Effects Of Digoxin Research Articles

Effect of Digoxin on the Color Vision Disorder, A Case-Control Study

Background and Aim: Digoxin is a drug commonly used in order to treat cardiac failure but its use has got different complications including color vision disorder .Regarding the high prevalence of cardiac failure and the role of taking this drug by patients, it was decided to study color vision disorder in patients who take digoxin.
 Materials and Methods: The present case-control study was conducted during 2008-2009 in Valli-e-asr hospital in Birjand.The case group consisted of 59 patients having cardiac failure who, at least, had taken oral digoxin for one year. The controls were non-cardiac patients referring to the hospital or were patients’ attendants who did not take digoxin. The controls were matched with the cases with respect to age and sex. Both groups were examined regarding whether they had color vision disorder or not by means of Ishiharatest. Venous blood was derived from all the cases to assess serum digoxin level.
 Then, the obtained data was an encoded and statistically analysed by means of SPSS software at the significant level α=0.05.
 Findings:In this survey, 59 patients with Heart failure who took digoxin and 59 controls were studied. Relative frequency of color vision disorder in the cases was estimated at 6.8%, but in the controls it was estimated at 1.7%; hence the difference was not statistically significant (P=0.36).Frequency of color vision disorder did not reveal a significant difference regarding age and sex. Serum digoxin level was abnormal in 5.1% of the patients. A significant difference was not found between mean serum digoxin and color vision disorder.
 Results:Using color vision disorder, as a diagnostic measure of Digoxin toxicity, is of no use.

Outcomes of digoxin vs. beta blocker in atrial fibrillation: report from ESC-EHRA EORP AF Long-Term General Registry.

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. Patients with AF who were treated with either digoxin or a beta blocker from the ESC-EHRA EORP AF (European Society of Cardiology-European Heart Rhythm Association EURObservational Research Programme Atrial Fibrillation) 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 hospitalizations. Of 6377 patients, 549 (8.6%) were treated with digoxin. Over 24months, there were 550 (8.6%) all-cause mortality events and 1304 (23.6%) patients with unplanned emergency hospitalizations. Compared to beta blocker, digoxin therapy was associated with increased all-cause mortality [hazard ratio (HR) 1.90 (95% confidence interval, 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 hospitalizations [HR 1.00 (95% CI 0.56-1.80)] or AF-related hospitalizations [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 were no differences in outcomes between AF patients receiving digoxin with and without chronic kidney disease. 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 hospitalizations.

Digoxin vs. beta-blocker therapy in atrial fibrillation: analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry

Abstract Background There is a long-standing and unresolved controversy over the effects of digoxin on mortality. Furthermore, there is scarce evidence comparing the use of digoxin to beta-blocker in the general population with atrial fibrillation (AF). In this study, we aimed to evaluate the effects of digoxin over beta-blocker therapy among patients with AF. Methods Patients from the EORP-AF General Long-Term Registry with AF who were treated with either digoxin or beta-blocker were included. All patients were over 18 years old and had documented evidence of AF within 12 months prior to enrolment. The outcomes of interest were all-cause mortality, cardiovascular (CV) mortality, non-CV mortality and number of patients with unplanned hospitalisation (total and AF-related). These were recorded until the last known follow-up available. Results Of 6377 patients, 549 (8.6%) and 5828 (91.4%) were treated with digoxin and beta-blockers, respectively. Patients in the digoxin group were older (73 vs. 71 years, p&amp;lt;0.001) with reduced renal function (eGFR 65.4 vs. 68.7 mL/min/1.73m2, p=0.002), and had (in general) greater burden of comorbidities in terms of chronic kidney disease, chronic obstructive pulmonary disease, heart failure, hypertension and peripheral artery disease. Nonetheless, the use of anticoagulation therapy was comparable between both groups (p=0.112). Over 24 months follow-up, there were 550 (8.6%) all-cause mortality and 1304 (23.6%) patients with unplanned emergency hospitalisation. Digoxin use was associated with increased all-cause mortality (hazard ratio [HR] 1.90 [95% CI, 1.48–2.44]), both from CV and non-CV causes (CV: HR 2.21 [95% CI, 1.49–3.26]); non-CV: HR 1.70 [95% CI, 1.04–2.79]). There was no statistical difference in terms of unplanned emergency hospitalisation (HR 0.99 [95% CI, 0.80–1.21]) and AF-related hospitalisation (HR 0.78 [95% CI, 0.58–1.06]) between both groups. Using multivariable cox regression analysis, digoxin compared to beta-blocker therapy was independently linked to increased all-cause mortality (HR 1.52 [95% CI, 1.11–2.09]) and CV mortality (HR 1.82 [95% CI, 1.11–2.97]), but was not related to non-CV mortality (HR 1.31 [95% CI, 0.71–2.41]), emergency hospitalisation (HR 0.91 [95% CI, 0.71–1.16]) or AF-related hospitalisation (HR 0.88 [95% CI, 0.62–1.24]), after adjustment for known risk factors. Conclusion We demonstrated that the use of digoxin was independently associated with excess all-cause mortality, driven by CV death, but was non-inferior to beta-blocker in terms of preventing unplanned emergency or AF-related hospitalisation, after accounting for important risk factors. Funding Acknowledgement Type of funding sources: None.

