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Environmental Toxicology and... Oct 2020Digoxin is a cardiac glycoside used as drug in case of heart problems, including congestive heart failure, atrial fibrillation or flutter, and certain cardiac... (Review)
Review
Digoxin is a cardiac glycoside used as drug in case of heart problems, including congestive heart failure, atrial fibrillation or flutter, and certain cardiac arrhythmias. It has a very narrow therapeutic window of the medication. Digoxin is toxic substance with well known cardiotoxic effect. In this work, pharmacology and toxicology of digoxin are summarized; Its pharmacokinetics, pharmacodynamics, available acute toxicity data (different species, different administration routes) are summarized in this article. Moreover, its treatment side effect and human poisonings are thoroughly discussed. Finally, appropriate therapy regimen is proposed.
Topics: Animals; Digoxin; Drug Interactions; Humans; Poisoning
PubMed: 32464466
DOI: 10.1016/j.etap.2020.103400 -
Journal of the American College of... Mar 2018Digoxin is widely used in patients with atrial fibrillation (AF). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Digoxin is widely used in patients with atrial fibrillation (AF).
OBJECTIVES
The goal of this paper was to explore whether digoxin use was independently associated with increased mortality in patients with AF and if the association was modified by heart failure and/or serum digoxin concentration.
METHODS
The association between digoxin use and mortality was assessed in 17,897 patients by using a propensity score-adjusted analysis and in new digoxin users during the trial versus propensity score-matched control participants. The authors investigated the independent association between serum digoxin concentration and mortality after multivariable adjustment.
RESULTS
At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 0.96 to 1.23; p = 0.19). However, patients with a serum digoxin concentration ≥1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR: 1.56; 95% CI: 1.20 to 2.04) compared with those not on digoxin. When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score-matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users.
CONCLUSIONS
In patients with AF taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations ≥1.2 ng/ml. Initiating digoxin was independently associated with higher mortality in patients with AF, regardless of heart failure.
Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Cause of Death; Correlation of Data; Death, Sudden; Digoxin; Female; Heart Failure; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Risk Assessment; Risk Factors
PubMed: 29519345
DOI: 10.1016/j.jacc.2017.12.060 -
Current Cardiology Reviews 2020Digoxin has been used for more than 50 years in patients with Atrial Fibrillation (AF), with the goal of Controlling Heart Rate (HR) and restoring sinus rhythm. In the... (Review)
Review
Digoxin has been used for more than 50 years in patients with Atrial Fibrillation (AF), with the goal of Controlling Heart Rate (HR) and restoring sinus rhythm. In the last two decades, several studies have correlated therapeutic use of digoxin with increased mortality. However, such studies have potential biases that cannot be disregarded, mainly because they are cross-sectional experiments or post-hoc analyses of Randomized Controlled Trials (RCTs). Despite uncertainties regarding the safety of digoxin in this setting, it remains one of the most prescribed drugs for AF worldwide. On the other hand, the absence of any RCTs designed to evaluate mortality makes a definitive conclusion more difficult to reach; therefore, this medication must be used with care. In this review, we explored the therapeutic use of digoxin in the context of AF, discussed mortality data by means of critical analysis in the light of the best available evidence, and position ourselves in relation to more rigorous control of serum levels of this drug in daily practice.
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Cross-Sectional Studies; Digoxin; Humans
PubMed: 31237216
DOI: 10.2174/1573403X15666190618110941 -
Annals of the Rheumatic Diseases Apr 2022Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage...
OBJECTIVES
Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA.
METHODS
Screening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of digoxin in vitro; Assays for defining the therapeutic effects of digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; identification and characterisation of the binding of digoxin to low-density lipoprotein receptor-related protein 4 (LRP4); various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of digoxin regulation of chondrocytes.
RESULTS
Serial screenings led to the identification of ouabain and digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and digoxin protected against OA and relieved OA-associated pain. The cohort study of 56 794 patients revealed that digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin's regulations of chondrocytes.
CONCLUSIONS
These findings not only provide new insights into the understanding of digoxin's chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for OA.
Topics: Cartilage, Articular; Chondrocytes; Cohort Studies; Digoxin; Drug Repositioning; Humans; LDL-Receptor Related Proteins; Osteoarthritis; Ouabain
PubMed: 34853001
DOI: 10.1136/annrheumdis-2021-221380 -
Nature Communications Jul 2023Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts...
Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.
Topics: Animals; Mice; Autophagy; Digoxin; Fatty Acids; Hepatitis; Hepatocytes; Lipid Metabolism; Lipids; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease
PubMed: 37443159
DOI: 10.1038/s41467-023-39404-6 -
JAMA Dec 2020There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure.
OBJECTIVE
To compare low-dose digoxin with bisoprolol (a β-blocker).
DESIGN, SETTING, AND PARTICIPANTS
Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019.
