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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 Bunyavirales 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 (IC50). 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 signaling 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 analyzed. In Vero cells, digoxin favored 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 harbor 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 digox, Ministerio de Economía y Competitividad (MINECO), Ministerio de Ciencia, Innovación y Universidades (MICINN), Fondo Europeo de Desarrollo Regional (FEDER), Sección Deptal. de Bioquímica y Biología Molecular (Farmacia), Fac. de Farmacia, TRUE, pub

Introdución: A taquicardia supraventricular fetal pode condicionar a aparición de hydrops fetalis e, en consecuencia, determinar a morte fetal. Non existe consenso sobre o tratamento antiarrítmico transplacentario e a digoxina segue sendo o fármaco máis utilizado pola súa longa historia de uso no embarazo, aínda que varias publicacións cuestionan a súa eficacia en comparación coa flecainida e o sotalol, principalmente en fetos hidrópicos. Obxectivos: O obxectivo principal é determinar se a digoxina é realmente o fármaco máis eficaz no tratamento da taquicardia supraventricular en comparación coa flecainida e o sotalol. En segundo lugar, interésanos determinar a seguridade materna e fetal, así como o tempo desde o inicio do tratamento ata a cardioversión asociada a cada fármaco. Métodos: Realizouse unha busca bibliográfica dos últimos 15 anos nas bases de datos PubMed, Scopus, Web of Science e Cochrane o 15 de marzo de 2023 tratada segundo os criterios de inclusión e exclusión definidos. Resultados: A flecainida demostrou taxas de conversión máis altas que a digoxina e o sotalol en todas taquicardias supraventriculares en presenza e ausencia de hidropesía, excepto no flutter auricular no que o sotalol foi superior. En casos esporádicos reportáronse efectos adversos fetais e maternos graves, pero parecen estar máis asociados co sotalol. Conclusión: O tratamento transplacentario da taquicardia supraventricular debe escollerse en función das complicacións hemodinámicas que presenta o feto e das características da taquicardia. A flecainida parece ser o fármaco de elección na maioría das taquicardias en presenza e ausencia de hydrops, con excepción do flutter auricular onde se debe considerar o sotalol. En casos de hidropesía, a digoxina non debe considerarse como primeira liña, Introducción: La taquicardia supraventricular fetal (TSVF) puede condicionar el aparecimiento de hydrops fetalis y consecuentemente determinar la muerte fetal. El tratamiento antiarrítmico transplacentario no está consensuado y la digoxina sigue siendo el fármaco más utilizado por su largo historial de uso en el embarazo aunque varias publicaciones cuestionen su eficacia frente a la flecainida y el sotalol, principalmente en fetos hidrópicos. Objetivos: El objetivo principal es determinar si la digoxina es efectivamente el fármaco más eficaz en el tratamiento de la TSVF frente a la flecainida y el sotalol. Secundariamente, interesa determinar la seguridad materna y fetal, así como el tiempo desde el inicio del tratamiento hasta la cardioversión asociados a cada fármaco. Métodos: Se realizó una búsqueda de literatura de los últimos 15 años en las bases de datos PubMed, Scopus, Web of Science y Cochrane el 15 de marzo de 2023 tratada de acuerdo con los criterios de inclusión y exclusión definidos. Resultados: La flecainida demostró tasas de conversión más altas que la digoxina y el sotalol en todas las TSVF en presencia y ausencia de hydrops a excepción del flutter auricular (AF) en que el sotalol fue superior. Los efectos adversos fetales y maternos graves fueron reportados en casos esporádicos, pero parecen tener mayor asociación con el sotalol. Conclusión: El tratamiento transplacentario de la TSVF debe de ser elegido con base a las complicaciones hemodinámicas presentadas pelo feto y a las características de la taquicardia. La flecainida parece ser el fármaco de elección en la mayoría de las TSVF en presencia y ausencia de hidropesía a excepción del AF en que se debe considerar el sotalol. En casos de hydrops la digoxina no debe ser considerada como primera línea, Background: The fetal supraventricular tachycardia can produce hydrops fetalis and ultimately determine fetal death. The transplacental antiarrhythmic treatment is not consensual and digoxin is often considered the first-line therapy due to its long history of use during pregnancy even though several publications question its efficiency comparing to flecainide and sotalol, especially in hydropic fetuses. Objective: The aim of this revision is to determine if digoxin is the most effective drug in supraventricular tachycardia treatment comparing to flecainide and sotalol. Secondarily is important to determine maternal and fetal security just as the time until cardioversion is achieved with each agent. Methods: A literature search was conducted on PubMed, Scopus, Web of Science and Cochrane databases on the march 15th of 2023 and was then screened according to the established inclusion and exclusion criteria. Results: Flecainide had higher conversion rates than digoxin and sotalol in all types of supraventricular tachycardia and in presence or absence of hydrops, except in atrial flutter where sotalol was superior. Serious adverse effects were documented in sporadic cases but seemed to be more associated with sotalol. Conclusion: Supraventricular tachycardia tansplacental treatment must be selected based on the hemodynamic fetal state as on tachycardia features. Flecainide seems to be the most effective drug in the majority of supraventricular tachycardias except in atrial flutter for which sotalol should be considered. In cases of hydrops digoxin should not be considered as first-line treatment

Digoxin is a cardiovascular drug obtained from the plant leaf of Digitalis lanata. Digoxin has a long history of usage in cardiovascular treatment. There is ongoing discussion over this drug's mode of action and therapeutic effectiveness. Positive inotropic and neurohormonal modulation effects of digoxin are found. Since the advent of beta-blockers and aldosterone antagonists as components of modern heart failure therapy, the rate of digoxin prescriptions has fallen. American and European heart failure therapy recommendations still include digoxin as a possible course of action. Since the first Digitalis Investigation Group trial findings were made public, observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In this review, we analyze the clinical evidence, effectiveness and the safety of digoxin in patients with heart failure and lower ejection fraction.

