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The Journal of General Virology Apr 2023Drug repurposing is a valuable source of new antivirals because many compounds used to treat a variety of pathologies can also inhibit viral infections. In this work, we...
Drug repurposing is a valuable source of new antivirals because many compounds used to treat a variety of pathologies can also inhibit viral infections. In this work, we have tested the antiviral capacity of four repurposed drugs to treat Bunyamwera virus (BUNV) infection in cell cultures. BUNV is the prototype of the order, a large group of RNA viruses that includes important pathogens for humans, animals and plants. Mock- and BUNV-infected Vero and HEK293T cells were treated with non-toxic concentrations of digoxin, cyclosporin A, sunitinib and chloroquine. The four drugs inhibited BUNV infection with varying potency in Vero cells, and all except sunitinib also in HEK293T cells, with digoxin rendering the lowest half maximal inhibitory concentration (IC). Since digoxin rendered the best results, we selected this drug for a more detailed study. Digoxin is an inhibitor of the Na/K ATPase, a plasma membrane enzyme responsible for the energy-dependent exchange of cytoplasmic Na for extracellular K in mammalian cells and involved in many signalling pathways. Digoxin was shown to act at an early time point after viral entry reducing the expression of the viral proteins Gc and N. Effects on the cell cycle caused by BUNV and digoxin were also analysed. In Vero cells, digoxin favoured the transition from G1 phase of the cell cycle to S phase, an effect that might contribute to the anti-BUNV effect of digoxin in this cell type. Transmission electron microscopy showed that digoxin impedes the assembly of the characteristic spherules that harbour the BUNV replication complexes and the morphogenesis of new viral particles. Both BUNV and digoxin induce similar changes in the morphology of mitochondria that become more electron-dense and have swollen cristae. The alterations of this essential organelle might be one of the factors responsible for digoxin-induced inhibition of viral infection. Digoxin did not inhibit BUNV infection in BHK-21 cells that have a digoxin-resistant Na/K ATPase, which suggests that the effects of the blockade of this enzyme is a key factor of the antiviral activity of digoxin in BUNV-infected Vero cells.
Topics: Humans; Animals; Chlorocebus aethiops; Bunyamwera virus; Vero Cells; Digoxin; Sunitinib; HEK293 Cells; Antiviral Agents; Cell Culture Techniques; Adenosine Triphosphatases; Mammals
PubMed: 37010894
DOI: 10.1099/jgv.0.001838 -
Cardiology 2016Digoxin is one of the oldest compounds used in cardiovascular medicine. Nevertheless, its mechanism of action and most importantly its clinical utility have been the... (Review)
Review
Digoxin is one of the oldest compounds used in cardiovascular medicine. Nevertheless, its mechanism of action and most importantly its clinical utility have been the subject of an endless dispute. Positive inotropic and neurohormonal modulation properties are attributed to digoxin, and it was the mainstay of heart failure therapeutics for decades. However, since the institution of β-blockers and aldosterone antagonists as part of modern heart failure medical therapy, digoxin prescription rates have been in free fall. The fact that digoxin is still listed as a valid therapeutic option in both American and European heart failure guidelines has not altered clinicians' attitude towards the drug. Since the publication of original Digitalis Investigation Group trial data, a series of reports based predominately on observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In the present review, we will attempt a critical appraisal of the available clinical evidence regarding the efficacy and safety of digoxin in heart failure patients with a reduced ejection fraction. The methodological issues, strengths, and limitations of individual studies will be highlighted.
Topics: Cardiotonic Agents; Digoxin; Heart Failure; Humans; Stroke Volume
PubMed: 26959501
DOI: 10.1159/000444078 -
Die Pharmazie Jul 2017Drug delivery systems could be applied to locally treat cervical cancer, thus preventing the drawbacks of conventional therapy. In this study, anti-proliferative and...