Digoxin exerts anticancer activity on human nonsmall cell lung cancer cells by blocking PI3K/Akt pathway.

Lung cancer remains the leading cause of cancer mortality because of its metastatic potential and high malignancy. The discovery of new applications for old drugs is a shortcut for cancer therapy. We recently investigated the antitumor effect of digoxin, a well-established drug for treating heart failure, against nonsmall cell lung cancer A549 and H1299 cells. Digoxin inhibited the proliferation and colony-forming ability of the two cell lines and arrested the cell cycle at the G0/G1 phase in A549 cells and the G2/M phase in H1299 cells. Mitochondria-mediated apoptosis was induced in A549 cells but not in H1299 cells after treatment with digoxin. Moreover, digoxin inhibited the migration, invasion, adhesion and epithelial–mesenchymal transition of A549 and H1299 cells. Autophagy was induced in both cell lines after treatment with digoxin, with an increase in autophagosome foci. In addition, digoxin inhibited the phosphorylation of Akt, mTOR and p70S6K, signaling molecules of the PI3K/Akt pathway that are known to be involved in tumor cell survival, proliferation, metastasis and autophagy. Our findings suggest that digoxin has the potential to be used for therapy for human nonsmall cell lung cancer, but further evidence is required.

A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin.

Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GGgenotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.

Association of Digoxin Application Approaches With Long-Term Clinical Outcomes in Rheumatic Heart Disease Patients With Heart Failure: A Retrospective Study.

Objective: This retrospective, case–control study was executed to assess the effects of digoxin (DGX) use approaches [continuous use of DGX (cDGX) vs. intermittent use of DGX (iDGX)] on the long-term prognosis in rheumatic heart disease (RHD) patients with heart failure (HF).Methods: A total of 642 RHD patients were enrolled to this study after propensity matching. The associations of DGX application approaches with the risks of all-cause mortality, cardiovascular death (CVD), HF re-hospitalization (1-, 3-, and 5-year), and new-onset atrial fibrillation (AF) were analyzed by multivariate Cox proportional hazards or binary logistic regression models, respectively.Results: cDGX was associated with increased risks of all-cause mortality (adjusted HR = 1.84, 95% CI: 1.27–2.65, P = 0.001) and CVD (adjusted HR = 2.23, 95% CI: 1.29–3.83, P = 0.004) in RHD patients with HF compared to iDGX. With exception of 1-year HF re-hospitalization risk, cDGX was associated with increased HF re-hospitalization risk of 3-year (adjusted OR = 1.53, 95% CI: 1.03–2.29, P = 0.037) and 5-year (adjusted OR = 1.61, 95% CI: 1.05–2.50, P = 0.031) as well as new-onset AF (adjusted OR = 2.06, 95% CI: 1.09–3.90, P = 0.027).Conclusion: cDGX was significantly associated with increased risks of all-cause mortality, CVD, medium-/long-term HF re-hospitalization, and new-onset AF in RHD patients with HF.

Digoxin reduces the incidence of prostate cancer but increases the cancer-specific mortality: A systematic review and pooled analysis.