Digoxin is a cardiovascular drug obtained from the plant leaf of Digitalis lanata. Digoxin has a long history of usage in cardiovascular treatment. There is ongoing discussion over this drug's mode of action and therapeutic effectiveness. Positive inotropic and neurohormonal modulation effects of digoxin are found. Since the advent of beta-blockers and aldosterone antagonists as components of modern heart failure therapy, the rate of digoxin prescriptions has fallen. American and European heart failure therapy recommendations still include digoxin as a possible course of action. Since the first Digitalis Investigation Group trial findings were made public, observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In this review, we analyze the clinical evidence, effectiveness and the safety of digoxin in patients with heart failure and lower ejection fraction.

Aims: The safety of digoxin therapy in atrial fibrillation (AF) remains ill-defined. We aimed to evaluate the effects of digoxin over beta-blocker therapy in AF. Methods and results: Patients with AF who were treated with either digoxin or beta-blocker from the ESC-EHRA EORP-AF General Long-Term Registry were included. Outcomes of interest were all-cause mortality, cardiovascular (CV) mortality, non-CV mortality, quality of life and number of patients with unplanned hospitalisations. Of 6377 patients, 549(8.6%) were treated with digoxin. Over 24 months, there were 550(8.6%) all-cause mortality events and 1304(23.6%) patients with unplanned emergency hospitalisations. Compared to beta-blocker, digoxin therapy was associated with increased all-cause mortality (HR 1.90 [95%CI,1.48-2.44], CV mortality (HR 2.18 [95%CI,1.47-3.21] and non-CV mortality (HR 1.68 [95%CI,1.02-2.75] with reduced quality of life (Health Utility Score 0.555[±0.406] vs. 0.705[±0.346], P<0.001) but no differences in emergency hospitalisations (HR 1.00 [95%CI,0.56-1.80]) or AF-related hospitalisations (HR 0.95 [95%CI,0.60-1.52]).On multivariable analysis, there were no differences in any of the outcomes between both groups, after accounting for potential confounders. Similar results were obtained in the subgroups of patients with permanent AF and coexisting heart failure. There was no differences in outcomes between AF patients receiving digoxin with and without chronic kidney disease. Conclusion: Poor outcomes related to the use of digoxin over beta-blocker therapy in terms of excess mortality and reduced quality of life are associated with the presence of other risk factors rather than digoxin per se. The choice of digoxin or beta-blocker therapy had no influence on the incidence of unplanned hospitalisations.

Digoxin is a cardiovascular drug obtained from the plant leaf of Digitalis lanata. Digoxin has a long history of usage in cardiovascular treatment. There is ongoing discussion over this drug's mode of action and therapeutic effectiveness. Positive inotropic and neurohormonal modulation effects of digoxin are found. Since the advent of beta-blockers and aldosterone antagonists as components of modern heart failure therapy, the rate of digoxin prescriptions has fallen. American and European heart failure therapy recommendations still include digoxin as a possible course of action. Since the first Digitalis Investigation Group trial findings were made public, observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In this review, we analyze the clinical evidence, effectiveness and the safety of digoxin in patients with heart failure and lower ejection fraction.

Digoxin is a cardiovascular drug obtained from the plant leaf of Digitalis lanata. Digoxin has a long history of usage in cardiovascular treatment. There is ongoing discussion over this drug's mode of action and therapeutic effectiveness. Positive inotropic and neurohormonal modulation effects of digoxin are found. Since the advent of beta-blockers and aldosterone antagonists as components of modern heart failure therapy, the rate of digoxin prescriptions has fallen. American and European heart failure therapy recommendations still include digoxin as a possible course of action. Since the first Digitalis Investigation Group trial findings were made public, observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In this review, we analyze the clinical evidence, effectiveness and the safety of digoxin in patients with heart failure and lower ejection fraction.

Digoxin is a cardiovascular drug obtained from the plant leaf of Digitalis lanata. Digoxin has a long history of usage in cardiovascular treatment. There is ongoing discussion over this drug's mode of action and therapeutic effectiveness. Positive inotropic and neurohormonal modulation effects of digoxin are found. Since the advent of beta-blockers and aldosterone antagonists as components of modern heart failure therapy, the rate of digoxin prescriptions has fallen. American and European heart failure therapy recommendations still include digoxin as a possible course of action. Since the first Digitalis Investigation Group trial findings were made public, observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In this review, we analyze the clinical evidence, effectiveness and the safety of digoxin in patients with heart failure and lower ejection fraction.

In this review, we evaluated the literature on the benefits and deleterious effects of digoxin in heart failure (HF) with reduced ejection fraction (EF). Although digoxin was considered an effective treatment for HF, the supporting evidence is conflicting. Before the conventional use of modern HF therapies, digoxin was widely used for symptomatic relief on these patients. Further randomized trials are required to reach a definite conclusion about its efficacy and safety in patients experiencing HF with a reduced EF (HFrEF).

Digoxin is a cardiovascular drug obtained from the plant leaf of Digitalis lanata. Digoxin has a long history of usage in cardiovascular treatment. There is ongoing discussion over this drug's mode of action and therapeutic effectiveness. Positive inotropic and neurohormonal modulation effects of digoxin are found. Since the advent of beta-blockers and aldosterone antagonists as components of modern heart failure therapy, the rate of digoxin prescriptions has fallen. American and European heart failure therapy recommendations still include digoxin as a possible course of action. Since the first Digitalis Investigation Group trial findings were made public, observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In this review, we analyze the clinical evidence, effectiveness and the safety of digoxin in patients with heart failure and lower ejection fraction.

