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Molecules (Basel, Switzerland) Jun 2021Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12,...
Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3'a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin's cytotoxicity and interactions with Na/K-ATPase. The docking profiles for digoxin and several derivatives and Na/K-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na/K-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na/K-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.
Topics: Animals; Antineoplastic Agents; Cardiac Glycosides; Cell Proliferation; Digoxin; Humans; Molecular Conformation; Molecular Docking Simulation; Neoplasms; Sodium-Potassium-Exchanging ATPase
PubMed: 34208576
DOI: 10.3390/molecules26123672 -
Open Veterinary Journal 2022Atrial fibrillation (AF) is the most common arrhythmia in dogs, most frequently diagnosed as chronic AF associated with a structural heart disease. The therapeutic...
BACKGROUND
Atrial fibrillation (AF) is the most common arrhythmia in dogs, most frequently diagnosed as chronic AF associated with a structural heart disease. The therapeutic strategy, in these cases, is based on the heart rate control and digoxin is one of the most used drugs.
AIM
The aim of this work was to study the serum digoxin concentration changes in dogs with AF under long-term treatment with digoxin. Furthermore, the remission of clinical signs and the correlation between digoxinemia and other clinical and laboratory variables were retrospectively evaluated.
METHODS
The prospective study was conducted on seven large breed dogs from the time of reaching the definitive digoxin dosage. Digoxinemia was determined at month: 1, 3, 6, 9, 12, then twice a year. A statistical analysis investigated the influence of selected clinical and laboratory variables on the risk to develop spikes in digoxinemia. Clinical data, heart rate, digoxin dosage (mg/m), and digoxinemia (ng/ml) at all available follow-ups were retrospectively evaluated from the medical records of 17 further dogs and a linear regression analysis was performed on the whole data set. The relation between the time of remission of AF clinical signs and variables was also investigated.
RESULTS
An unexpected increase in digoxin serum concentration was recorded in three dogs after one year monitoring, in absence of digoxin dosage changes. No statistical significance of all the studied variables on the risk to develop spikes of digoxinemia was registered. Two dogs, reaching digoxinemia 4.46 and 5.24 ng/ml, showed symptoms that reversed after digoxin withdrawal. From retrospective data, 88% of dogs reached complete reverse of AF clinical signs in 2.1 months from digoxin treatment starting, regardless of digoxin initial dosage, digoxinemia, and heart rate.
CONCLUSION
Digoxin in monotherapy remain a good option to treat AF in dogs, anyway digoxin toxicity could emerge during long-term therapy, similarly to what happen in human medicine. Life-threatening spikes of digoxinemia could occur, especially after 1-year treatment with digoxin. It is very important that practitioners be aware of this possibility and encourage the owners to monitor digoxinemia during long-term treatment to avoid dangerous and toxic effects.
Topics: Animals; Atrial Fibrillation; Digoxin; Dog Diseases; Dogs; Heart Rate; Humans; Prospective Studies; Retrospective Studies
PubMed: 35821778
DOI: 10.5455/OVJ.2022.v12.i3.9 -
Pediatric Critical Care Medicine : a... Jun 2022To examine the association between digoxin use and cardiac function assessed by echocardiographic indices in infants with single-ventricle (SV) congenital heart disease...
OBJECTIVES
To examine the association between digoxin use and cardiac function assessed by echocardiographic indices in infants with single-ventricle (SV) congenital heart disease (CHD) during the interstage period.
DESIGN
Retrospective cohort study.
SETTING
Fifteen North American hospitals.
PATIENTS
Infants discharged home following stage 1 palliation (S1P) and prior to stage 2 palliation (S2P). Infants with no post-S1P and pre-S2P echocardiograms were excluded.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Of 373 eligible infants who met inclusion criteria, 140 (37.5%) were discharged home on digoxin. In multivariable linear and logistic regressions, we found that compared with infants discharged home without digoxin, those discharged with digoxin had a smaller increase in end-systolic volume (β = -8.17 [95% CI, -15.59 to -0.74]; p = 0.03) and area (β = -1.27 [-2.45 to -0.09]; p = 0.04), as well as a smaller decrease in ejection fraction (β = 3.38 [0.47-6.29]; p = 0.02) and fractional area change (β = 2.27 [0.14-4.41]; p = 0.04) during the interstage period.
