development process because, in many instances, compound-induced QT prolongation...
In vitro electrophysiological safety studies have become an integral part of the drug development process because, in many instances, compound-induced QT prolongation has been associated with a direct block of human ether-a-go-go-related gene (hERG) potassium channels or their native current, the rapidly activating delayed rectifier potassium current (I ). Therefore, according to the ICH S7B guideline, the in vitro hERG channel patch-clamp assay is commonly used as an early screen to predict the ability of a compound to prolong the QT interval prior to first-in-human testing. The protocols described in this article are designed to assess the effects of acute or long-term exposure to new chemical entities on the amplitude of I in HEK293 cells stably transfected with the hERG channel (whole-cell configuration of the patch-clamp technique). Examples of results obtained with moxifloxacin, terfenadine, arsenic, pentamidine, erythromycin, and sotalol are provided for illustrative purposes. © 2024 Wiley Periodicals LLC. Basic Protocol: Measurement of the acute effects of test items in the hERG channel test Alternate Protocol: Measurement of the long-term effects of test items in the hERG channel test.
Topics: Humans; Ether-A-Go-Go Potassium Channels; Patch-Clamp Techniques; HEK293 Cells; Sotalol; Erythromycin
PubMed: 38334240
DOI: 10.1002/cpz1.959 -
Environmental Science and Pollution... Mar 2024Wastewater-based epidemiology (WBE) has been already proposed by several authors for estimating the consumption of drugs, mainly the illicit ones. However, not much...
Wastewater-based epidemiology (WBE) has been already proposed by several authors for estimating the consumption of drugs, mainly the illicit ones. However, not much information is available about the actual reliability of this tool given the absence of comparison with the actual consumption. This work aims to evaluate the reliability of the WBE as a tool for estimating the consumption of pharmaceuticals in urban area. Measured consumption back-calculated with a WBE approach was compared with prescription of pharmaceutical products as "control." Moreover, seasonal influence on (i) pharmaceutical consumption, (ii) load of pharmaceutical products in the sewer system, and (iii) reliability of WBE was evaluated. Ciprofloxacin, sulfamethoxazole, metoprolol, carbamazepine, and citalopram were estimated by WBE with a difference respect to the "control" value lower than 0.2 order of magnitude while only trimethoprim and sotalol exceeded the 0.5 order of magnitude of difference but below the 1 order of magnitude. Sedatives were the best represented by WBE (on average 0.15 order of magnitude of difference compared to prescription data). However, further studies are suggested to fully estimate the influence of the type of APs on the reliability of the WBE. Seasonal patterns were found for the load of ciprofloxacin in the sewer and for the consumption of sulfamethoxazole and trimethoprim by population but seasonal changes did not have a significant impact (p > 0.05) on the reliability of WBE. Despite some gaps remained to optimize the reliability of the tool, WBE can be considered a valid method to estimate the consumption of prescribed drugs from the analysis of the sewer system.
Topics: Wastewater-Based Epidemiological Monitoring; Seasons; Wastewater; Reproducibility of Results; Water Pollutants, Chemical; Ciprofloxacin; Sulfamethoxazole; Trimethoprim; Pharmaceutical Preparations
PubMed: 38316739
DOI: 10.1007/s11356-024-32110-w -
Primary Care Mar 2024Ventricular tachyarrhythmias remain a major cause of sudden cardiac arrest (SCA) that leads to sudden cardiac death (SCD). Primary prevention strategies to prevent SCD... (Review)
Review
Ventricular tachyarrhythmias remain a major cause of sudden cardiac arrest (SCA) that leads to sudden cardiac death (SCD). Primary prevention strategies to prevent SCD include promoting a healthy lifestyle, following United States Preventive Service Task Force recommendations related to cardiovascular disease, and controlling comorbid conditions. For a patient experiencing SCA, early cardiopulmonary resuscitation and defibrillation should be performed. Implantable cardioverter defibrillators are more effective at secondary prevention compared with drug therapy but medications such as amiodarone, beta-blockers, and sotalol may be helpful adjuncts to reduce the risk of SCD or improve a patient's symptoms (eg, palpitations and inappropriate defibrillator shocks).
Topics: Humans; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Heart Arrest; Defibrillators, Implantable; Sotalol
PubMed: 38278568
DOI: 10.1016/j.pop.2023.07.008 -
Journal of Cardiovascular Pharmacology... 2024Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly...
Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% ( = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.
Topics: Aged, 80 and over; Humans; Inpatients; Phenethylamines; Retrospective Studies; Sotalol; Sulfonamides
PubMed: 38258374
DOI: 10.1177/10742484231224536 -
Europace : European Pacing,... Feb 2024Although guidelines for the management of atrial fibrillation (AF) are regularly published, many controversial issues remain, limiting their implementation. We aim to...
Current management of atrial fibrillation in routine practice according to the last ESC guidelines: an EHRA physician survey-how are we dealing with controversial approaches?
AIMS
Although guidelines for the management of atrial fibrillation (AF) are regularly published, many controversial issues remain, limiting their implementation. We aim to describe current clinical practice among European Heart Rhythm Association (EHRA) community according to last guidelines.
METHODS AND RESULTS
A 30 multiple-choice questionnaire covering the most controversial topics related to AF management was distributed through the EHRA Research Network, National Societies, and social media between January and February 2023. One hundred and eighty-one physicians responded the survey, 61% from university hospitals. Atrial fibrillation screening in high-risk patients is regularly performed by 57%. Only 42% has access to at least one programme aiming at diagnosing/managing comorbidities and lifestyle modifications, with marked heterogeneity between countries. Direct oral anticoagulants are the preferred antithrombotic (97%). Rhythm control is the preferred strategy in most AF phenotypes: symptomatic vs. asymptomatic paroxysmal AF (97% vs. 77%), low vs. high risk for recurrence persistent AF (90% vs. 72%), and permanent AF (20%). I-C drugs and amiodarone are preferred while dronedarone and sotalol barely used. Ablation is the first-line therapy for symptomatic paroxysmal AF (69%) and persistent AF with markers of atrial disease (57%) and is performed independently of symptoms by 15%. In persistent AF, 68% performs only pulmonary vein isolation and 32% also additional lesions.
CONCLUSION
There is marked heterogeneity in AF management and limited accordance to last guidelines in the EHRA community. Most of the discrepancies are related to the main controversial issues, such as those related to AF screening, management of comorbidities, pharmacological treatment, and ablation strategy.
Topics: Humans; Atrial Fibrillation; Comorbidity; Surveys and Questionnaires; Sotalol; Anticoagulants; Treatment Outcome
PubMed: 38227804
DOI: 10.1093/europace/euae012 -
Journal of Veterinary Cardiology : the... Feb 2024A one-year-and-seven-month-old, 28 kg, male castrated crossbreed dog was presented for supraventricular tachycardia causing recurrent episodes of anorexia and lethargy....
A one-year-and-seven-month-old, 28 kg, male castrated crossbreed dog was presented for supraventricular tachycardia causing recurrent episodes of anorexia and lethargy. Sotalol (2.2 mg/kg q12 h) reduced the frequency of symptomatic episodes but did not provide full relief. Three-dimensional electroanatomical mapping was performed at the Ghent University Small Animal Teaching hospital using the CARTO 3. Right atrial activation mapping identified the earliest atrial activation right posteroseptal, near the tricuspid annulus. Fast retrograde ventriculoatrial conduction during tachycardia and extrastimulus testing confirmed the presence of a concealed right posteroseptal accessory pathway. Six radiofrequency catheter ablation applications were delivered, and tachycardia remained uninducible. The dog recovered well from the procedure. Sotalol was stopped three weeks later, and no more clinical signs were noted by the owner. Repeated 24-hour electrocardiography monitoring on day one and at one, three, and 12 months after the procedure showed no recurrence of tachycardia.
Topics: Humans; Male; Dogs; Animals; Heart Conduction System; Sotalol; Tachycardia, Supraventricular; Tachycardia; Electrocardiography; Catheter Ablation; Dog Diseases
PubMed: 38198978
DOI: 10.1016/j.jvc.2023.12.002 -
The Medical Letter on Drugs and... Jan 2024
Topics: Humans; Atrial Fibrillation
PubMed: 38180321
DOI: 10.58347/tml.2024.1693a -
Journal of Veterinary Cardiology : the... Feb 2024The objective of this study was to describe the single- and multiple-dose pharmacokinetics and urinary elimination of sotalol in healthy cats.