To evaluate the ocular safety of intravitreal carboplatin and digoxin injections as a new intravitreal chemotherapy option for retinoblastoma tumor vitreous seeds. Eighteen rabbits were divided randomly into three groups to receive intravitreal injection of Digoxin (6 rabbits), Carboplatin (7 rabbits), or Saline (5 rabbits). In every group, one eye randomly treated with 10 µg Digoxin in 0.1 cc or 1 µg Carboplatin or Saline, and the contralateral eye was considered as the control. All groups underwent three consecutive injections of the drugs with 1-week intervals. Baseline electroretinography (ERG) was recorded from both eyes of all the animals prior to injection and was repeated 1st day, 1st week, and 1st month after the last injection. All rabbits were sacrificed 1 month after the last injection, and histological studies were done. Mean a and b wave amplitudes decreased significantly at 1st day, 1st week, and 1st month after the last intravitreal injection of 10 µg Digoxin in comparison with other groups (p-value: .02). Contradictory, 1 µg Carboplatin injected eyes had minimal ERG changes. There were some nonspecific ERG changes with unclear clinical significance in non-injected contralateral control eyes of Digoxin and Carboplatin groups in comparison with the control eyes of the Saline group. Histological studies revealed considerable neural retinal atrophy in injected eyes of the Digoxin group. Intravitreal 10 µg Digoxin might have more local ocular toxicity in comparison with intravitreal Carboplatin in albino rabbit eyes. Future studies should assess the induced toxicity of intravitreal injection of these drugs on the non-injected contralateral eye.

Background: The European Heart Rhythm Association (EHRA) score is a proven and validated tool for assessing the symptoms of atrial fibrillation (AF). Little is known about the variables related to this score and how it changes after cardioversion. Methods: We analyzed 744 patients undergoing elective cardioversion in whom AF-related symptoms were assessed at baseline and after 6 months of follow-up using the EHRA score. We assessed the association between the EHRA score and other clinical and echocardiographic variables at baseline and after 6 months of follow-up. Results: At 6 months of follow-up, we observed a reduction in the EHRA score in 50% and worsening in 2.8% of patients who remained in sinus rhythm (SR) compared with 34.6% and 11.3%, respectively, of patients with AF episodes (p<0.0001). Patients who maintained SR at 6 months were less symptomatic than those with AF (EHRA score 1.13 +/- 0.35 vs 1.42 +/- 0.59; p<0.0001). The independent predictors for reduction in the EHRA score after cardioversion were NYHA >= II at baseline and maintenance of SR (p<0.0001). Conclusion: The greatest improvement in AF-related symptoms was in patients who remained in SR at 6 months after cardioversion and in patients with worse NYHA functional class at baseline.

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.

BACKGROUND: Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. METHODS: In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. RESULTS: Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. CONCLUSION: Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

BACKGROUND: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS: Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of H

BACKGROUND: Heart failure is a leading cause for hospital readmission. Digoxin use may lower this risk in patients with heart failure with reduced ejection fraction (HFrEF), but data on contemporary patients receiving other evidence-based therapies are lacking. METHODS: Of the 11,900 patients with HFrEF (ejection fraction ≤45%) in Medicare-linked OPTIMIZE-HF, 8401 were not on digoxin, of whom 1571 received discharge prescriptions for digoxin. We matched 1531 of these patients with 1531 not receiving digoxin by propensity scores for digoxin use. The matched cohort (n = 3062; mean age, 76 years; 44% women; 14% African American) was balanced on 52 baseline characteristics. We assembled a second matched cohort of 2850 patients after excluding those with estimated glomerular filtration rate <15 mL/min/1.73 m2 and heart rate <60 beats/min. Hazard ratios (HRs) and 95% confidence intervals (CIs) for digoxin-associated outcomes were estimated in the matched cohorts. RESULTS: Among the 3062 matched patients, digoxin use was associated with a significantly lower risk of heart failure readmission at 30 days (HR, 0.74; 95% CI, 0.59-0.93), 1 year (HR, 0.81; 95% CI, 0.72-0.92), and 6 years (HR, 0.90; 95% CI 0.81-0.99). The association with all-cause readmission was significant at 1 and 6 years but not 30 days. There was no association with mortality. Similar associations were observed among the 2850 matched patients without bradycardia or renal insufficiency. CONCLUSIONS: Among hospitalized older patients with HFrEF receiving contemporary treatments for heart failure, digoxin use is associated with a lower risk of hospital readmission but not all-cause mortality.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

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.

Binding to Na+,K+-ATPase, cardiotonic steroids (CTS) activate intracellular signaling cascades that affect gene expression and regulation of proliferation and apoptosis in cells. Ouabain is the main CTS used for studying these processes. The effects of other CTS on nervous tissue are practically uncharacterized. Previously, we have shown that ouabain affects the activation of mitogen-activated protein kinases (MAP kinases) ERK1/2, p38, and JNK. In this study, we compared the effects of digoxin and bufalin, which belong to different subclasses of CTS, on primary culture of rat cortical cells. We found that CTS toxicity is not directly related to the degree of Na+,K+-ATPase inhibition, and that bufalin and digoxin, like ouabain, are capable of activating ERK1/2 and p38, but with different concentration and time profiles. Unlike bufalin and ouabain, digoxin did not decrease JNK activation after long-term incubation. We concluded that the toxic effect of CTS in concentrations that inhibit less than 80% of Na+,K+-ATPase activity is related to ERK1/2 activation as well as the complex profile of MAP kinase activation. A direct correlation between Na+,K+-ATPase inhibition and the degree of MAP kinase activation is only observed for ERK1/2. The different action of the three CTS on JNK and p38 activation may indicate that it is associated with intracellular signaling cascades triggered by protein-protein interactions between Na+,K+-ATPase and various partner proteins. Activation of MAP kinase pathways by these CTS occurs at concentrations that inhibit Na+,K+-ATPase containing the alpha 1 subunit, suggesting that these signaling cascades are realized via alpha 1. The results show that the signaling processes in neurons caused by CTS can differ not only because of different inhibitory constants for Na+,K+-ATPase., QC 20180404

Although the human gut microbiome plays a prominent role in xenobiotic transformation, most of the genes and enzymes responsible for this metabolism are unknown. Recently, we linked the two-gene 'cardiac glycoside reductase' (cgr) operon encoded by the gut Actinobacterium Eggerthella lenta to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 E. lenta strains and close relatives, revealing an expanded 8-gene cgr-associated gene cluster present in all digoxin metabolizers and absent in non-metabolizers. Using heterologous expression and in vitro biochemical characterization, we discovered that a single flavin- and [4Fe-4S] cluster-dependent reductase, Cgr2, is sufficient for digoxin inactivation. Unexpectedly, Cgr2 displayed strict specificity for digoxin and other cardenolides. Quantification of cgr2 in gut microbiomes revealed that this gene is widespread and conserved in the human population. Together, these results demonstrate that human-associated gut bacteria maintain specialized enzymes that protect against ingested plant toxins.