CONCLUSIONS
Digoxin may partially mitigate the expected decrease in cardiac function during the interstage period through its positive inotropic effects. Prospective clinical trials are needed to establish the pharmacokinetics, safety, and efficacy of digoxin use in SV CHD.
Topics: Digoxin; Heart Defects, Congenital; Heart Ventricles; Humans; Hypoplastic Left Heart Syndrome; Infant; Norwood Procedures; Palliative Care; Prospective Studies; Retrospective Studies; Treatment Outcome; Univentricular Heart
PubMed: 35404313
DOI: 10.1097/PCC.0000000000002946 -
Cureus Sep 2023Renal dysfunction is a common complication among patients with congestive heart failure (CHF) and can significantly impact their management, especially when medications...
INTRODUCTION
Renal dysfunction is a common complication among patients with congestive heart failure (CHF) and can significantly impact their management, especially when medications like digoxin are involved. The clearance of digoxin is closely tied to the glomerular filtration rate (GFR), which suggests that the safety and efficacy of digoxin may vary with renal function. Therefore, this study aimed to assess the potential effects of digoxin on renal function in patients diagnosed with CHF at a tertiary hospital in the Asir region of Saudi Arabia.
METHODS
A retrospective study examined the records of 30 CHF patients treated with digoxin. Renal function markers like estimated GFR (eGFR), creatinine, blood urea nitrogen (BUN), albumin, and urine levels were compared before and after digoxin treatment. Liver enzymes and other relevant parameters were also examined. A statistical analysis using t-tests was conducted to evaluate the changes in renal function indicators before and after digoxin treatment.
RESULTS
The mean eGFR decreased significantly from 65.4 ± 8.9 mL/min/1.73m before digoxin to 57.7 ± 7.8 mL/min/1.73m after (p = 0.001). Creatinine, BUN, albumin, and urine levels showed no significant changes. Digoxin significantly increased aspartate aminotransferase (AST) from 34.5 ± 11.6 U/L to 53.8 ± 14.6 U/L (p = 0.002), alanine aminotransferase (ALT) from 38.5 ± 12.6 U/L to 55.3 ± 17.6 U/L (p = 0.013), and creatine kinase from 117.7 ± 22.5 U/L to 133.9 ± 15.8 U/L (p = 0.012). Hemoglobin decreased significantly from 12.8 ± 1.4 g/dL to 12.1 ± 1.4 g/dL (p = 0.034). No significant changes occurred in myoglobin, troponin, bilirubin, platelets, potassium, calcium, or chloride levels. Effects on kidney function did not differ significantly by gender or age, except blood urea nitrogen was higher in patients over 50 years (8.3 ± 2.3 vs. 5.6 ± 2.7 mg/dL, p = 0.015).
CONCLUSION
This study suggests digoxin may adversely affect renal function in CHF patients, as evidenced by reduced eGFR. However, the small retrospective design limits definitive conclusions. Further prospective research with larger samples is warranted to elucidate digoxin's renal effects in CHF patients.
PubMed: 37854741
DOI: 10.7759/cureus.45419 -
Saudi Pharmaceutical Journal : SPJ :... Mar 2022The cardiotonic digoxin has been recently shown to possess an anti-inflammatory potential in numerous metabolic and inflammatory disorders. However, data about digoxin's...