Digoxin, a commonly used drug for congestive heart failure and cardiac arrhythmias, has been reported to exert cytotoxic and apoptosis-inducing effects on prostate cancer (PCa) cells. In this study, we aimed to perform a pooled analysis to summarise all the evidence related to the effects of digoxin on PCa development. Four electronic databases were systematically searched to filter the eligible studies. The hazard ratio (HR) with its 95% confidence interval (CI) was calculated. This study was registered on PROSPERO (ID: CRD42021226885). Ten clinical studies with a total of 108,444 participants (15,835 individuals were digoxin users) were included. The pooled result from 6 included studies demonstrated that digoxin usage was correlated with a significant decrease in PCa risk (adjusted RR=0.892, 95% CI: 0.799-0.997, p=.044) when compared with the nonusers. Synthetic result of 4 eligible studies revealed that digoxin significantly correlated with higher prostate cancer-specific mortality than the controls (adjusted HR=1.142, 95% CI: 1.005-1.297). No statistical heterogeneity was detected during this analysis (all I2 <50%, p>.1). Our study confirmed a preventive effect of digoxin usage for the risk of PCa in men. However, digoxin use was associated with a significantly elevated risk of prostate cancer-specific mortality. This finding needs more well-designed studies to better interpret the causality.

Pharmacokinetics Parameters of Diagoxin among Saudi Patients in Qassim Region, Saudi Arabia.

The pharmacodynamic effects of digoxin are susceptible to multiple factors, most notably, heart uptake of the digoxin dose and its concentration in the serum. Another important factor to mention is the renal function state of an individual. In this study, we aimed to develop a simple algorithm based on subsets of clinically relevant information, which will help to personalize digoxin based on pharmacokinetic (PK) approach which can help in marketing the appropriate utilization of this medication. This was a retrospective chart review and analysis of 48 patients who were admitted to the Drug and Poison Information center in Buraidah, Saudi Arabia, between January 2016 and April 2019. All pharmacokinetic parameters were added according to the C-peaks and C-troughs. MONOLiX® was used for data pharmacokinetic analysis. Twenty-seven (56%) were males and twenty-one (44%) were females with an average age of 63.6 years across both genders. The mean volume of distribution was 496.6 litres with an average clearance of 6.6 L/h. For females, their average volume of distribution was slightly higher than that for males (526 litres compared to 473 litres). In addition, the clearance rate between both genders showed a 2.1 litre/hour discrepancy (7.8 L/h for females compared to 5.7 L/h for males). In order to individualize the digoxin dosage regimens, this model can be used to predict digoxin serum concentration. Further studies are needed to clarify the effects of nutritional status and co-administration of medications on digoxin pharmacokinetics.

Effects of ACE Inhibitors, Angiotensin Receptor Blockers and Angiotensin Receptor-Neprilysin Inhibitors on Survival Free from Gastrointestinal Bleeding in HeartMate 3 Patients - A Marginal Structural Modeling Analysis

<h3>Purpose</h3> The HeartMate 3 (HM3) is superior to HMII in survival free from disabling stroke and pump exchange, however, rates of GIB remain high. Prior studies show a protective effect of digoxin and ACEi/ARB on risk for GIB, whereas phosphodiesterase 5 inhibitors (PDE5i) have opposite effect in HMII using Cox Proportional Hazard (PH) models with inverse probability weighting (IPW). Compared to this approach, marginal structural modeling (MSM) accounts for time-dependent confounding thereby producing results closer to true causal effect. Targeted Maximum Likelihood Estimation (TMLE) can help estimate MSM effects making minimal assumptions on data distribution. We studied the impact of outpt medications on survival free from GIB in HM3 pts using TMLE-MSM. <h3>Methods</h3> Data were retrospectively collected in HM3 pts up to 18 mo after discharge from implant and summarized in 3-mo time intervals. Medication status was defined as receiving vs. not ACEi/ARB/ARNi, PDE5i and digoxin at each time-node. Medication use was calculated by summarizing duration in days within each time node. Creatinine, potassium, INR and mean arterial pressure of each node were averaged. We fit TMLE-MSMs and compared results to IPW Cox PH models using both time variant and invariant covariates. Endpoint was survival free from GIB. <h3>Results</h3> 128 HM3 pts (60±13 y, 16% F) were studied. 5 deaths and 19 first GIB events occurred in 22 (17.2%) pts during follow up. 60 pts were exposed to ACEi/ARB/ARNi, 43 to digoxin and 39 to PDEi5. There was no effect of ACEi/ARB/ARNi, PDE5i or digoxin on the endpoint when using IPW Cox PH model. When using TMLE-MSM a statistically significant effect between ACEi/ARB/ARNi and the endpoint was observed (Table). <h3>Conclusion</h3> ACEi/ARB/ARNi improves survival free from GIB in HM3 pts using TMLE-MSM. Prospective randomized studies are needed to further test the impact of pharmacotherapy on outcomes in HM3 pts.

