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Journal of the American College of... Oct 1996Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its... (Review)
Review
Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.
Topics: Anti-Arrhythmia Agents; Cardiac Output, Low; Cardiotonic Agents; Digoxin; Heart Failure; Humans
PubMed: 8837553
DOI: 10.1016/s0735-1097(96)00247-1 -
Proceedings of the National Academy of... Mar 2009
Topics: Animals; Cell Survival; Digoxin; Humans; Hypoxia-Inducible Factor 1; Neoplasms
PubMed: 19240208
DOI: 10.1073/pnas.0813047106 -
Journal of Pharmacy & Pharmaceutical... 2019Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured...
PURPOSE
Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH.
METHODS
Rosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate.
RESULTS
For rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive.
CONCLUSIONS
These data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.
Topics: Biological Transport; Cell Culture Techniques; Cells, Cultured; Digoxin; Erythromycin Estolate; Hepatocytes; Humans; Membrane Transport Proteins; Metformin; Molecular Probes; Rosuvastatin Calcium
PubMed: 31804919
DOI: 10.18433/jpps30706 -
International Journal of Cardiology Apr 2016Digoxin is recommended in symptomatic heart failure patients with reduced ejection fraction (HF-REF) in sinus rhythm and refractory to other evidence-based therapy.... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of digoxin in patients with heart failure and reduced ejection fraction according to diabetes status: An analysis of the Digitalis Investigation Group (DIG) trial.
BACKGROUND
Digoxin is recommended in symptomatic heart failure patients with reduced ejection fraction (HF-REF) in sinus rhythm and refractory to other evidence-based therapy. Although HF-REF patients with diabetes have worse functional status than those without, the effects of digoxin have not been specifically evaluated according to diabetes status.
METHODS
We examined the efficacy and safety of digoxin in HF-REF patients with and without diabetes in the Digitalis Investigation Group trial. Mortality from all-cause, cardiovascular (CV) causes and heart failure (HF), along with HF hospitalisation and suspected digoxin toxicity were analyzed according to diabetes status and randomised treatment assignment.
RESULTS
Of the 6800 patients, those with diabetes (n=1933) were older, more often women, had worse clinical status and more co-morbidity than those without diabetes. All-cause and CV mortality were higher in patients with diabetes than in those without and digoxin did not reduce mortality in either sub-group. The rate of HF hospitalization (per 100 person-years) in patients with diabetes was higher than in those without and was reduced by digoxin in both patient groups: diabetes - placebo 20.5 and digoxin 16.0 (HR 0.79, 95% CI: 0.68-0.91); no diabetes - placebo 12.7 and digoxin 8.7 (HR 0.69, 0.62-0.77); interaction p=0.14. Suspected digoxin toxicity in patients randomised to digoxin was more common among patients with diabetes than without (6.5% versus 5.8%), as was hospitalisation for digoxin toxicity (1.4% versus 0.8%).
CONCLUSION
Added to an ACE inhibitor, digoxin reduced HF hospitalisation in HF-REF patients with and without diabetes without a substantial risk of toxicity.
Topics: Aged; Cardiotonic Agents; Diabetes Mellitus; Digitalis; Digoxin; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Male; Middle Aged; Retrospective Studies; Risk Factors; Stroke Volume; Treatment Outcome
PubMed: 26913372
DOI: 10.1016/j.ijcard.2016.02.074 -
Scientific Reports Nov 2019Cardiac glycosides, such as digoxin, inhibit Na/K-ATPases and cause secondary activation of Na/Ca exchangers. Preclinical investigations have suggested that digoxin may...
Cardiac glycosides, such as digoxin, inhibit Na/K-ATPases and cause secondary activation of Na/Ca exchangers. Preclinical investigations have suggested that digoxin may have anticancer properties. In order to clarify the functional mechanisms of digoxin in cancer, we performed an integrative analysis of clinical and bioinformatics databases. The US Food and Drug Administration Adverse Event Reporting System and the Japan Medical Data Center claims database were used as clinical databases to evaluate reporting odds ratios and adjusted sequence ratios, respectively. The BaseSpace Correlation Engine and Connectivity Map bioinformatics databases were used to investigate molecular pathways related to digoxin anticancer mechanisms. Clinical database analyses suggested an inverse association between digoxin and four cancers: gastric, colon, prostate and haematological malignancy. The bioinformatics database analysis suggested digoxin may exert an anticancer effect via peroxisome proliferator-activated receptor α and apoptotic caspase cascade pathways. Our integrative analysis revealed the possibility of digoxin as a drug repositioning candidate for cancers.