The cardiotonic digoxin has been recently shown to possess an anti-inflammatory potential in numerous metabolic and inflammatory disorders. However, data about digoxin's impact in the setting of acute liver injury and sterile inflammation are still limited. Here, we investigated the potential effect of digoxin pretreatments (0.25 and 0.5 mg/kg, oral) on the severity of acute hepatotoxicity in mice challenged with a single dose of diethylnitrosamine (DN; 150 mg/kg, intraperitoneal) for 24 h. Our results indicated that digoxin pretreatments dose-dependently mitigated DN-induced rise of hepatocellular injury parameters and necroinflammation scores. Digoxin, particularly at dose of 0.5 mg/kg, boosted the number of PCNA positive hepatocytes, leading to improvement of the reparative potential in hepatocytes of DN-intoxicated livers. Digoxin's ameliorative effect on DN-hepatotoxicity coincided with (i) lowering the increased hepatic production and release of the proinflammatory mediators IL-17A, IL-1β and TNF-α, and (ii) impeding the attraction and infiltration of monocytes to the liver, as denoted by decreasing serum MCP-1 and F4/80 immunohistochemical expression. These effects were attributed to reducing DN-induced activation of NF-κB and overexpression of CD98 in the liver. Meanwhile, DN elicited a decline in the hepatic production and release of the anti-inflammatory cytokines IL-22 and IL-6, which was intensified by digoxin, especially at a dose 0.5 mg/kg. In conclusion, digoxin conferred liver protection against DN-insult by impairing the overproduction of proinflammatory cytokines and infiltration of inflammatory cells to the liver.
PubMed: 35498227
DOI: 10.1016/j.jsps.2022.01.007 -
Lakartidningen Jun 2020Right-sided heart failure is a common disease that leads to increased morbidity and mortality. Despite this it is ill understood. Echocardiography is currently the...
Right-sided heart failure is a common disease that leads to increased morbidity and mortality. Despite this it is ill understood. Echocardiography is currently the primary mode for diagnosis and tricuspid annular plane systolic excursion and fractional area change are good measurements to use for assessment. Volume management is central in treatment of both acute and chronic right-sided heart failure. In acute failure achieving effective diuresis is often more important than the addition of fluids. In the treatment of chronic heart failure, no strong evidence supports the use of RAAS-blockers, beta-blockers, aldosterone antagonists or digoxin. In the case of right-sided heart failure caused by pulmonary arterial hypertension vasodilator therapy may be of use, but not in cases of other forms of pulmonary hypertension.
Topics: Heart Failure; Heart Ventricles; Humans; Hypertension, Pulmonary; Ventricular Dysfunction, Right; Ventricular Function, Right
PubMed: 32542616
DOI: No ID Found -
Emergencias : Revista de La Sociedad... Dec 2023To analyze factors related to the use of digoxin to treat patients with acute heart failure (AHF) in emergency departments (EDs) and the impact of digoxin treatment on...
OBJECTIVES
To analyze factors related to the use of digoxin to treat patients with acute heart failure (AHF) in emergency departments (EDs) and the impact of digoxin treatment on short-term outcomes.
MATERIAL AND METHODS
We included patients diagnosed with AHF in 45 Spanish EDs. The patients, who were not undergoing long-term treatment for heart failure, were classified according to whether or not they were given intravenous digoxin in the ED. Fifty-one patient or cardiac decompensation episode variables were recorded to profile ED patients treated with digoxin. Outcome variables studied were the need for hospital admission, prolonged stay in the ED (> 24 hours) for discharged patients, prolonged hospitalization (> 7 days) for admitted patients, and all-cause in-hospital or 30-day mortality. The associations between digoxin treatment and the outcomes were studied with odds ratios (ORs) adjusted for patient and AHF episode characteristics.
RESULTS
Data for 15 549 patients (median age, 83 years; 55% women) were analyzed; 1430 (9.2%) were treated with digoxin. Digoxin was used more often in women, young patients, and those with better New York Heart Association (NYHA) classifications but more severe cardiac decompensation, especially if the trigger was atrial fibrillation with rapid ventricular response. Admissions were ordered for 75.4% of the patients overall (81.6% of digoxin-treated patients vs 74.8% of nontreated patients; P .001). The ED stay was prolonged in 38.3% of patients discharged from the ED (52.9% of digoxin-treated patients vs 37.2% of nontreated patients; P .001). The duration of hospital stay was prolonged in 48.1% (digoxin-treated, 49.3% vs 47.9%; P = .385). In-hospital mortality was 7.2% overall (6.9% vs 7.2%, P= .712), and 30-day mortality was 9.7% (9.3% vs 9.7%, P = .625). ED use of digoxin was associated with a prolonged stay in the department (adjusted OR, 1.883; 95% CI, 1.359-2.608) but not with hospitalization or mortality.
