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Circulation Oct 2023In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory... (Review)
Review
2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.
Topics: Humans; Adrenergic beta-Antagonists; American Heart Association; Benzodiazepines; Cardiopulmonary Resuscitation; Digoxin; Heart Arrest; United States
PubMed: 37721023
DOI: 10.1161/CIR.0000000000001161 -
JACC. Clinical Electrophysiology Apr 2020Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium leading to restrictive heart failure. Both atrial and ventricular... (Review)
Review
Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium leading to restrictive heart failure. Both atrial and ventricular arrhythmias, along with conduction disease, are common in cardiac amyloidosis, and are often highly symptomatic and poorly tolerated. Many commonly used therapeutics such as beta-blockers, calcium-channel blockers, and digoxin may be poorly tolerated and lead to clinical decompensation in this population, adding complexity to the co-management of these conditions. In addition, studies have shown that atrial fibrillation with cardiac amyloidosis carries a high risk of stroke and systemic embolism, making anticoagulation indicated in all patients regardless of CHADS-VASc score. Ventricular arrhythmias are common, whereas an implantable cardioverter-defibrillator has not been shown to improve survival. Conduction disease is also common and permanent pacemaker placement is often needed. High-quality evidence and guideline recommendations are limited with regard to the management of arrhythmias in cardiac amyloidosis. Providers are often left to clinical experience and expert consensus to aid in decision-making. In this focused review, we outline current guideline recommendations, summarize both historical and contemporary data, and describe evidence-based strategies for managing arrhythmias and their sequelae in patients with cardiac amyloidosis.
Topics: Amyloidosis; Atrial Fibrillation; Defibrillators, Implantable; Heart; Humans; Stroke
PubMed: 32327068
DOI: 10.1016/j.jacep.2020.01.004 -
Circulation Aug 2019
2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
Topics: Adrenergic beta-Antagonists; Arrhythmias, Cardiac; Bradycardia; Cardiac Conduction System Disease; Electrocardiography; Electrophysiological Phenomena; Epilepsy; Heart Diseases; Humans; Myocardial Infarction; Quality of Life
PubMed: 30586772
DOI: 10.1161/CIR.0000000000000628 -
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 -
European Geriatric Medicine Jun 2021Adverse drug reactions (ADRs) represent a common and potentially preventable cause of unplanned hospitalization, increasing morbidity, mortality, and healthcare costs.... (Review)
Review
PURPOSE
Adverse drug reactions (ADRs) represent a common and potentially preventable cause of unplanned hospitalization, increasing morbidity, mortality, and healthcare costs. We aimed to review the classification and occurrence of ADRs in the older population, discuss the role of age as a risk factor, and identify interventions to prevent ADRs.
METHODS
We performed a narrative scoping review of the literature to assess classification, occurrence, factors affecting ADRs, and possible strategies to identify and prevent ADRs.
RESULTS
Adverse drug reactions (ADRs) are often classified as Type A and Type B reactions, based on dose and effect of the drugs and fatality of the reaction. More recently, other approaches have been proposed (i.e. Dose, Time and Susceptibility (DoTS) and EIDOS classifications). The frequency of ADRs varies depending on definitions, characteristics of the studied population, and settings. Their occurrence is often ascribed to commonly used drugs, including anticoagulants, antiplatelet agents, digoxin, insulin, and non-steroidal anti-inflammatory drugs. Age-related factors-changes in pharmacokinetics, multimorbidity, polypharmacy, and frailty-have been related to ADRs. Different approaches (i.e. medication review, software identifying potentially inappropriate prescription and drug interactions) have been suggested to prevent ADRs and proven to improve the quality of prescribing. However, consistent evidence on their effectiveness is still lacking. Few studies suggest that a comprehensive geriatric assessment, aimed at identifying individual risk factors, patients' needs, treatment priorities, and strategies for therapy optimization, is key for reducing ADRs.
CONCLUSIONS
Adverse drug reactions (ADRs) are a relevant health burden. The medical complexity that characterizes older patients requires a holistic approach to reduce the burden of ADRs in this population.
Topics: Aged; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Inappropriate Prescribing; Multimorbidity; Polypharmacy
PubMed: 33738772
DOI: 10.1007/s41999-021-00481-9 -
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 -
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 -
British Journal of Pharmacology Mar 2020The first clinically relevant reports of preparations of St. John's wort (SJW), a herbal medicine with anti-depressant effects, interacting with other drugs, altering... (Review)
Review
The first clinically relevant reports of preparations of St. John's wort (SJW), a herbal medicine with anti-depressant effects, interacting with other drugs, altering their bioavailability and efficacy, were published about 20 years ago. In 2000, a pharmacokinetic interaction between SJW and cyclosporine caused acute rejection in two heart transplant patients. Since then, subsequent research has shown that SJW altered the pharmacokinetics of drugs such as digoxin, tacrolimus, indinavir, warfarin, alprazolam, simvastatin, or oral contraceptives. These interactions were caused by pregnane-X-receptor (PXR) activation. Preparations of SJW are potent activators of PXR and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P-glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation. Twenty years after the first occurrence of clinically relevant pharmacokinetic drug interactions with SJW, this review revisits the current knowledge of the mechanisms of action and on how pharmacokinetic drug interactions with SJW could be avoided. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.
Topics: Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Herb-Drug Interactions; Humans; Hypericum; Phytotherapy; Plant Preparations
PubMed: 31742659
DOI: 10.1111/bph.14936