Topics: Antineoplastic Agents; Cardiotonic Agents; Computational Biology; Databases, Factual; Digoxin; Drug Repositioning; Humans; Neoplasms
PubMed: 31719612
DOI: 10.1038/s41598-019-53392-y -
British Journal of Pharmacology May 2016Numerous in vitro studies have suggested that digoxin suppresses inflammation and alters lipid metabolism. However, the effect of dioxin on atherosclerosis is poorly...
BACKGROUND AND PURPOSE
Numerous in vitro studies have suggested that digoxin suppresses inflammation and alters lipid metabolism. However, the effect of dioxin on atherosclerosis is poorly understood. The present study was conducted to determine whether digoxin affects the development of atherosclerosis in a murine model of atherosclerotic disease.
EXPERIMENTAL APPROACH
Apolipoprotein E-deficient mice maintained on a Western-type diet were administered PBS (control), low-dose digoxin (1 mg · kg(-1) · day(-1)) or high-dose digoxin (2 mg · kg(-1) · day(-1)) via i.p. injection for 12 weeks.
KEY RESULTS
Digoxin dose-dependently reduced atherosclerotic lesion formation and plasma lipid levels (reductions of 41% in total cholesterol, 54% in triglycerides and 20% in low-density lipoprotein cholesterol in the high-dose digoxin-treated group). Moreover, treatment with digoxin markedly attenuated IL-17A expression and IL-17A-related inflammatory responses and increased the abundance of regulatory T cells (Tregs).
CONCLUSIONS AND IMPLICATIONS
Our data demonstrate that digoxin acts as a specific antagonist of retinoid-related orphan receptor-γ to decrease atherosclerosis by suppressing lipid levels and IL-17A-related inflammatory responses.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Digoxin; Dose-Response Relationship, Drug; Inflammation; Interleukin-17; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 3
PubMed: 26879387
DOI: 10.1111/bph.13453 -
Annales de Biologie Clinique 2003Following administration of anti-digoxin Fab fragments, monitoring unbound digoxin concentrations may help ensure appropriate dosing, and prevent recrudescent toxicity.... (Review)
Review
Following administration of anti-digoxin Fab fragments, monitoring unbound digoxin concentrations may help ensure appropriate dosing, and prevent recrudescent toxicity. Ultrafiltration by using Centrifree system and measurement of digoxin in the ultrafiltrate is considered as reference technique. However, ultrafiltration method is cumbersome, costly, and some immunoassays are affected by matrix differences. Another approach is to analyse the serum directly by digoxin immunoassays without ultrafiltering it. The validity of results obtained depends on the architecture of the immunoassay and the amount of Fab in the sample. The old radioimmunoassays and usually the other competitive immunoassays give inaccurate results. The fluorescence polarization immunoassay (FPIA) slightly underestimates the total digoxin concentrations. Total digoxin levels obtained at 24 hours and 48 hours after treatment permit measurement of the half-life of digoxin Fab complexes and can be used to estimate when the patient can be redigitalized, if necessary. The sequential immunoassays usually overestimate the free digoxin concentrations. The differences observed are >25% and cannot be explained solely by albumin binding (normal range, 20% +/- 5%). To date, ultrafiltration remains the best strategy for accurate determination of digoxin concentrations in the presence of antidigoxin Fab fragments.
Topics: Aged; Aged, 80 and over; Digoxin; Drug Monitoring; Female; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Ultrafiltration
PubMed: 14711605
DOI: No ID Found -
British Journal of Clinical Pharmacology Sep 1989Anti-digoxin antibody fragments (ADAF, 80 mg) were infused intravenously to successfully treat severe digoxin toxicity in an 82 year old woman. During treatment, total...