CONCLUSION
Digoxin continues to be used in one out of ten ED patients who are not already on long-term treatment with the drug. Digoxin use is associated with cardiac decompensation triggered by atrial fibrillation with rapid ventricular response, younger age, women, and patients with better initial NYHA function status but possibly more severe decompensation. Digoxin use leads to a longer ED stay but is safe, as it is not associated with need for admission, prolonged hospitalization, or short-term mortality.
Topics: Humans; Female; Aged, 80 and over; Male; Digoxin; Atrial Fibrillation; Heart Failure; Emergency Service, Hospital; Hospitalization
PubMed: 38116968
DOI: 10.55633/s3me/E08.2023 -
Scientific Reports Nov 2023Lung adenocarcinoma (LUAD) is one of the most widespread and fatal types of lung cancer. Oxidative stress, resulting from an imbalance in the production and accumulation...
Lung adenocarcinoma (LUAD) is one of the most widespread and fatal types of lung cancer. Oxidative stress, resulting from an imbalance in the production and accumulation of reactive oxygen species (ROS), is considered a promising therapeutic target for cancer treatment. Currently, immune checkpoint blockade (ICB) therapy is being explored as a potentially effective treatment for early-stage LUAD. In this research, we aim to identify distinct subtypes of LUAD patients by investigating genes associated with oxidative stress and immunotherapy. Additionally, we aim to propose subtype-specific therapeutic strategies. We conducted a thorough search of the Gene Expression Omnibus (GEO) datasets. From this search, we pinpointed datasets that contained both expression data and survival information. We selected genes associated with oxidative stress and immunotherapy using keyword searches on GeneCards. We then combined expression data of LUAD samples from both The Cancer Genome Atlas (TCGA) and 11 GEO datasets, forming a unified dataset. This dataset was subsequently divided into two subsets, Dataset_Training and Dataset_Testing, using a random bifurcation method, with each subset containing 50% of the data. We applied consensus clustering (CC) analysis to identify distinct LUAD subtypes within the Dataset_Training. Molecular variances associated with oxidative stress levels, the tumor microenvironment (TME), and immune checkpoint genes (ICGs) were then investigated among these subtypes. Employing feature selection combined with machine learning techniques, we constructed models that achieved the highest accuracy levels. We validated the identified subtypes and models from Dataset_Training using Dataset_Testing. A hub gene with the highest importance values in the machine learning model was identified. We then utilized virtual screening to discover potential compounds targeting this hub gene. In the unified dataset, we integrated 2,154 LUAD samples from TCGA-LUAD and 11 GEO datasets. We specifically selected 1,311 genes associated with immune and oxidative stress processes. The expression data of these genes were then employed for subtype identification through CC analysis. Within Dataset_Training, two distinct subtypes emerged, each marked by different levels of immune and oxidative stress pathway values. Consequently, we named these as the OX and IM subtypes. Notably, the OX subtype showed increased oxidative stress levels, correlating with a worse prognosis than the IM subtype. Conversely, the IM subtype demonstrated enhanced levels of immune pathways, immune cells, and ICGs compared to the OX subtype. We reconfirmed these findings in Dataset_Testing. Through gene selection, we identified an optimal combination of 12 genes for predicting LUAD subtypes: ACP1, AURKA, BIRC5, CYC1, GSTP1, HSPD1, HSPE1, MDH2, MRPL13, NDUFS1, SNRPD1, and SORD. Out of the four machine learning models we tested, the support vector machine (SVM) stood out, achieving the highest area under the curve (AUC) of 0.86 and an accuracy of 0.78 on Dataset_Testing. We focused on HSPE1, which was designated as the hub gene due to its paramount importance in the SVM model, and computed the docking structures for four compounds: ZINC3978005 (Dihydroergotamine), ZINC52955754 (Ergotamine), ZINC150588351 (Elbasvir), and ZINC242548690 (Digoxin). Our study identified two subtypes of LUAD patients based on oxidative stress and immunotherapy-related genes. Our findings provided subtype-specific therapeutic strategies.
