-
Molecules (Basel, Switzerland) Aug 2020Cardiac glycosides (CGs) have a long history of treating cardiac diseases. However, recent reports have suggested that CGs also possess anticancer and antiviral... (Review)
Review
Cardiac glycosides (CGs) have a long history of treating cardiac diseases. However, recent reports have suggested that CGs also possess anticancer and antiviral activities. The primary mechanism of action of these anticancer agents is by suppressing the Na/k-ATPase by decreasing the intracellular K and increasing the Na and Ca. Additionally, CGs were known to act as inhibitors of IL8 production, DNA topoisomerase I and II, anoikis prevention and suppression of several target genes responsible for the inhibition of cancer cell proliferation. Moreover, CGs were reported to be effective against several DNA and RNA viral species such as influenza, human cytomegalovirus, herpes simplex virus, coronavirus, tick-borne encephalitis (TBE) virus and Ebola virus. CGs were reported to suppress the HIV-1 gene expression, viral protein translation and alters viral pre-mRNA splicing to inhibit the viral replication. To date, four CGs (Anvirzel, UNBS1450, PBI05204 and digoxin) were in clinical trials for their anticancer activity. This review encapsulates the current knowledge about CGs as anticancer and antiviral drugs in isolation and in combination with some other drugs to enhance their efficiency. Further studies of this class of biomolecules are necessary to determine their possible inhibitory role in cancer and viral diseases.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Autophagy; Cardiac Glycosides; Clinical Trials as Topic; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Immunologic Factors; Signal Transduction
PubMed: 32784680
DOI: 10.3390/molecules25163596 -
International Journal of... 2021The role of digoxin (cardiac glycoside) in controlling the heart rate (HR) for the treatment of atrial fibrillation (AF) patients has not been explored in depth.
INTRODUCTION
The role of digoxin (cardiac glycoside) in controlling the heart rate (HR) for the treatment of atrial fibrillation (AF) patients has not been explored in depth.
METHODS
To contribute to the limited data, our team conducted retrospective analysis of the clinical records of 1444 AF patients. We divided the AF patients into two groups, wherein group 1 patients were treated with beta-blockers (BB), low-dose digoxin, and an anticoagulant (vitamin K antagonist/factor-IIa inhibitor/factor-Xa inhibitor), and group 2 patients were treated with just BB and an anticoagulant. Our objectives were to compare the impact of combination therapy of BB and digoxin on the resting HR in patients with permanent AF and the patients' quality of life (QOL) at periodic intervals.
RESULTS
The findings of our study showed a better control of the resting HR rate (<110bpm) and an improved QOL among the group 1 patients when compared with group 2 patients.
CONCLUSION
Our findings are indicative of the favorable clinical outcomes that resulted from the addition of a low-dose of digoxin to the AF treatment regimen. However, larger studies/trials elucidating the outcomes of AF patients treated with the dual rate control therapy are required to clarify the role of digoxin, guide the choice of agents, and standardize the AF treatment protocol.
Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Digoxin; Drug Therapy, Combination; Female; Heart Rate; Humans; Male; Middle Aged; Quality of Life; Retrospective Studies
PubMed: 34724841
DOI: 10.1177/20587384211051955 -
Cureus Mar 2022In this review, we evaluated the literature on the benefits and deleterious effects of digoxin in heart failure (HF) with reduced ejection fraction (EF). Although... (Review)
Review
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).
PubMed: 35371861
DOI: 10.7759/cureus.22778 -
Cardiology in ReviewFetal supraventricular tachycardia management is challenging, with consequences for both the fetus and the mother. If left untreated, fetal hydrops may ensue, at which... (Review)
Review
Fetal supraventricular tachycardia management is challenging, with consequences for both the fetus and the mother. If left untreated, fetal hydrops may ensue, at which point delivery and treatment of the arrhythmia is preferred. However, if the fetus is not at term nor near-term, significant doses of antiarrhythmics may be needed to achieve adequate transplacental bioavailability. Although digoxin has classically been the mainstay of treatment, the use of flecainide or sotalol as monotherapy or in combination with digoxin is being studied. Interdisciplinary team management and shared decision-making between the physician and patient are key to achieving successful outcomes. Adult cardiologists, particularly inpatient consultation services or through burgeoning cardio-obstetrics programs, may, in some practice settings, be asked to evaluate or comanage pregnant women with fetal arrhythmia.