Digoxin treatment reactivates in vivo radioactive iodide uptake and correlates with favorable clinical outcome in non\u2010medullary thyroid cancer

PurposeNon-medullary thyroid cancer (NMTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). However, in a subset of NMTC patients tumor dedifferentiation occurs, leading to RAI resistance. Digoxin has been demonstrated to restore iodide uptake capacity in vitro in poorly differentiated and anaplastic NMTC cells, termed redifferentiation. The aim of the present study was to investigate the in vivo effects of digoxin in TPO-Cre/LSL-BrafV600E mice and digoxin-treated NMTC patients.MethodsMice with thyroid cancer were subjected to 3D ultrasound for monitoring tumor growth and 124I PET/CT for measurement of intratumoral iodide uptake. Post-mortem analyses on tumor tissues comprised gene expression profiling and measurement of intratumoral autophagy activity. Through PALGA (Dutch Pathology Registry), archived tumor material was obtained from 11 non-anaplastic NMTC patients who were using digoxin. Clinical characteristics and tumor material of these patients were compared to 11 matched control NMTC patients never treated with digoxin.ResultsWe found that in mice, tumor growth was inhibited and 124I accumulation was sustainably increased after short-course digoxin treatment. Post-mortem analyses revealed that digoxin treatment increased autophagy activity and enhanced expression of thyroid-specific genes in mouse tumors compared to vehicle-treated mice. Digoxin-treated NMTC patients exhibited significantly higher autophagy activity and a higher differentiation status as compared to matched control NMTC patients, and were associated with favourable clinical outcome.ConclusionsThese in vivo data support the hypothesis that digoxin may represent a repositioned adjunctive treatment modality that suppresses tumor growth and improves RAI sensitivity in patients with RAI-refractory NMTC.

Inhibitory Effects of Digoxin and Digitoxin on Cell Growth in Human Ovarian Cancer Cell Line SKOV-3.

Background:Cardiac glycosides (CGs) possess a chemical structure similar to steroids, and are inhibitors of the sodium potassium pump. An anti-tumor effect of CGs in breast and prostate cancers has been reported, but the effect of CGs on ovarian cancer is still unclear.Aims:In this study, the effects of CGs on proliferation, cytotoxicity and cell cycle of ovarian cancer cell line (SKOV-3) have been investigated.Procedure:The cell proliferation and cytotoxicity were detected by MTT assay and LDH activity assay, respectively. CGs, at concentrations higher than IC50, decreased cell proliferation and showed increased cytotoxicity toward SKOV-3 cells. The colony-formation ability was reduced after treatment with digoxin and digitoxin for 10 days. Furthermore, we explored the effect of digoxin and digitoxin on the distribution of cell cycle by flow cytometry.Results:Results revealed that both digoxin and digitoxin led to cell cycle arrest in G0/G1 phase with 24 or 48 hours, but the arrest of G0/G1 phase was not observed at 72 hours. We evaluated the percentage of hypodiploid cell population as an index of the cellular fragments through flow cytometry. The data indicated that cellular fragments were significantly increased by treating with digitoxin at the concentrations of IC50 and 10−6 M for 72 hours.Conclusion:Taken together, these data suggest that CGs decreased cell proliferation and increased cytotoxicity through cell cycle arrest at the G0/G1 phase. CGs have anti-tumor effect in SKOV-3 cells and might be a potential therapeutic drug for ovarian cancer. Since this study is a preliminary investigation of CGs on SKOV-3 cells, more experiments might be performed in the future. Furthermore, more ovarian cancer cell lines might also be employed in the future studies to confirm the effect of CGs in ovarian cancer.

Effects of Digoxin and Digitoxin on Cell Viability and Migration in Hepatocellular Carcinoma

Effects of Digoxin and Digitoxin on Cell Viability and Migration in Hepatocellular Carcinoma

Digitalis Glycosides for Heart Rate Control in Atrial Fibrillation

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Patients With Permanent Atrial Fibrillation

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life

There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure. To compare low-dose digoxin with bisoprolol (a β-blocker). Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019. Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d). The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting. Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, -2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group. Among patients with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support potentially basing decisions about treatment on other end points. ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13.

Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer.

Simple SummaryBreast cancer (BC) treatment relies on the detection of the estrogen receptor α (ERα). ERα-expressing BC patients are treated with anti-estrogen drugs (i.e., tamoxifen and fulvestrant). Despite their proven efficacy, these drugs cause serious side effects in a significant fraction of the patients, including both tumor insurgence in secondary organs, and resistant phenotypes, which result in a relapsing disease with scarce treatment options. Thus, new drugs for treatment of primary and metastatic BC (MBC) are needed. Here, we report the characterization of two cardiac glycosides (CGs) (i.e., ouabain and digoxin), approved by the FDA for treatment of heart disease, as novel ‘anti-estrogen’-like drugs. We found that these drugs induce ERα degradation, and prevent the proliferation of cellular models of primary and metastatic BC cells. Remarkably, we discovered that these CGs are activators of the proteasome, and therefore may be repurposed for treatment not only of BC, but also for other proteasome-based diseases.Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.

Multifaceted anti-colorectal tumor effect of digoxin on HCT8 and SW620 cells in vitro.

BackgroundColorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Novel drugs for CRC therapy are urgently needed. Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years. Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC. Here, we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism.MethodsCell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and plate colony formation assay. The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry. The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay. Anti-angiogenic effect was examined by determining the inhibition against proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Mechanism study was performed by Western blot, enzyme-linked immunosorbent assay (ELISA), and gelatin-zymography assay.ResultsDigoxin potently inhibited cell proliferation, induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells, respectively. No obvious apoptosis was observed in the treated cells. Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion. Meanwhile, the expression of MMP2, MMP9, and phosphorylated Integrinβ1 were decreased. Digoxin inhibited the proliferation, migration, and tube formation of HUVECs and reduced HIF1α expression and vascular endothelial growth factor A (VEGF-A) secretion in HCT8 cells, suggesting anti-angiogenic activity. Furthermore, digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells.ConclusionOur findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.

Ion Transport Modulators as Antimycobacterial Agents

There is an urgent need for better and safer therapeutic interventions for tuberculosis (TB). We assessed the effects of FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide (HCTZ), metformin, omeprazole, pantoprazole, phenytoin, verapamil, and drug X and Y on the growth of free and intracellular Mycobacterium bovis BCG. Free and intracellular M. bovis BCG were cultured in the presence or absence of the test drugs for 3 to 9 days and then quantified. For both free and intracellular bacteria, cultures that were exposed to furosemide, phenytoin, or drug Y yielded lower bacteria counts compared to drug-free controls (p < 0.05). The same was observed with diazoxide, HCTZ, verapamil, and drug X, but only for intracellular M. bovis BCG (p < 0.05). To assess the effects of the drugs on bactericidal activity of rifampicin, free and intracellular M. bovis BCG were treated with rifampicin alone or in combination with each of the thirteen test drugs for 3 to 9 days. For extracellular bacteria, higher bacteria clearance rates were observed in cultures exposed to rifampicin in combination with amiloride HCl, diazoxide, digoxin, furosemide, HCTZ, metformin, pantoprazole, phenytoin, drug X, or drug Y than those exposed to rifampicin alone, indicating that rifampicin had a synergistic effect with these test drugs. Rifampicin was also synergistic with ambroxol HCl, diazoxide, digoxin, furosemide, HCTZ, omeprazole, pantoprazole, phenytoin, verapamil, and drug X against intracellular M. bovis BCG. The antimycobacterial properties exhibited by the ion transport modulators in this study make them viable candidates as adjuncts to the current anti-TB regimens.