INTRODUCTION/OBJECTIVES
The objective of this study was to describe the single- and multiple-dose pharmacokinetics and urinary elimination of sotalol in healthy cats.
ANIMALS
Six adult purpose-bred cats MATERIALS AND METHODS: Cats were administered 2 mg sotalol/kg body weight as a single intravenous bolus and as a single oral dose in a randomized crossover study with a two-week washout period. The same cats then received 3 mg sotalol/kg orally every 12 h for two weeks. Blood samples were collected at predetermined time points for 48 h postdose for quantification of sotalol using ultra-high-pressure liquid chromatography with mass spectrometry. Non-compartmental analysis was used to obtain pharmacokinetic parameters. Data are presented as median (min-max).
RESULTS
Following intravenous administration, plasma clearance and volume of distribution were 9.22 mL/min/kg (5.69-10.89 mL/min/kg) and 2175.56 mL/kg (1961-2341.57 mL/kg), respectively. Bioavailability was 88.41% (62.75-130.29) following a single oral dose. Peak plasma concentration (C) and time to C were 0.94 μg/mL (0.45-1.17 μg/mL) and 1.5 h (0.5-4 h) after a single oral dose (2 mg/kg), and 2.29 μg/mL (1.91-2.48 μg/mL) and 1.0 h (0.5-1.5 h) with chronic oral dosing (3 mg/kg), respectively. Elimination half-life was 2.75 h (2.52-4.10 h) and 4.29 h (3.33-5.53 h) for single and chronic oral dosing, respectively. Accumulation index was 1.17 (1.09-1.29) after chronic dosing. Urinary sotalol recovery was 81-108% of the intravenous dose.
CONCLUSIONS
Oral sotalol administration resulted in plasma concentrations reportedly efficacious in other species, with good to excellent oral bioavailability. Urinary excretion appears to be a major route of elimination. Following repeated oral dosing, minimal drug accumulation was estimated. Additional studies in cats are recommended due to the possibility of nonlinear kinetics.
Topics: Cats; Animals; Sotalol; Cross-Over Studies; Infusions, Intravenous; Chromatography, High Pressure Liquid; Biological Availability; Administration, Oral; Half-Life
PubMed: 38118234
DOI: 10.1016/j.jvc.2023.11.015 -
JACC. Clinical Electrophysiology Jan 2024
Topics: Humans; Sotalol; Anti-Arrhythmia Agents; Atrial Fibrillation; Administration, Intravenous; Heart Defects, Congenital
PubMed: 38099879
DOI: 10.1016/j.jacep.2023.09.021 -
Journal of Arrhythmia Dec 2023Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF....
OBJECTIVE
Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF. However, no studies have examined the relationship between antidepressant use and AF burden (time in AF). This retrospective cohort study examined cardiac implantable device-detected AF episodes and their relationship with antidepressant use, among other treatment factors.
METHODS
Consecutive patients from the Western Health Cardiology Department attending pacemaker checks between 2015 and 2021 were included. Patients with permanent AF were excluded, yielding 285 patients with no or paroxysmal AF, with a total of 772 patient encounters. Generalized estimating equations were used to model two processes: binary AF (present/absent) and the number of days in AF for patients with AF.
RESULTS
Each yearly increase with age was associated with an increase in the odds of developing AF (OR 1.03 [1.00-1.05], = .027). Male gender conferred a reduction in AF incidence (OR 0.30 [0.13-0.68], = .004). Digoxin use was associated with incident AF (OR 4.43 [1.07-18.4], = .04). Sotalol and heart-failure beta blocker use were associated with a decrease in AF burden (IRR 0.30 [0.12-0.78], = .013 and 0.33 [0.14-0.81], = .015). Selective serotonin reuptake inhibitor antidepressant use was associated with reduced AF burden (IRR 0.27 [0.09-0.81], = .019), as was selective serotonin/noradrenaline reuptake inhibitor use (IRR 0.07 [0.03-0.15], < .001).
CONCLUSIONS
Older age, female gender and digoxin are associated with a higher odds of developing incident AF. Sotalol, heart failure beta blockers and serotonin-based antidepressants are associated with reduced AF burden. Further prospective study into the effects of antidepressants on atrial arrhythmias is warranted.
PubMed: 38045466
DOI: 10.1002/joa3.12948