Topics: Anti-Arrhythmia Agents; Cardiologists; Female; Fetal Diseases; Humans; Pregnancy; Tachycardia, Supraventricular
PubMed: 33165088
DOI: 10.1097/CRD.0000000000000370 -
Frontiers in Cardiovascular Medicine 2021Whether digoxin is associated with increased mortality in atrial fibrillation (AF) remains controversial. We aimed to assess the risk of mortality and clinical effects...
Whether digoxin is associated with increased mortality in atrial fibrillation (AF) remains controversial. We aimed to assess the risk of mortality and clinical effects of digoxin use in patients with AF. PubMed, Embase, and the Cochrane library were systematically searched to identify eligible studies comparing all-cause mortality of patients with AF taking digoxin with those not taking digoxin, and the length of follow-up was at least 6 months. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted and pooled. A total of 29 studies with 621,478 patients were included. Digoxin use was associated with an increased risk of all-cause mortality in all patients with AF (HR 1.17, 95% CI 1.13-1.22, < 0.001), especially in patients without HF (HR 1.28, 95% CI 1.11-1.47, < 0.001). There was no significant association between digoxin and mortality in patients with AF and HF (HR 1.06, 95% CI 0.99-1.14, = 0.110). In all patients with AF, regardless of concomitant HF, digoxin use was associated with an increased risk of sudden cardiac death (SCD) (HR 1.40, 95% CI 1.23-1.60, < 0.001) and cardiovascular (CV) mortality (HR 1.27, 95% CI 1.08-1.50, < 0.001), and digoxin use had no significant association with all-cause hospitalization (HR 1.13, 95% CI 0.92-1.39, = 0.230). We conclude that digoxin use is associated with an increased risk of all-cause mortality, CV mortality, and SCD, and it does not reduce readmission for AF, regardless of concomitant HF. Digoxin may have a neutral effect on all-cause mortality in patients with AF with concomitant HF. https://www.crd.york.ac.ukPROSPERO.
PubMed: 34660731
DOI: 10.3389/fcvm.2021.731135 -
Scientific Reports Oct 2020The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, patients with COVID-19 and comorbidities such as...
The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, patients with COVID-19 and comorbidities such as hypertension and cardiac diseases have a higher mortality rate. An efficient strategy in response to this issue is repurposing drugs with antiviral activity for therapeutic effect. Digoxin (DIG) and ouabain (OUA) are FDA drugs for heart diseases that have antiviral activity against several coronaviruses. Thus, we aimed to assess antiviral activity of DIG and OUA against SARS-CoV-2 infection. The half-maximal inhibitory concentrations (IC) of DIG and OUA were determined at a nanomolar concentration. Progeny virus titers of single-dose treatment of DIG, OUA and remdesivir were approximately 10-, 10- and 10-fold lower (> 99% inhibition), respectively, than that of non-treated control or chloroquine at 48 h post-infection (hpi). Furthermore, therapeutic treatment with DIG and OUA inhibited over 99% of SARS-CoV-2 replication, leading to viral inhibition at the post entry stage of the viral life cycle. Collectively, these results suggest that DIG and OUA may be an alternative treatment for COVID-19, with potential additional therapeutic effects for patients with cardiovascular disease.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Betacoronavirus; Chlorocebus aethiops; Chloroquine; Digoxin; Inhibitory Concentration 50; Ouabain; SARS-CoV-2; Vero Cells; Virus Replication
PubMed: 33004837
DOI: 10.1038/s41598-020-72879-7 -
Clinical Science (London, England :... Oct 2023In the vascular wall, the Na,K-ATPase plays an important role in the control of arterial tone. Through cSrc signaling, it contributes to the modulation of Ca2+... (Review)
Review