Abstract 16085: Digoxin is Associated With Increased Mortality in Patients With Atrial Fibrillation Without Concomitant Heart Failure

Introduction: There is conflicting data on the effect of digoxin on all-cause mortality in patients with atrial fibrillation (AF), especially in patients with heart failure (HF). Hypothesis: We hypothesized that in patients with AF, mortality rates associated with digoxin treatment are different among patients with HF and without HF. Methods: We conducted a cohort study of hospitalized patients with AF assessing the effects of digoxin on all-cause mortality. We divided patients into two groups: with and without HF. We performed Cox regression analysis to assess hazard ratios (HR) for all-cause mortality depending on digoxin treatment and used propensity score matching to adjust for differences in background characteristics between treatment groups. Results: Among 2179 consecutive patients, the median age was 73 ± 14 (table), 53% patient were male, 49% had HF, 19% were discharged on digoxin. Median left ventricular ejection fraction in the cohort was 60 (IQR 40-65). Among patients with HF, 35% had preserved, 18% had mid-range and 48% had reduced left ventricular ejection fraction. The mean follow-up time was 3 ± 2.1 years. After adjustment, in patients with HF, there was no statistically significant difference in mortality between the digoxin subgroups ( A , HR=1.01 [95% CI 0.76 to 1.35], p=0.92). In contrast, after adjustment, in patients without HF there was a statistically significant increased mortality in the digoxin subgroup ( B , HR=2.23, [95% CI 1.42 to 3.51], p&lt;0.001). Conclusions: Digoxin use was associated with increased mortality in patients with AF and without concomitant HF. This suggests that clinicians should be careful in prescribing digoxin for rate control in AF, especially in patients without concomitant HF.

Abstract 17337: The Effect of Digoxin on Hemocompatibility Related Adverse Events in Patients With Durable Left Ventricular Assist Devices

Introduction: Hemocompatibility-related adverse events (HRAE) including stroke, pump thrombosis, and gastrointestinal bleeding (GIB), is a major cause of mortality in patients with continuous flow left ventricular assist devices (CF-LVAD). Digoxin (dig) is used in treatment of advanced heart failure, and has been implicated in decreasing angiogenesis via HIF-alpha/TGF inhibition. There is conflicting data regarding the effect of dig on GIB rates in patients with cf-LVADs. We investigated the association of dig use in patients implanted with CF-LVADs with HRAE with both centrifugal and axial flow devices. Methods: 12,002 patients from the INTERMACS registry implanted with cf-LVADs between 2012-2017 and were alive at 1-month were included. The event rates of HRAE at 1-yr post implant were compared in patients with or without dig use at 1-month post implant. Cox proportional hazards modeling was used to assess the independent association of dig use and HRAE. Results: There was no significant difference in age, sex, race, Cr, INR, DM, and AST in those who were prescribed vs. not prescribed dig at 1 month. On univariate analysis, dig was associated with decreased HRAE in patients with CF-LVADs at 1-year post implantation (37% vs 41%, p&lt;0.01) (Fig. 1) however this was primarily driven by decreased neurologic events. There was no association with GIB (p 0.18). On multivariate analysis, dig was not found to be an independent predictor of HRAE (HR 0.95, 95% CI 0.89-1.02, p 0.2) (Figure 2). Conclusions: Despite previous smaller studies which suggested a decreased risk of HRAE and GIB in patients with cf-LVADs, we found that dig was not an independent predictor of HRAE.

The Effect of Digoxin on Mortality in Congestive Heart Failure Patients in Normal Sinus Rhythm

Digoxin is an antiarrhythmic medication that has been used to manage chronic heart failure. Despite more than 200 years of research, the role of digoxin in patients with heart failure and sinus rhythm remains controversial. Recent studies have shown digoxin to reduce heart failure associated morbidity without having any effect on mortality. The purpose of our study was to study the impact of digoxin on mortality in heart failure patients in sinus rhythm. Objective • Effect of digoxin on mortality in heart failure patients in sinus rhythm • Study impact of covariates such as age, gender, race, previous MI, and NYHA class Methods: Heart failure patients with LVEF ≤0.45 were randomly assigned to digoxin group (n=3392) or placebo group (n=3401) and were followed on average for 38.4 months. Patients were enrolled at multiple clinical centers in the United States and Canada. Results: In the study, mortality was unaffected. There were 1180 deaths in the digoxin group (34.77%) and 1194 deaths in the placebo group (35.09%). The adjusted hazard ratio (AHR) for the digoxin group compared with placebo group was 0.981 (p=0.6425) which was not statistically significant. The unadjusted median survival time for the placebo group was 58.37 months. The median survival time for the treatment group could was not reported because the group did not reach 50% survival probability during the study. Conclusions: After controlling for age, gender, race, previous MI, and NYHA functional class, we found no difference in the hazard of death between those receiving digoxin and those receiving placebo. Our study demonstrated that digoxin did not reduce the overall mortality and has no survival benefit in the management of chronic heart failure.