Although the human gut microbiome plays a prominent role in xenobiotic transformation, most of the genes and enzymes responsible for this metabolism are unknown. Recently, we linked the two-gene 'cardiac glycoside reductase' (cgr) operon encoded by the gut Actinobacterium Eggerthella lenta to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 E. lenta strains and close relatives, revealing an expanded 8-gene cgr-associated gene cluster present in all digoxin metabolizers and absent in non-metabolizers. Using heterologous expression and in vitro biochemical characterization, we discovered that a single flavin- and [4Fe-4S] cluster-dependent reductase, Cgr2, is sufficient for digoxin inactivation. Unexpectedly, Cgr2 displayed strict specificity for digoxin and other cardenolides. Quantification of cgr2 in gut microbiomes revealed that this gene is widespread and conserved in the human population. Together, these results demonstrate that human-associated gut bacteria maintain specialized enzymes that protect against ingested plant toxins.

Introduction: Digoxin is one of the most used drugs in cardiovascular diseases, frequent in the geriatric patient, characterized by its narrow therapeutic margin.Objectives: To characterize the prescription of digoxin and identify problems related to its prescription in geriatric patients.Method: A descriptive and cross-sectional study was carried out on the use of drugs, indication-prescription type, in 23 patients with digoxin indication, treated at the Policlínico José Martí in Santiago de Cuba, from April to June 2017.Results: In the case study, women (78.26%), ages between 70-74 years (26.08%), and patients with one or two associated diseases were more likely to use it. Diagnosis of cardiovascular diseases by Comprehensive General Medicine was prevalent, associated with a greater frequency of diuretics and antiplatelet drugs intervention group. The group with the lowest probability of survival was that of late treatment.Conclusions: The prescription of digoxin may be considered as rational, although there is a possibility of drug interactions that could lead to toxic effects or therapeutic failure., Introducción: La digoxina es un medicamento muy empleado en algunas enfer-medades cardiovasculares, que son frecuentes en el paciente geriátrico, y está caracterizada por su estrecho margen terapéutico.Objetivo: Caracterizar la prescripción de digoxina e identificar problemas relacio-nados con su prescripción en pacientes geriátricos.Método: Se realizó un estudio descriptivo y transversal, de utilización de medicamentos, de tipo indicación-prescripción, en 23 pacientes con indicación de digoxina, atendidos en el Policlínico José Martí de Santiago de Cuba, Cuba, desde abril hasta junio de 2017. Resultados: En la casuística predominó su uso en el sexo femenino (78,26%), entre 70 y 74 años (26,08%), con una o dos enfermedades asociadas. Fue prevalente el diagnóstico de las enfermedades cardiovasculares por especialistas de Medicina General Integral, y la indicación de digoxina se asoció con mayor frecuencia a diuréticos y antiagregantes plaquetarios.Conclusiones: La prescripción de digoxina puede considerarse como racional, aunque existe posibilidad de interacciones medicamentosas, que pudieran conllevar efectos tóxicos o falla terapéutica.

Introduction: A healthy gut microbiota is necessary for the normal operation of several body functions, including gastrointestinal sensitivity and motility, lipid and glucid metabolism, immune surveillance, and host behavior. In addition, intestinal bacteria contribute to determining the pharmacological properties of several drugs by producing different drug metabolizing enzymes. Areas covered: Four enzymatic processes are discussed: prodrug activation; drug inactivation; drug deconjugation; and hydrolysis of natural glycosides with further metabolism of released aglycones. For each of these processes, a literature search has been undertaken on certain paradigmatic examples that have significant clinical implications: aminosalicylates and anthranoid laxatives; digoxin; irinotecan and non-steroidal anti-inflammatory drugs (NSAIDs); rutin, diosmin, and baicalin. Expert commentary: The modulation of certain reactions catalyzed by gut bacterial enzymes may offer new opportunities to improve the clinical efficacy of drugs such as aminosalicylates, and natural glycosides by increasing their metabolic transformation, and of digoxin by reducing its inactivation, or to decrease the lower intestinal toxicity of irinotecan, and NSAIDs by inhibiting the hydrolytic cleavage of their conjugates. Randomized clinical trials are awaited to clarify whether new intervention strategies may modulate these processes and provide clinical benefits such as improved therapeutic outcomes and drug safety profiles.

Background: Current epidemiological data suggests that postoperative atrial fibrillation or atrial flutter (POAF) causes significant morbidity and mortality after cardiac surgery. The literature for prophylactic management of POAF is limited, resulting in lack of clear guideline management recommendations. Aim(s): To examine the efficacy of prophylactic rate control agents in reducing the incidence of new-onset POAF in patients undergoing elective cardiac surgery. Method(s): Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and MEDLINE were systematically searched for blinded randomised controlled studies (RCT) evaluating adults with no history of atrial fibrillation randomised to a pharmacological agent (either beta blocker, calcium channel blocker or digoxin), compared to placebo. Utilising Cochrane guidance, three reviewers screened, extracted and assessed the quality of the evidence. We used a random effects meta-analysis to compare a rate-control agent with placebo. Result(s): Five RCTs (688 subjects, mean age 61 +/- 8.9, 69% male) were included. Beta blocker administration prior to elective cardiac surgery significantly reduced the incidence of POAF (OR 0.43,95%Cl [0.30, 0.61], I2 = 0%) without significant impact on ischaemic stroke (OR 0.49, 95%Cl [0.10, 2.44], I2 = 0%), non-fatal myocardial infarction (OR 0.76, 95%Cl [0.08-7.44]), overall mortality (OR 0.83, 95%Cl [0.19-3.66], I2 = 0%), or length of stay-0.96 days (95%Cl-1.49 to-0.42, I2 = 0%). An increased rate of bradycardic episodes was observed (OR 3.53, 95%Cl [1.22-10.23], I2 = 0%). Conclusion(s): This review suggests that selective administration of prophylactic oral beta blockers prior to elective cardiac surgery is safe and may reduce the incidence of POAF.