Anti-digoxin antibody fragments (ADAF, 80 mg) were infused intravenously to successfully treat severe digoxin toxicity in an 82 year old woman. During treatment, total and free digoxin were determined using an Abbot TDX analyser and an ultrafiltration technique. ADAF were measured by an enzyme-linked immunosorbent assay. By 1 h after ADAF, total serum digoxin concentrations had risen 12-fold from a pretreatment level of 15.4 nmol l-1 but free digoxin fell from 10 to 0.1 nmol l-1, indicating greater than 99.9% digoxin binding to ADAF. However, the low free levels had rebounded to 7.7 nmol l-1 by 12 h, but despite this rise the patient's condition had improved. A serum ADAF/digoxin molar ratio of around five was associated with the low concentration of free digoxin at 1 h, while at later times with ratios roughly between 3 and 4, the free digoxin concentrations ranged between 2.0 and 7.7 nmol l-1. ADAF were mainly confined to the plasma during the first hour, but subsequently distributed into an apparent volume of 193 ml kg-1. The elimination half-lives of ADAF and total digoxin were 96 and 55 h, respectively. More than 50% of the estimated digoxin load had been excreted in the urine by 5 days; for ADAF the equivalent figure was only about 3%. Renal and/or bacterial degradation may have contributed to the low detection of urinary ADAF.
Topics: Aged; Aged, 80 and over; Digoxin; Enzyme-Linked Immunosorbent Assay; Female; Half-Life; Humans; Immunoglobulin Fragments; Potassium
PubMed: 2789929
DOI: 10.1111/j.1365-2125.1989.tb05437.x -
Biological & Pharmaceutical Bulletin May 2020Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal... (Observational Study)
Observational Study
Frequency of Clinical Monitoring of Serum Concentrations of Digoxin, Potassium, and Creatinine, and Recording of Electrocardiograms in Digoxin-Treated Patients: A Japanese Claims Database Analysis.
Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal dysfunction and hypokalemia. However, only a few studies have reported the prevalence of SDC monitoring and laboratory testing in clinical practice. Therefore, the aim of this study was to describe the frequency of SDC monitoring and laboratory testing in digoxin users and to assess the association between SDC monitoring and patient characteristics. We used the Japanese insurance claims data covering approximately 1.7 million patients aged 20-74 years between January 1, 2005 and March 31, 2014. All patients who had at least one prescription for digoxin were included. The frequency of SDC and laboratory tests was calculated and the association between patient characteristics and SDC monitoring was assessed using logistic regression analysis. A total of 98867 prescriptions of digoxin were issued to 3458 patients between 2005 and 2014. The annual mean frequencies of monitoring SDC, serum potassium level and serum creatinine level and of recording electrocardiograms was 16.8, 34.8, 38.7, and 24.1%, respectively. Atrial fibrillation, chronic heart failure, renal diseases, and use of oral anticoagulants were associated with SDC monitoring. We found the frequency of SDC monitoring to be relatively low in Japanese clinical practice.
Topics: Adult; Aged; Cardiotonic Agents; Creatinine; Databases, Factual; Digoxin; Drug Monitoring; Electrocardiography; Humans; Insurance, Health; Japan; Middle Aged; Potassium; Young Adult
PubMed: 32132314
DOI: 10.1248/bpb.b19-01116 -
The Journal of Biological Chemistry Aug 2019Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the...
Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the pharmaceutical market. Among these drugs are plant-derived cardiac glycosides, which have been used by various cultures over millennia as both medicines and poisons. We report that digoxin and related compounds activate the NLRP3 inflammasome in macrophages and cardiomyocytes at concentrations achievable during clinical use. Inflammasome activation initiates the maturation and release of the inflammatory cytokine IL-1β and the programmed cell death pathway pyroptosis in a caspase-1-dependent manner. Notably, the same fluxes of potassium and calcium cations that affect heart contraction also induce inflammasome activation in human but not murine cells. Pharmaceuticals that antagonize these fluxes, including glyburide and verapamil, also inhibit inflammasome activation by cardiac glycosides. Cardiac glycoside-induced cellular cytotoxicity and IL-1β signaling are likewise antagonized by inhibitors of the NLRP3 inflammasome or the IL-1 receptor-targeting biological agent anakinra. Our results inform on the molecular mechanism by which the inflammasome integrates the diverse signals that activate it through secondary signals like cation flux. Furthermore, this mechanism suggests a contribution of the inflammasome to the toxicity and adverse events associated with cardiac glycosides use in humans and that targeted anti-inflammatories could provide an additional adjunct therapeutic countermeasure.
Topics: Animals; Cell Death; Cells, Cultured; Cytokines; Digoxin; Humans; Inflammasomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 31300552
DOI: 10.1074/jbc.RA119.008330