Digoxin Concentrations Research Articles

Digoxin Effectively Inhibited Cell Growth and Induced Senescence in Cervical Cancer Cell Line

Background: Digoxin, which is used in heart failure patients, contributes to inhibition of cell proliferation and induction of apoptosis. Therefore, digoxin could have a therapeutic potential in helping determine which individuals may suffer from cancer. This study was conducted to determine whether digoxin declines HeLa cells proliferation and viability or induces senescence. Methods: HeLa cell line was cultured with different concentrations of digoxin in RPMI-1640 medium for 6, 12, 24, and 48 hours. Cell proliferation and viability were assessed with MTT and trypan blue, respectively. To detect cell morphology and senescence, hematoxilin and gimsa staining were used. One way ANOVA was used for data analysis using SPSS Version 20 software. Results: Cell proliferation and viability decreased in all concentrations of digoxinin compared to controls. Colony formation was inhibited significantly after digoxin treatment (P < 0.05). Presence of giant cells in the treated groups indicated senescence induction, and dense nucleus was presented as cell death Conclusions: Our findings clearly revealed that dixogin inhibited HeLa cell growth, but it was not time and dose dependent. The apoptosis and senescence, which were detected in the present study, were based on non-advance methods. Therefore, for reliable results, it is necessary to prove the anticancer properties of digoxin through advanced methods. Although the antitumoral effects of digoxin are still being investigated, more studies should be conducted to clarify the related mechanism in cellular, biochemical, and molecular aspects.

Extracts of Immature Orange (Aurantii fructus immaturus) and Citrus Unshiu Peel (Citri unshiu pericarpium) Induce P-Glycoprotein and Cytochrome P450 3A4 Expression via Upregulation of Pregnane X Receptor.

P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) are expressed in the intestine and are associated with drug absorption and metabolism. Pregnane X receptor (PXR) is the key molecule that regulates the expression of P-gp and CYP3A4. Given that PXR activity is regulated by a variety of compounds, it is possible that unknown PXR activators exist among known medicines. Kampo is a Japanese traditional medicine composed of various natural compounds. In particular, immature orange [Aurantii fructus immaturus (IO)] and citrus unshiu peel [Citri unshiu pericarpium (CP)] are common ingredients of kampo. A previous study reported that kampo containing IO or CP decreased the blood concentration of concomitant drugs via upregulation of CYP3A4 although the mechanism was unclear. Some flavonoids are indicated to alter P-gp and CYP3A4 activity via changes in PXR activity. Because IO and CP include various flavonoids, we speculated that the activity of P-gp and CYP3A4 in the intestine may be altered via changes in PXR activity when IO or CP is administered. We tested this hypothesis by using LS180 intestinal epithelial cells. The ethanol extract of IO contained narirutin and naringin, and that of CP contained narirutin and hesperidin. Ethanol extracts of IO and CP induced P-gp, CYP3A4, and PXR expression. The increase of P-gp and CYP3A4 expression by the IO and CP ethanol extracts was inhibited by ketoconazole, an inhibitor of PXR activation. The ethanol extract of IO and CP decreased the intracellular concentration of digoxin, a P-gp substrate, and this decrease was inhibited by cyclosporine A, a P-gp inhibitor. In contrast, CP, but not IO, stimulated the metabolism of testosterone, a CYP3A4 substrate, and this was inhibited by a CYP3A4 inhibitor. These findings indicate that the ethanol extract of IO and CP increased P-gp and CYP3A4 expression via induction of PXR protein. Moreover, this induction decreased the intracellular substrate concentration.

ABCB1 and SLCO1B3 Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population

Background: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. Methods:ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. Results: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. Conclusion: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.

Prediciendo la Actividad Cardíaca de la Almeja Tivela stultorumcon Digoxina Utilizando Redes Neuronales Artificiales

Artificial neural networks (ANN) are a computational method that has been widely used to solve complex problems and carry out predictions on nonlinear systems. Multilayer perceptron artificial neural networks were used to predict the physiological response that would be obtained by adding a specific concentration of digoxin to Tivela stultorum hearts, this organism is a model for testing cardiac drugs that pretends to be used in humans. The MLPANN inputs were weight, volume, length, and width of the heart, digoxin concentration and volume used for diluting digoxin, and maximum contraction, minimum contraction, filling time, and heart rate before adding digoxin, and the outputs were the maximum contraction, minimum contraction, filling time, and heart rate that would be obtained after adding digoxin to the heart. ANNs were trained, validated, and tested with the results obtained from the in vivo experiments. To choose the optimal network, the smallest square mean error value was used. Perceptrons obtained a high performance and correlation between predicted and calculated values, except in the case of the filling time output. Accurate predictions of the T. stultorum clams cardioactivity were obtained when a specific concentration of digoxin was added using ANNs with one hidden layer; this could be useful as a tool to facilitate laboratory experiments to test digoxin effects.

Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations.

Development of submodels of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology. In the current study, a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CLR) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CLR, in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modeling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients.

Altered mRNA Expression and Cell Membrane Potential in the Differentiated C17.2 Cell Model as Indicators of Acute Neurotoxicity

Abstract Using general cytotoxicity assays in combination with in vitro tests for organ-specific toxicity has been proposed as an alternative approach to animal tests for estimation of acute systemic toxicity. Here, we present the C17.2 neural progenitor cell line as an option for estimation of acute neurotoxicity. The C17.2 cells were differentiated for 6 days in serum-free N2 medium with brain-derived neurotrophic factor and nerve growth factor to a mixed culture of neurons and astrocytes. The cells were then exposed to noncytotoxic concentrations of acetylsalicylic acid, atropine, digoxin, ethanol, nicotine, or strychnine for 48 hours and the mRNA levels of glial fibrillary acidic protein, βIII-tubulin, and heat shock protein 32 were analyzed as biomarkers for astrocytes, neurons, and cellular stress respectively. As a functional endpoint, the cell membrane potential (CMP) was monitored after acute addition of each compound to the differentiated C17.2 cells, by using the fluorescent FLIPR® membrane pot...