Background: Current epidemiological data suggests that postoperative atrial fibrillation or atrial flutter (POAF) causes significant morbidity and mortality after cardiac surgery. The literature for prophylactic management of POAF is limited, resulting in lack of clear guideline management recommendations. Aim(s): To examine the efficacy of prophylactic rate control agents in reducing the incidence of new-onset POAF in patients undergoing elective cardiac surgery. Method(s): Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and MEDLINE were systematically searched for blinded randomised controlled studies (RCT) evaluating adults with no history of atrial fibrillation randomised to a pharmacological agent (either beta blocker, calcium channel blocker or digoxin), compared to placebo. Utilising Cochrane guidance, three reviewers screened, extracted and assessed the quality of the evidence. We used a random effects meta-analysis to compare a rate-control agent with placebo. Result(s): Five RCTs (688 subjects, mean age 61 +/- 8.9, 69% male) were included. Beta blocker administration prior to elective cardiac surgery significantly reduced the incidence of POAF (OR 0.43,95%Cl [0.30, 0.61], I2 = 0%) without significant impact on ischaemic stroke (OR 0.49, 95%Cl [0.10, 2.44], I2 = 0%), non-fatal myocardial infarction (OR 0.76, 95%Cl [0.08-7.44]), overall mortality (OR 0.83, 95%Cl [0.19-3.66], I2 = 0%), or length of stay-0.96 days (95%Cl-1.49 to-0.42, I2 = 0%). An increased rate of bradycardic episodes was observed (OR 3.53, 95%Cl [1.22-10.23], I2 = 0%). Conclusion(s): This review suggests that selective administration of prophylactic oral beta blockers prior to elective cardiac surgery is safe and may reduce the incidence of POAF.

BackgroundDigoxin use has been shown to be associated with a lower risk of 30-day all-cause hospital readmissions in older patients with heart failure (HF). In the current study, we examined this association among long-term care (LTC) residents hospitalized for HF.MethodsOf the 8049 Medicare beneficiaries discharged alive after hospitalization for HF from 106 Alabama hospitals, 545 (7%) were LTC residents, of which 227 (42%) received discharge prescriptions for digoxin. Propensity scores for digoxin use, estimated for each of the 545 patients, were used to assemble a matched cohort of 158 pairs of patients receiving and not receiving digoxin who were balanced on 29 baseline characteristics. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin among matched patients were estimated using Cox regression models.ResultsMatched patients (n = 316) had a mean age of 83 years, 74% were women, and 18% African American. Thirty-day all-cause readmission occurred in 21% and 20% of patients receiving and not receiving digoxin, respectively (HR, 1.02; 95% CI, 0.63-1.66). Digoxin had no association with all-cause mortality (HR, 0.90; 95% CI, 0.48-1.70), HF readmission (HR, 0.90; 95% CI, 0.38-2.12), or a combined endpoint of all-cause readmission or all-cause mortality (HR, 0.97; 95% CI, 0.65-1.45) at 30 days. These associations remained unchanged at 1 year postdischarge.ConclusionsThe lack of an association between digoxin and 30-day all-cause readmission in older nursing home residents hospitalized for HF is intriguing and needs to be interpreted with caution given the small sample size.

Digoxin, one of the digitalis glycosides has specific effects on the myocardium. The effects of Digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. It is the most common drug used in treatment of congestive heart failure and tachy-arrhythmias. It is used in treatment of arrhythmias but when arrhythmias occur in a patient on maintenance dose of Digoxin, its toxicity should be suspected. Here we report a case of Digoxin toxicity with the therapeutic dose confirmed by elevated Serum Digoxin levels. This occurrence could be due to Digoxin itself or this adverse effect could be predisposed by a suspected drug –dug interaction (SDDI) with the concomitant drugs this patient was prescribed.

Objective: Bradycardia is common in chronic digoxin poisoning and often used as an indication to administer digoxin-Fab, however 60% of patients treated with digoxin-Fab failed to increase heart rate more than 10 beats/min (bpm) 4 hours postadministration despite undetectable free serum digoxin concentrations.[ 1] Methods: Retrospective analysis of patients with suspected chronic digoxin intoxication; those treated with digoxin-Fab were compared to patients where it was not recommended (by the on-call toxicologist). Data included demographics, cardiac medications, presenting complaint, serum digoxin, creatinine and potassium concentration, digoxin-Fab dose, heart rate (HR) before and at various time points post-treatment with digoxin-Fab or post-consult time if not administered. Result(s): From August 2013 to October 2015, there were 47 consults: 21 digoxin-Fab recommended and 26 Fab not recommended. Mean age was 80.1 (48% female) versus 79.2 years (61% female), respectively. Digoxin-Fab was recommended more frequently when HR was <50 bpm and/or serum potassium >5mmol/L with renal impairment. Patients receiving digoxin-Fab more frequently also took beta- or calcium channel blockers (CCBs) (95% versus 61%; OR 13.1, 95% CI 1.5-113) or potassium-increasing medications (95% versus 54%; OR 17.1, 95% CI 2.0-147), had elevated serum creatinine (76% versus 42%; OR 8.2, 95% CI 1.9-34), higher serum potassium (median 5.1mmol/L versus 4.2mmol/L, p=0.02), higher serum digoxin concentrations (median 3.5nmol/L versus 2.3nmol/L, p=0.02), and had pre-treatment HR <=50 bpm (66% versus 31%; OR 4.5, 95% CI 1.3-15). Mean pre-treatment systolic blood pressure was Fab 129mmHg versus no FAB 128mmHg. Median Fab dose was 80mg (range 40-160mg). For patients with HR <=50 bpm, mean HR before treatment was similar for both groups (Fab 37 bpm versus no FAB 39 bpm) and mean HR 4 hours (Fab 48 bpm versus no Fab 49 bpm) and 8 hours (Fab 55 bpm versus no FAB 54 bpm) post-treatment. For patients with