Drug delivery systems could be applied to locally treat cervical cancer, thus preventing the drawbacks of conventional therapy. In this study, anti-proliferative and anti-angiogenic effects of digoxin incorporated into poly(ε-caprolactone) implants were evaluated, aiming at the local treatment of cervical cancer. Implants were characterized, and the in vitro release profile of digoxin was demonstrated. Anti-proliferative and anti-angiogenic activities of digoxin were investigated by using chorioallantoic membrane and human cervix carcinoma (HeLa) cells, respectively. The chemical structure of digoxin and the semi-crystalline nature of poly(ε-caprolactone) were preserved after designing implants. The hydrophobicity of drug and polymer as well as the semi-crystalline structure provided a controlled diffusion of digoxin from implants. Digoxin released from implantable devices exhibited anti-proliferative activity against HeLa cells. The anti-angiogenic effect was also shown. Finally, implants composed of digoxin and poly(ε-caprolactone) could be applied as a therapeutic alternative to treat the early stage of cervical cancer, once they were able to locally control the release of this anti-angiogenic and anti-proliferative drug, minimizing its systemic side effects and toxicity.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Chickens; Chorioallantoic Membrane; Crystallization; Digoxin; Drug Carriers; Drug Delivery Systems; Drug Implants; Drug Liberation; Female; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Polyesters; Uterine Cervical Neoplasms
PubMed: 29441934
DOI: 10.1691/ph.2017.6195 -
Current Problems in Cardiology Nov 2023The BRASH (bradycardia, renal failure, atrioventricular block, shock, and hyperkalaemia) syndrome is a recently recognized condition which may lead to life-threatening...
The BRASH (bradycardia, renal failure, atrioventricular block, shock, and hyperkalaemia) syndrome is a recently recognized condition which may lead to life-threatening complications if not correctly identified and treated early. We report here the case of a 74-year-old woman with type 2 diabetes, hypertension and atrial flutter who presented to the emergency department with 2-day history of dizziness, presyncope, and bradycardia, and a junctional rhythm at 61 beat per minute on initial ECG. She was on apixaban, digoxin, prazosin, and telmisartan. Serum biochemistry revealed severe hyperkalaemia with a potassium 8.4 mmol/L, creatinine 161 mmol/L, glucose 15.3 mmol/L and an upper normal digoxin level of 1.2 mmol/L (ref. 0.6-1.2). Arterial blood pH was 7.2. Given the constellation of biochemical and clinical findings a diagnosis of BRASH syndrome was made, though her blood pressure values at presentation were rather high (180/65-179/59 mmHg). The patient was rapidly stabilised with the administration of intravenous insulin and dextrose, fluid resuscitation, and zirconium cyclosilicate (SZC), followed by haemodialysis. Following the correction of the serum potassium to 4.7 mmol/L, a further ECG performed 6 hours later, showed a restoration of sinus rhythm with a rate of 65 bpm, normalization of the QRS duration. The digoxin and telmisartan were discontinued, and the patient was commenced on a calcium channel antagonist for hypertension. Clinicians should be alerted to patients who present with either a BRASH (shock) or BRAHH (hypertensive manifestation) where timely intervention is essential to avoid life-threatening brady-and tachyarrhythmias in these patients.
Topics: Aged; Female; Humans; Arrhythmias, Cardiac; Bradycardia; Diabetes Mellitus, Type 2; Digoxin; Hyperkalemia; Hypertension; Potassium; Telmisartan
PubMed: 37473946
DOI: 10.1016/j.cpcardiol.2023.101984 -
Current Heart Failure Reports Oct 2016Digoxin remains one of the oldest therapies for heart failure; however, its safety and efficacy have been controversial since its initial use. Questions that remain... (Review)
Review
Digoxin remains one of the oldest therapies for heart failure; however, its safety and efficacy have been controversial since its initial use. Questions that remain include the clinical efficacy of digoxin when added to contemporary medical therapy, when and if it should be added, and how to minimize adverse effects. In this review, we will summarize recent data on the use of digoxin in systolic heart failure and address some of the controversies regarding the role of digoxin in the modern era of heart failure treatment.
Topics: Cardiotonic Agents; Digoxin; Heart Failure, Systolic; Humans; Treatment Outcome
PubMed: 27696142
DOI: 10.1007/s11897-016-0302-z -
BMC Nephrology Oct 2021Digoxin is used in patients with chronic heart failure (CHF) who remain symptomatic despite optimal medical treatment. Impaired renal function is commonly associated...