In the vascular wall, the Na,K-ATPase plays an important role in the control of arterial tone. Through cSrc signaling, it contributes to the modulation of Ca2+ sensitivity in vascular smooth muscle cells. This review focuses on the potential implication of Na,K-ATPase-dependent intracellular signaling pathways in severe vascular disorders; ischemic stroke, familial migraine, and arterial hypertension. We propose similarity in the detrimental Na,K-ATPase-dependent signaling seen in these pathological conditions. The review includes a retrospective proteomics analysis investigating temporal changes after ischemic stroke. The analysis revealed that the expression of Na,K-ATPase α isoforms is down-regulated in the days and weeks following reperfusion, while downstream Na,K-ATPase-dependent cSrc kinase is up-regulated. These results are important since previous studies have linked the Na,K-ATPase-dependent cSrc signaling to futile recanalization and vasospasm after stroke. The review also explores a link between the Na,K-ATPase and migraine with aura, as reduced expression or pharmacological inhibition of the Na,K-ATPase leads to cSrc kinase signaling up-regulation and cerebral hypoperfusion. The review discusses the role of an endogenous cardiotonic steroid-like compound, ouabain, which binds to the Na,K-ATPase and initiates the intracellular cSrc signaling, in the pathophysiology of arterial hypertension. Currently, our understanding of the precise control mechanisms governing the Na,K-ATPase/cSrc kinase regulation in the vascular wall is limited. Understanding the role of vascular Na,K-ATPase signaling is essential for developing targeted treatments for cerebrovascular disorders and hypertension, as the Na,K-ATPase is implicated in the pathogenesis of these conditions and may contribute to their comorbidity.
Topics: Humans; Sodium-Potassium-Exchanging ATPase; Retrospective Studies; Muscle, Smooth, Vascular; Hypertension; Sodium; Stroke; Ischemic Stroke; Migraine Disorders
PubMed: 37877226
DOI: 10.1042/CS20220796 -
Chest Apr 2021Atrial fibrillation (AF) with rapid ventricular response frequently complicates the management of critically ill patients with sepsis and may necessitate the initiation... (Comparative Study)
Comparative Study
BACKGROUND
Atrial fibrillation (AF) with rapid ventricular response frequently complicates the management of critically ill patients with sepsis and may necessitate the initiation of medication to avoid hemodynamic compromise. However, the optimal medication to achieve rate control for AF with rapid ventricular response in sepsis is unclear.
RESEARCH QUESTION
What is the comparative effectiveness of frequently used AF medications (β-blockers, calcium channel blockers, amiodarone, and digoxin) on heart rate (HR) reduction among critically ill patients with sepsis and AF with rapid ventricular response?
STUDY DESIGN AND METHODS
We conducted a multicenter retrospective cohort study among patients with sepsis and AF with rapid ventricular response (HR > 110 beats/min). We compared the rate control effectiveness of β-blockers to calcium channel blockers, amiodarone, and digoxin using multivariate-adjusted, time-varying exposures in competing risk models (for death and addition of another AF medication), adjusting for fixed and time-varying confounders.
RESULTS
Among 666 included patients, 50.6% initially received amiodarone, 10.1% received a β-blocker, 33.8% received a calcium channel blocker, and 5.6% received digoxin. The adjusted hazard ratio for HR of < 110 beats/min by 1 h was 0.50 (95% CI, 0.34-0.74) for amiodarone vs β-blocker, 0.37 (95% CI, 0.18-0.77) for digoxin vs β-blocker, and 0.75 (95% CI, 0.51-1.11) for calcium channel blocker vs β-blocker. By 6 h, the adjusted hazard ratio for HR < 110 beats/min was 0.67 (95% CI, 0.47-0.97) for amiodarone vs β-blocker, 0.60 (95% CI, 0.36-1.004) for digoxin vs β-blocker, and 1.03 (95% CI, 0.71-1.49) for calcium channel blocker vs β-blocker.
INTERPRETATION
In a large cohort of patients with sepsis and AF with rapid ventricular response, a β-blocker treatment strategy was associated with improved HR control at 1 h, but generally similar HR control at 6 h compared with amiodarone, calcium channel blocker, or digoxin.
Topics: Adrenergic beta-Antagonists; Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Calcium Channel Blockers; Comparative Effectiveness Research; Critical Illness; Digoxin; Female; Heart Rate; Humans; Male; Middle Aged; Retrospective Studies; Sepsis; United States
PubMed: 33619010
DOI: 10.1016/j.chest.2020.10.049 -
Cellular and Molecular Life Sciences :... May 2022Thoracic aortic aneurysms (TAA) in Marfan syndrome, caused by fibrillin-1 mutations, are characterized by elevated cytokines and fragmentated elastic laminae in the...