Being a narrow therapeutic index drug, digoxin may cause harm if dosed without regular measurements of serum levels. Due to various limitations in its dosing, different challenges still exist in clinical practice. This study aimed to assess digoxin though concentrations after different regimens in adult and elderly patients, and to identify predictor variables for the ratio of given dose and digoxin trough level. This was prospective open-label study. Digoxin was administered per os as 0.125. or 0.25 mg during different continuous and interrupted dosage regimens. Study protocol allowed an additional therapy according to contemporary guidelines. Digoxin concentrations were determined using Abbott AxSYM Digoxin II assay in trough samples (1-3 per patient) after 3-4 weeks stable regimen. In total, 191 concentrations (104 patients) were analyzed. Digoxin weekly dose was in range 0.375-1.75 mg. On average, we observed slightly lower digoxin levels in 1-117 patients. Results showed that in patients receiving digoxin with interrupted dosage regimen post pause digoxin level was statistically significantly lower than pre-pause (p lt 0.05). Based on multiple linear regression, the ratio of given dose and trough concentration was mainly predicted by clearance creatinine, and to lesser extent by patient's ideal body weight. Interrupted dosing schedule shows greater variability in drug levels comparing to continuous dosing, and it additionally causes difficulties in reaching and maintaining steady trough levels between doses. Hence, individualization of dosing regimen should he carefully guided based on target levels and not solely on clinical signs and symptoms.

Introduction: Atrial fibrillation is the most common arrhythmia within the rhythm disorders that motivate consultation in the emergency room. Affects the 0.4% of the population general increasing its incidence with the age, approximately a 75% of carriers between 65 and 85 years. Objetive: To describe the treatment of the fibrillation atrial in the service of emergency of the Policlinico Pedro Borrás, Pinar del Río city. Methods: Was conducted a prospective and descriptive research in patients with cardiac arrhythmias in the emergency room of the Pedro Borrás polyclinic of the Pinar del Río city, from january to march 2015. A model of computable survey that was applied to each of the medical records, was made performing the analysis of the results using the statistical descriptive statisticians. Results: Atrial fibrillation was presented at 67,7% of the patients, arterial hypertension and idiopathic atrial fibrillation being the most frequent etiologies. 22,6% presented signs of heart failure at admission and 41,7% had more than 24 hours of evolution. Reversion to sinus rhythm occurred in 36 of 84 patients in 24 hours. The drug most commonly used in the episode was the digoxin. Conclusions: Several factors influenced the conversion to sinus in patients with atrial fibrillation rhythm, but the time evolution and the presence of heart failure allowed to estimate the probability of passage to sinus rhythm in the first 24 hours., Introducción: La fibrilación auricular constituye la arritmia más frecuente dentro de los trastornos del ritmo que motivan consulta en el servicio de urgencias. Afecta el 0,4% de la población general aumentando su incidencia con la edad, aproximadamente un 75% de portadores entre 65 y 85 años.Objetivo: Describir el tratamiento de la fibrilación auricular en el servicio de urgencias del Policlínico Pedro Borrás de la ciudad de Pinar del Río.Métodos: Se realizó una investigación prospectiva y descriptiva en pacientes con arritmias cardíacas en el servicio de urgencias del policlínico Pedro Borrás de la ciudad de Pinar del Río, de enero a marzo de 2015. Se confeccionó un modelo de encuesta computable que se aplicó a cada una de las historias clínicas, realizándose el análisis de los resultados utilizando estadígrafos de la estadística descriptiva.Resultados: La fibrilación auricular se presentó en el 67,7% de los pacientes, siendo la hipertensión arterial y la fibrilación auricular idiopática las etiologías más frecuentes. El 22,6% presentó signos de insuficiencia cardíaca al ingreso y el 41,7% presentó más de 24 horas de evolución. La reversión a ritmo sinusal se produjo en 36 de 84 pacientes en las primeras 24 horas. El fármaco más utilizado en el episodio agudo fue la digoxina.Conclusiones: Varios factores influyeron en la no conversión a ritmo sinusal en pacientes con fibrilación auricular, pero el tiempo de evolución y la presencia de insuficiencia cardiaca permitieron estimar de la probabilidad de paso a ritmo sinusal en las primeras 24 horas.

Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca(2+)-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca(2+) modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca(2+) imaging experiments revealed that both digoxin and ATP were able to increase Ca(2+) oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca(2+) modulators.

Significant efforts have been invested into the differentiation of stem cells into functional hepatocyte-like cells that can be used for cell therapy, disease modeling and drug screening. Most of these efforts have been concentrated on the use of growth factors to recapitulate developmental signals under in vitro conditions. Using small molecules instead of growth factors would provide an attractive alternative since small molecules are cell-permeable and cheaper than growth factors. We have developed a protocol for the differentiation of human embryonic stem cells into hepatocyte-like cells using a predominantly small molecule-based approach (SM-Hep). This 3 step differentiation strategy involves the use of optimized concentrations of LY294002 and bromo-indirubin-3'-oxime (BIO) for the generation of definitive endoderm; sodium butyrate and dimethyl sulfoxide (DMSO) for the generation of hepatoblasts and SB431542 for differentiation into hepatocyte-like cells. Activin A is the only growth factor required in this protocol. Our results showed that SM-Hep were morphologically and functionally similar or better compared to the hepatocytes derived from the growth-factor induced differentiation (GF-Hep) in terms of expression of hepatic markers, urea and albumin production and cytochrome P450 (CYP1A2 and CYP3A4) activities. Cell viability assays following treatment with paradigm hepatotoxicants Acetaminophen, Chlorpromazine, Diclofenac, Digoxin, Quinidine and Troglitazone showed that their sensitivity to these drugs was similar to human primary hepatocytes (PHHs). Using SM-Hep would result in 67% and 81% cost reduction compared to GF-Hep and PHHs respectively. Therefore, SM-Hep can serve as a robust and cost effective replacement for PHHs for drug screening and development.

Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca(2+)-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca(2+) modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca(2+) imaging experiments revealed that both digoxin and ATP were able to increase Ca(2+) oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca(2+) modulators.

BackgroundAlthough digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial.ObjectivesThis study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes.MethodsLongitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011.ResultsAmong 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99).ConclusionsAfter adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed.

BackgroundDigoxin remains commonly used for rate control in atrial fibrillation, but limited data exist supporting this practice and some studies have shown an association with adverse outcomes. We examined the independent association between digoxin and risks of death and hospitalization in adults with incident atrial fibrillation and no heart failure.Methods and resultsWe performed a retrospective cohort study of 14,787 age, sex, and high-dimensional propensity score-matched adults with incident atrial fibrillation and no previous heart failure or digoxin use in the AnTicoagulation and Risk factors In Atrial fibrillation-Cardiovascular Research Network (ATRIA-CVRN) study within Kaiser Permanente Northern and Southern California. We examined the independent association between newly initiated digoxin and the risks of death and hospitalization using extended Cox regression. During a median 1.17 (interquartile range, 0.49-1.97) years of follow-up among matched patients with atrial fibrillation, incident digoxin use was associated with higher rates of death (8.3 versus 4.9 per 100 person-years; P<0.001) and hospitalization (60.1 versus 37.2 per 100 person-years; P<0.001). Incident digoxin use was independently associated with a 71% higher risk of death (hazard ratio, 1.71; 95% confidence interval, 1.52-1.93) and a 63% higher risk of hospitalization (hazard ratio, 1.63; 95% confidence interval, 1.56-1.71). Results were consistent in subgroups of age and sex and when using intent-to-treat or on-treatment analytic approaches.ConclusionsIn adults with atrial fibrillation, digoxin use was independently associated with higher risks of death and hospitalization. Given other available rate control options, digoxin should be used with caution in the management of atrial fibrillation.

BACKGROUND: Digoxin is widely used for rate control of atrial fibrillation. However, recent studies have reported conflicting results on the association of digoxin with mortality when used in patients with atrial fibrillation. Moreover, the relationship of digoxin use to mortality in hypertensive patients with atrial fibrillation has not been examined.METHODS AND RESULTS: All-cause mortality was examined in relation to in-treatment digoxin use in 937 hypertensive patients with ECG left ventricular hypertrophy in atrial fibrillation at baseline (n = 134) or who developed atrial fibrillation during follow-up (n = 803), randomly assigned to losartan or atenolol-based treatment, in post-hoc analysis of a substudy of the Losartan Intervention For Endpoint Reduction in hypertension (LIFE) trial. During 4.7 ± 1.1 years of mean follow-up, 167 patients died (17.8%) and 372 (39.7%) were treated with digoxin. In univariate Cox analyses, in-treatment digoxin use, entered as a time-varying covariate, was associated with a 61% higher risk of dying (hazard ratio 1.61, 95% confidence interval 1.18-2.19, P = 0.003). After adjusting for other univariate predictors of death in this population, including age, diabetes, history of ischemic heart disease, stroke, or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and high-density lipoprotein cholesterol, and a propensity score for digoxin use entered as standard covariates, and for in-treatment heart rate, pulse pressure, and Sokolow-Lyon voltage treated as time-varying covariates, digoxin use was no longer a significant predictor of mortality (hazard ratio 1.04, 95% confidence interval 0.73-1.48, P = 0.839).CONCLUSION: In hypertensive patients with ECG left ventricular hypertrophy with existing or new atrial fibrillation, digoxin use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for t

Rapid ventricular pacing rates induces two types of beats following pacing cessation: recovery cycle length (RCL) prolongation (overdrive suppression) and RCL shortening (overdrive excitation). The goals of this study were to compare common experimental protocols for studying triggered activity in whole-heart preparations and differentiate between recovery beats using a new methodology. Post-pacing recovery beat cycle length (RCL) and QRS were normalized to pre-paced R-R and QRS intervals and analyzed using a K-means clustering algorithm. Control hearts only produced suppressed beats: RCL ratio increased with rapid pacing (25 +/- 4.0%, n = 10) without changing QRS duration. Rapid pacing during hypercalcemia + hypothermia (5.5 mM and 34 degrees C) produced significantly earlier excited beats (53 +/- 14%, n = 5) with wider QRS durations (58 +/- 6.3%, n = 5) than suppressed beats. Digoxin + hypothermia (0.75 mu M) produced the most excited beats with significantly earlier RCL (44 +/- 3.2%, n = 6) and wider QRS (60 +/- 3.1%, n = 6) ratios relative to suppressed beats. Increasing pacing further shortened RCL (30 +/- 7.8%, n = 6). In a prospective study, TTX (100 nM) increased RCL ratio (15 +/- 6.0%, n = 10) without changing the QRS duration of excited beats. The algorithm was compared to a cross-correlation analysis with 93% sensitivity and 94% specificity. This ECG based algorithm distinguishes between triggered and automatic activity.