INTRODUCTION
Digoxin is used in patients with chronic heart failure (CHF) who remain symptomatic despite optimal medical treatment. Impaired renal function is commonly associated with CHF. We investigated the relation between digoxin use and change in renal function over time in patients with CHF.
METHODS
One thousand two hundred forty-one patients with symptoms and signs of CHF (average age 72 years (64% male), and median NTproBNP 1426 ng/l (interquartile range 632-2897) were divided into four groups: never on digoxin (N = 394); digoxin throughout (N = 449); started digoxin at some point after baseline (N = 367); and stopped digoxin at some point after baseline (N = 31). The rate of change of estimated glomerular filtration rate (eGFR) was calculated using linear regression.
RESULTS
Patients on digoxin throughout had a significantly greater rate of decline in eGFR per year than patients not on digoxin throughout (mean (± standard deviation); - 5 (14) ml/min/1.73m per year v - 2 (11) ml/min/1.73m per year, P = 0.02). In those patients who started digoxin during follow up, there was no significant difference in the rate of decline in eGFR before and after starting digoxin. There was no correlation between baseline eGFR (or rate of decline in eGFR) and age, haemoglobin or NTproBNP. Compared to patients taking both angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) and beta-blocker (BB), patients who were not taking an ACEi/ARB or BB had a numerically faster rate of decline in eGFR, although this was not statistically significant.
CONCLUSION
The rate of decline in renal function is greater in patients with CHF who are taking digoxin.
Topics: Aged; Aged, 80 and over; Cardiotonic Agents; Digoxin; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Male; Middle Aged; Retrospective Studies; Time Factors
PubMed: 34702219
DOI: 10.1186/s12882-021-02562-0 -
Current Drug Targets 2023One of the major indications for digoxin use is the treatment of heart failure (HF). Although the clinical application of digoxin in long-term outcomes in patients with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
One of the major indications for digoxin use is the treatment of heart failure (HF). Although the clinical application of digoxin in long-term outcomes in patients with HF and reduced ejection fraction (HFrEF) patients is well explained, the association between digoxin therapy and outcomes in patients with HF and preserved ejection fraction (HFpEF) is not very clear.
OBJECTIVES
The aim of this study was to show the clinical efficacy of digoxin on long-term outcomes in subjects with HFpEF.
METHODS
PubMed, Embase, Scopus and Web of Science (ISI) electronic databases were searched until May 2021 to obtain relevant studies. The primary outcome was all-cause mortality attributed to treatment with digoxin. The secondary outcomes were "all-cause hospitalization", "hospitalization because of HF" and "all-cause mortality or hospitalization of HF".
RESULTS
Seven studies with more than 23000 patients with HFpEF, of which more than 4900 were treated with digoxin, fulfilled the eligibility criteria and were included in this meta-analysis. Treatment with digoxin was associated with a neutral effect on all-cause mortality (HR 1.04, 95 % CI 0.91-1.20, I2 = 57.9 %), all-cause hospitalization (HR 0.97, 95 % CI 0.88-1.07, I2 = 0.0 %), HFhospitalization (HR 0.96, 95 % CI 0.90-1.02, I2 = 41.4 %), and all-cause mortality or HFhospitalization (HR 1.07, 95 % CI 0.91-1.26, I2 = 81.2 %). In subgroup meta-analyses based on ejection fraction (EF), treatment with digoxin did not significantly alter these outcomes in each subset of patients.
CONCLUSION
The results of this meta-analysis suggest that digoxin does not have any significant effect on long-term outcomes of HFpEF patients, including "all-cause mortality", "all-cause hospitalization", "hospitalization because of HF" and "all-cause mortality or hospitalization of HF".
Topics: Humans; Digoxin; Heart Failure; Hospitalization; Prognosis; Stroke Volume; Treatment Outcome; Cardiotonic Agents
PubMed: 36065922
DOI: 10.2174/1389450123666220906093058 -
American Journal of Cardiovascular... Sep 2022Digoxin is indicated for the management of heart failure with reduced ejection fraction and atrial fibrillation. Despite stronger guideline recommendations for other...