Thoracic aortic aneurysms (TAA) in Marfan syndrome, caused by fibrillin-1 mutations, are characterized by elevated cytokines and fragmentated elastic laminae in the aortic wall. This study explored whether and how specific fibrillin-1-regulated miRNAs mediate inflammatory cytokine expression and elastic laminae degradation in TAA. miRNA expression profiling at early and late TAA stages using a severe Marfan mouse model (Fbn1) revealed a spectrum of differentially regulated miRNAs. Bioinformatic analyses predicted the involvement of these miRNAs in inflammatory and extracellular matrix-related pathways. We demonstrate that upregulation of pro-inflammatory cytokines and matrix metalloproteinases is a common characteristic of mouse and human TAA tissues. miR-122, the most downregulated miRNA in the aortae of 10-week-old Fbn1 mice, post-transcriptionally upregulated CCL2, IL-1β and MMP12. Similar data were obtained at 70 weeks of age using Fbn1 mice. Deficient fibrillin-1-smooth muscle cell interaction suppressed miR-122 levels. The marker for tissue hypoxia HIF-1α was upregulated in the aortic wall of Fbn1 mice, and miR-122 was reduced under hypoxic conditions in cell and organ cultures. Reduced miR-122 was partially rescued by HIF-1α inhibitors, digoxin and 2-methoxyestradiol in aortic smooth muscle cells. Digoxin-treated Fbn1 mice demonstrated elevated miR-122 and suppressed CCL2 and MMP12 levels in the ascending aortae, with reduced elastin fragmentation and aortic dilation. In summary, this study demonstrates that miR-122 in the aortic wall inhibits inflammatory responses and matrix remodeling, which is suppressed by deficient fibrillin-1-cell interaction and hypoxia in TAA.
Topics: Animals; Aortic Aneurysm, Thoracic; Cytokines; Digoxin; Disease Models, Animal; Fibrillin-1; Humans; Hypoxia; Marfan Syndrome; Matrix Metalloproteinase 12; MicroRNAs
PubMed: 35606547
DOI: 10.1007/s00018-022-04337-8 -
Journal of the American Heart... Mar 2023Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic...
Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic digoxin use in PAH are unclear. Methods and Results Data from the Minnesota Pulmonary Hypertension Repository were used. The primary analysis used likelihood of digoxin prescription. The primary end point was a composite of all-cause mortality or heart failure (HF) hospitalization. Secondary end points included all-cause mortality, HF hospitalization, and transplant-free survival. Multivariable Cox proportional hazards analyses determined the hazard ratios (HR) and 95% CIs for the primary and secondary end points. Among 205 patients with PAH in the repository, 32.7% (n=67) were on digoxin. Digoxin was more often prescribed to patients with severe PAH and right ventricular failure. After propensity score-matching, 49 patients were digoxin users, and 70 patients were nonusers; of these 31 (63.3%) in the digoxin group and 41 (58.6%) in nondigoxin group met the primary end point during a median follow-up time of 2.1 (0.6-5.0) years. Digoxin users had a higher combined all-cause mortality or HF hospitalization (HR, 1.82 [95% CI, 1.11-2.99]), all-cause mortality (HR, 1.92 [95% CI, 1.06-3.49]), HF hospitalization (HR, 1.89 [95% CI, 1.07-3.35]), and worse transplant-free survival (HR, 2.00 [95% CI, 1.12-3.58]) even after adjusting for patient characteristics and severity of PAH and right ventricular failure. Conclusions In this retrospective, nonrandomized cohort, digoxin treatment was associated with greater all-cause mortality and HF hospitalization, even after multivariate correction. Future randomized controlled trials should assess the safety and efficacy of chronic digoxin use in PAH.
Topics: Humans; Digoxin; Pulmonary Arterial Hypertension; Retrospective Studies; Heart Failure; Hospitalization; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Treatment Outcome
PubMed: 36892094
DOI: 10.1161/JAHA.122.027559