INTERVENTIONS
Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d).
MAIN OUTCOMES AND MEASURES
The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting.
RESULTS
Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, -2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group.
CONCLUSIONS AND RELEVANCE
Among patients with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support potentially basing decisions about treatment on other end points.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13.
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Fibrillation; Bisoprolol; Digoxin; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Quality of Life; Single-Blind Method; Stroke Volume
PubMed: 33351042
DOI: 10.1001/jama.2020.23138 -
Heart Rhythm Jun 2023Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting.
OBJECTIVES
The objectives of this study were to evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety in atrial fibrillation.
METHODS
The effects of ivabradine on atrioventricular node and ventricular cells were studied by in vitro whole-cell patch-clamp experiments and mathematical simulation of human action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine with digoxin for uncontrolled permanent atrial fibrillation despite β-blocker or calcium channel blocker treatment.
RESULTS
Ivabradine 1 μM inhibited "funny" current and rapidly activating delayed rectifier potassium channel current by 28.9% and 22.8%, respectively (P < .05). The sodium channel current and L-type calcium channel current were reduced only at 10 μM. Ivabradine slowed the firing frequency of a modeled human atrioventricular node action potential by 10.6% and induced a minimal prolongation of ventricular action potential. Thirty-five (51.5%) patients were randomized to ivabradine and 33 (49.5%) to digoxin. The mean daytime heart rate decreased by 11.6 beats/min (-11.5%) in the ivabradine arm (P = .02) vs 19.6 (-20.6%) in the digoxin arm (P < .001), although the noninferiority margin of efficacy was not met (Z = -1.95; P = .97). The primary safety end point occurred in 3 patients (8.6%) on ivabradine and in 8 (24.2%) on digoxin (P = .10).
CONCLUSION
Ivabradine produced a moderate rate reduction in patients with permanent atrial fibrillation. The inhibition of funny current in the atrioventricular node seems to be the main mechanism responsible for this reduction. Compared with digoxin, ivabradine was less effective, was better tolerated, and had a similar rate of serious adverse events.
Topics: Humans; Ivabradine; Atrial Fibrillation; Heart Rate; Digoxin; Adrenergic beta-Antagonists
PubMed: 37245897
DOI: 10.1016/j.hrthm.2023.02.012 -
Tidsskrift For Den Norske Laegeforening... Oct 2018
Topics: Anti-Arrhythmia Agents; Digitoxin; Digoxin; Drug Substitution; Humans; Norway
PubMed: 30277041
DOI: 10.4045/tidsskr.18.0700 -
Trends in Cardiovascular Medicine Oct 2016After 230 years of use, digitalis remains an important and useful therapy for patients with atrial fibrillation, heart failure, and the 30-50 % of patients with both... (Review)
Review
After 230 years of use, digitalis remains an important and useful therapy for patients with atrial fibrillation, heart failure, and the 30-50 % of patients with both conditions. Although the combination of positive inotropic activity with negative chronotropic effects has been shown to reduce hospital admissions in heart failure, there is a distinct lack of robust trial data, particularly in patients with atrial fibrillation. We recently performed a comprehensive meta-analysis of all digoxin studies and demonstrated a neutral effect on mortality. This contradicts prior observational data that overlook the fact that digitalis is usually given as second-line therapy to the sickest patients. Use of these agents in clinical practice should take account of appropriate dose, serum concentration, drug interactions, and potential side effects. The aim of this review is to evaluate the evidence base for cardiac glycosides and provide a pragmatic guide to their advantages and disadvantages.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiotonic Agents; Digoxin; Heart Conduction System; Heart Failure; Heart Rate; Heart Ventricles; Humans; Myocardial Contraction; Patient Admission; Patient Selection; Risk Factors; Treatment Outcome
PubMed: 27156593
DOI: 10.1016/j.tcm.2016.03.011 -
BMJ Clinical Evidence May 2015Atrial fibrillation is a supraventricular tachyarrhythmia characterised by the presence of fast and uncoordinated atrial activation leading to reduced atrial mechanical... (Review)
Review
INTRODUCTION
Atrial fibrillation is a supraventricular tachyarrhythmia characterised by the presence of fast and uncoordinated atrial activation leading to reduced atrial mechanical function. Risk factors for atrial fibrillation include increasing age, male sex, co-existing cardiac and thyroid disease, pyrexial illness, electrolyte imbalance, cancer, and co-existing infection.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of oral medical treatments to control heart rate in people with chronic (defined as longer than 1 week for this review) non-valvular atrial fibrillation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found four studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta-blockers (rate-limiting, with or without digoxin), calcium-channel blockers (with or without digoxin), and digoxin.
Topics: Adrenergic beta-Antagonists; Atrial Fibrillation; Digoxin; Drug Therapy, Combination; Humans; Treatment Outcome
PubMed: 25994013
DOI: No ID Found