BACKGROUND
Digoxin is indicated for the management of heart failure with reduced ejection fraction and atrial fibrillation. Despite stronger guideline recommendations for other pharmacologic and device therapies, digoxin retains a role in select patients unable to tolerate or refractory to standard therapies. Contemporary utilization of and costs related to digoxin in the United States of America (USA) remain uncharacterized. The objective of this study was to estimate trends in digoxin use and expenditures across the USA from 2010 to 2017.
METHODS
We utilized the Medical Expenditure Panel Survey to estimate trends in digoxin use and expenditures across the USA from 2010 to 2017. The Medical Expenditure Panel Survey is an overlapping panel survey that interviews households in the USA to ascertain their healthcare utilization and expenditures. Complex sampling procedures allow for nationally representative estimates of utilization and expenditures. We report the number of digoxin users and expenditures across key subgroups in 2-year increments from 2010 to 2017.
RESULTS
The number of digoxin users in the USA declined by 47% from 766 users per 100,000 adults in 2010-11 to 402 users per 100,000 adults in 2016-17. While digoxin use declined among women and self-identified White adults, adults living at or below the federal poverty level and those who self-identified as Asian or Hispanic represent an increasing proportion of overall digoxin users. While nationwide digoxin expenditures declined by 26% from 2010-11 to 2012-13, they peaked at $260.3 million in 2014-15 and remained elevated at $188.7 million in 2016-17.
CONCLUSIONS
Despite a nationwide trend towards declining use, digoxin remains prevalent amongst people of Asian and Hispanic descent in the USA. After a spike in cost in 2013, digoxin prices have yet to return to pre-spike levels. The role of digoxin in contemporary heart failure and arrhythmia management will continue to evolve as additional randomized and observational analyses become available.
Topics: Adult; Digoxin; Female; Health Expenditures; Heart Failure; Humans; Patient Acceptance of Health Care; Surveys and Questionnaires; United States
PubMed: 35739347
DOI: 10.1007/s40256-022-00540-x -
European Heart Journal Jul 2015There are conflicting data regarding the effect of digoxin use on mortality in patients with atrial fibrillation (AF) or with congestive heart failure (CHF). The aim of... (Meta-Analysis)
Meta-Analysis Review
There are conflicting data regarding the effect of digoxin use on mortality in patients with atrial fibrillation (AF) or with congestive heart failure (CHF). The aim of this meta-analysis was to provide detailed analysis of the currently available study reports. We performed a MEDLINE and a COCHRANE search (1993-2014) of the English literature dealing with the effects of digoxin on all-cause-mortality in subjects with AF or CHF. Only full-sized articles published in peer-reviewed journals were considered for this meta-analysis. A total of 19 reports were identified. Nine reports dealt with AF patients, seven with patients suffering from CHF, and three with both clinical conditions. Based on the analysis of adjusted mortality results of all 19 studies comprising 326 426 patients, digoxin use was associated with an increased relative risk of all-cause mortality [Hazard ratio (HR) 1.21, 95% confidence interval (CI), 1.07 to 1.38, P < 0.01]. Compared with subjects not receiving glycosides, digoxin was associated with a 29% increased mortality risk (HR 1.29; 95% CI, 1.21 to 1.39) in the subgroup of publications comprising 235 047 AF patients. Among 91.379 heart failure patients, digoxin-associated mortality risk increased by 14% (HR 1.14, 95% CI, 1.06 to 1.22). The present systematic review and meta-analysis of all available data sources suggest that digoxin use is associated with an increased mortality risk, particularly among patients suffering from AF.
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Digoxin; Epidemiologic Methods; Heart Failure; Humans
PubMed: 25939649
DOI: 10.1093/eurheartj/ehv143 -
British Journal of Clinical Pharmacology Jan 2016
Topics: Atrial Fibrillation; Cardiotonic Agents; Digoxin; Heart Failure; Humans
PubMed: 26390833
DOI: 10.1111/bcp.12791