Topics: Humans; Adenocarcinoma of Lung; Immunotherapy; Oxidative Stress; Lung Neoplasms; Radioimmunotherapy; Tumor Microenvironment
PubMed: 38017020
DOI: 10.1038/s41598-023-47659-8 -
BMC Pharmacology & Toxicology Feb 2022Digoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow...
BACKGROUND
Digoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow therapeutic window and large interindividual variability. A low target blood concentration, especially ≤0.9 ng/mL, is recommended for patients with HF who are taking digoxin. This study aimed to develop a population pharmacokinetic model and to identify clinical factors that affect digoxin exposure and an optimal digoxin dosing regimen in Japanese patients with AF and HF.
METHODS
A population pharmacokinetic analysis was performed by using a nonlinear mixed effects model based on 3465 concentration points from 391 patients (>18 years) who were receiving oral digoxin. Using trough serum digoxin concentrations and clinical data, a population pharmacokinetic model was developed for determining covariates of clearance. A 1-compartment model was used to examine the interindividual variability of the oral clearance (CL/F) of digoxin. An appropriate dosage of digoxin was identified using Monte Carlo simulation.
RESULTS
The final model demonstrated that creatinine clearance (CL) and the use of amiodarone were factors that contributed to the CL/F of digoxin. Monte Carlo simulation results showed that with a daily maintenance dose of 0.25 mg, the intoxication risk window of a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients regardless of renal function category or concurrent use of amiodarone. The appropriate maintenance dosage was 0.125 mg daily for most Japanese patients with AF and HF. However, with a daily dose of 0.125 mg, a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients with renal impairments (CL 30 mL/min) or concurrent use of amiodarone. A daily maintenance dose of 0.0625 mg was acceptable for these patients.
CONCLUSIONS
CL and the use of amiodaron were found to contribute to digoxin clearance using a population pharmacokinetic methodology. For Japanese patients with AF and HF, 0.125 mg is an appropriate daily digoxin maintenance dose, but a dose reduction is required for patients with CL <30 mL/min or concurrent amiodarone use.
Topics: Amiodarone; Atrial Fibrillation; Digoxin; Heart Failure; Humans; Japan
PubMed: 35144695
DOI: 10.1186/s40360-022-00552-y -
Turkish Journal of Obstetrics and... Dec 2022Fetal arrhythmias complicate 1-2% of all pregnancies. Ultrasound evaluation and Doppler technology are indispensable in both diagnosis and management. Digoxin, sotalol,...
OBJECTIVE
Fetal arrhythmias complicate 1-2% of all pregnancies. Ultrasound evaluation and Doppler technology are indispensable in both diagnosis and management. Digoxin, sotalol, flecainide and amiodarone are widely accepted antiarrhythmic agents that are frequently. We reviewed the maternal and fetal outcomes in cases with fetal arrhythmia in a tertiary care center in the last decade.
MATERIALS AND METHODS
Fetal arrhythmias were classified under three main groups: Irregular rhythms, tachyarrhythmia and bradyarrhythmia. Detailed anatomical evaluation and fetal echocardiography were performed in all cases to determine whether a structural cardiac and extracardiac anomaly accompanied fetal arrhythmia and the type of fetal arrhythmia. Digoxin was started primarily as first-line therapy in patients with persistent fetal tachyarrhythmia. In cases, not responding to digoxin, other antiarrhythmic agents (sotalol, flecainide) were combined with treatment without discontinuing digoxin.
RESULTS
Fetal arrhythmia was detected in 36 cases during the study period. 50% (n=18/36) of the cases had supraventricular tachycardia, whereas 28% (n=10/36) of them were fetal bradyarrhythmia and 22% (n=8/36) of them were with various irregular rhythms. Transplacental therapy was initiated in 13 patients with persistent supraventricular tachycardia and atrial flutter regardless of the presence of hydrops. The success rate in transplacental therapy was 77% (n=10/13).
CONCLUSION
Successful transplacental therapy was achieved in approximately 80% of cases and delivery could be postponed to advanced gestational weeks, confirming the crucial role of this treatment for the management of tachyarrhythmia.
PubMed: 36511630
DOI: 10.4274/tjod.galenos.2022.61818