Rapid ventricular pacing rates induces two types of beats following pacing cessation: recovery cycle length (RCL) prolongation (overdrive suppression) and RCL shortening (overdrive excitation). The goals of this study were to compare common experimental protocols for studying triggered activity in whole-heart preparations and differentiate between recovery beats using a new methodology. Post-pacing recovery beat cycle length (RCL) and QRS were normalized to pre-paced R-R and QRS intervals and analyzed using a K-means clustering algorithm. Control hearts only produced suppressed beats: RCL ratio increased with rapid pacing (25 +/- 4.0%, n = 10) without changing QRS duration. Rapid pacing during hypercalcemia + hypothermia (5.5 mM and 34 degrees C) produced significantly earlier excited beats (53 +/- 14%, n = 5) with wider QRS durations (58 +/- 6.3%, n = 5) than suppressed beats. Digoxin + hypothermia (0.75 mu M) produced the most excited beats with significantly earlier RCL (44 +/- 3.2%, n = 6) and wider QRS (60 +/- 3.1%, n = 6) ratios relative to suppressed beats. Increasing pacing further shortened RCL (30 +/- 7.8%, n = 6). In a prospective study, TTX (100 nM) increased RCL ratio (15 +/- 6.0%, n = 10) without changing the QRS duration of excited beats. The algorithm was compared to a cross-correlation analysis with 93% sensitivity and 94% specificity. This ECG based algorithm distinguishes between triggered and automatic activity.

The present doctoral dissertation deals with the fermentation of leaves of Digitalis lanata Ehrh. (woolly foxglove) causing the enzymatic transformation of lanatoside A, B and C (LA, LB and LC) into the secondary glycosides digitoxin (Dx), gitoxin (Gx) and digoxin (Dgx), the extraction of the secondary glycosides by percolation using the aqueous solutions of methanol and ethanol (10-50 % v/v), the purification of the percolates, the preparation of dry extracts of secondary glycosides using chloroform or trichlorethylene and the isolation of highly pure Dgx (>96 %) from the solution of the dry extracts by fractional dissolution employing either the batch liquid-liquid extraction or continuous countercurrent liquid-liquid extraction in a Karr’s extraction reciprocating plate column. Ground dried leaves cultivated of Digitalis lanata Ehrh. were used. The main goal was to develop the process for obtaining Dgx from the leaves of Digitalis lanata Ehrh. At first, the optimal operating conditions of the fermentation of leaves of Digitalis lanata Ehrh. under anaerobic conditions at 37 oC were determined to be as following: the mean size of plant particles of 7 mm and the water-to-plant material 1:2 g/cm3. Then, the optimal operating conditions of Dgx extraction from the fermented plant material by percolation ensuring the Dgx extraction degree higher than 95 % were found to be as follows: the mean size of plant particles of 7 mm, the depth of the plant material in the extractor of 30 cm, the 10 % vol. ethanol solution as the extracting solvent and the percolate flow rate of 4 dm3/h (i.e. the residence time of 4 h). Also the optimal conditions of purification of the liquid extract using chloroform or trichlorethylene. The obtained liquid extracts were evaporated under vacuum, treated by MgO, filtrated under vacuum and evaporated under vacuum (60 oC). The obtained dry extract contained about 80 % of the secondary glycosides. It was treated with a mixture of acetone and water (

BACKGROUND: Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone-digoxin interaction might explain these adverse outcomes. METHODS AND RESULTS: Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events. CONCLUSIONS: In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01151137.

Digitalis purpurea L. is one of the main sources of cardenolides such as digitoxin and digoxin. These drugs are widely used to strengthen cardiac diffusion and to regulate heart rhythm. The aim of this study was to evaluate the influence of three elicitors on shoots of Digitalis purpurea var. Roter Berggold in semisolid media in order to increase cardenolides biosynthesis. Elicitation is a strategy to increase biomass and secondary metabolites production on in vitro cultures. The elicitors evaluated were ChitoPlant (0,001; 0,01; 0,1 g.L-1); SilioPlant (0,01; 0,1; 1,0 g.L-1) and Methyl jasmonate (60, 80, 100 µM), which are reported here to induce cardenolide production for first time. Elicitation resulted an effective strategy to increase cardenolide production on D. purpurea shoot cultures. ChitoPlant induced a decrease in shoots length, but had no effect on the rest of morphological parameters evaluated. As well, ChitoPlant increased cardenolide content. SilioPlant (0,01 g.L-1) did not affect biomass production and at the same time, increased in 3,6-fold and 6,9-fold digoxin and digitoxin content respectively. Elicitation with Methyl jasmonate resulted in decreased biomass production. Digoxin and digitoxin content was slight and significantly increased by Methyl jasmonate 80 and 100 µM respectively. The best integral result was reached with 0,01 g.L-1 of SilioPlant, which induced the highest net yields per culture flask (4,72 µg of digoxin and 88,27 µg of digitoxin)., Digitalis purpurea L. es una de las principales fuentes de cardenólidos tales como digoxina y digitoxina. Estos fármacos son ampliamente usados en la disfunción cardíaca y para regular las arritmias del corazón. El presente trabajo se realizó con el objetivo de estudiar el efecto de tres elicitores en el cultivo de brotes de Digitalis purpurea var. Roter Berggold para incrementar la producción in vitro de cardenólidos. La elicitación es una estrategia para incrementar la producción de biomasa y metabolitos secundarios en el cultivo in vitro. Los elicitores evaluados fueron ChitoPlant (0,001; 0,01; 0,1 g.L-1); SilioPlant (0,01; 0,1; 1,0 g.L-1) y Jasmonato de metilo (60, 80 y 100 µM), descritos por primera vez para el incremento de cardenólidos. Se demostró que la elicitación es una estrategia viable para el incremento de cardenólidos en brotes de D. purpurea. El ChitoPlant®, redujo la altura sin afectación en el resto de las variables morfológicas evaluadas. Además indujo un incremento significativo en el contenido de cardenólidos. El SilioPlant® (0,01 g.L-1) no provocó afectaciones en la biomasa e incrementó significativamente la síntesis de cardenólidos en los brotes en 3,6 y 6,9 veces el contenido de digoxina y digitoxina respectivamente. La elicitación con el jasmonato de metilo provocó una reducción de la biomasa. Los contenidos de digoxina y digitoxina se incrementaron ligera y significativamente con 80 y 100 µM de jasmonato de metilo respectivamente. El mejor resultado integral se obtuvo con 0,01 g.L-1 de SilioPlant, el cual indujo la mayor producción neta de cardenólidos por frasco de cultivo (4,72 µg digoxina y 88,27 µg digitoxina).