A Study of Digoxin Concentrations in the Mouse Brain after Chronic Treatment with Escitalopram

A Study of Digoxin Concentrations in the Mouse Brain after Chronic Treatment with Escitalopram

Predicting the physiological response of Tivela stultorum hearts with digoxin from cardiac parameters using artificial neural networks

Multi-layer perceptron artificial neural networks (MLP-ANNs) were used to predict the concentration of digoxin needed to obtain a cardio-activity of specific biophysical parameters in Tivela stultorum hearts. The inputs of the neural networks were the minimum and maximum values of heart contraction force, the time of ventricular filling, the volume used for dilution, heart rate and weight, volume, length and width of the heart, while the output was the digoxin concentration in dilution necessary to obtain a desired physiological response. ANNs were trained, validated and tested with the dataset of the in vivo experiment results. To select the optimal network, predictions for all the dataset for each configuration of ANNs were made, a maximum 5% relative error for the digoxin concentration was set and the diagnostic accuracy of the predictions made was evaluated. The double-layer perceptron had a barely higher performance than the single-layer perceptron; therefore, both had a good predictive ability. The double-layer perceptron was able to obtain the most accurate predictions of digoxin concentration required in the hearts of T. stultorum using MLP-ANNs.

Digoxin-Specific Antibody Fragment Dosing: A Case Series.

Digoxin-specific antibody fragments (DSFab) are used for the treatment of poisoning by cardiac glycosides, such as pharmaceutical digoxin. Dosing of this therapy for chronic and acute poisonings is based on the steady-state serum concentrations of digoxin, historical data in acute ingestions, or empiric regimens purportedly based on the average requirements. Empiric dosing for adult patients involves utilization of 3-6 vials for chronic poisoning and 10-20 vials for acute poisoning. The aim of this study was to describe the average dosing requirements based on the steady-state serum concentration of digoxin or historical data and compare this with the empiric dosing regimens. We performed a retrospective analysis of cases over an 11-year period presented to the Illinois Poison Center where administration of DSFab was recommended. We identified 140 cases of chronic digoxin poisoning and 26 cases or acute digoxin poisoning for analysis. The average dose of DSFab recommended in the cases of chronic digoxin poisoning was 3.05 vials (SD ± 1.31). The average dose of DSFab recommended in the cases of acute digoxin poisoning was 6.33 vials (SD ± 5.26). These values suggest that empiric dosing regimens may overestimate the need for DSFab in cases of both chronic and acute poisonings of pharmaceutical digoxin.

Progress on the study of pharmacokinetics of digoxin and rational drug use in pediatrics

Digoxin is the most frequently prescribed cardiac glucoside in pediatrics.Owing to its pharmacokinetics profile and narrow therapeutic index, some cases such as digoxin intoxication or dose insufficient are not rare.Recent evidence suggests that age, weight, hepatic and renal function, intestinal microbiome, drug interactions and others have influence on the pharmacokinetics of digoxin.So more attentions should be paid to the influencing factors mentioned above when digoxin concentration is monitored except observing intoxication to ensure rational drug use. Key words: Digoxin; Pharmacokinetics; Rational drug use; Factor; Children

Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial.

Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety. Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (≥0.5 ng/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14-1.38, P < 0.001 per 0.5 ng/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5-0.7 ng/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67-0.89, P < 0.001) while high serum concentrations (1.6-2.0 ng/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12-1.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5-0.7 ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure. These findings favour targeting serum concentrations from 0.5 to 0.7 ng/mL when dosing digoxin in patients with heart failure and reduced EF.

Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives

Mirabeg ron is a selective β3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC). Thirty-two male subjects received metformin (500mg twice daily) or mirabegron (160mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25mg) alone and in combination with mirabegron (100mg once daily). Twenty-five male and female subjects were administered digoxin (0.25mg) alone and in combination with mirabegron (100mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150µg once daily) in combination with mirabegron (100mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90% confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (C max) were contained within the standard 80-125% no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed. Mirabegron increased digoxin AUC and Cmax by 27 and 29%, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90% CI for the C max ratio for metformin (lower limit 79%). Metformin decreased mirabegron AUC and C max by 21%. Most treatment-emergent adverse events were mild, and all resolved by study end. No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.

The effect of 17α-ethynylestradiol induced intrahepatic cholestasis of pregnancy on placental P-glycoprotein in mice: Implications in the individualized transplacental digoxin treatment for fetal heart failure

IntroductionPlacental P-glycoprotein (P-gp) plays a significant role in controlling transplacental digoxin transfer rate. Investigations on P-gp regulation in placenta of women with different pregnant pathological states are of great significance to individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of 17α-ethynylestradiol induced intrahepatic cholestasis of pregnancy (ICP) on placental P-gp in mice. MethodsICP model in mice was induced by subcutaneous injection of 17α-ethynylestradiol dissolved in propylene glycol once daily from E12.5 to E16.5. Maternal plasma ALT, AST, TB, DBIL, γ-GT, LDH, ALP and TBA concentrations were measured. HE staining was applied for observation of maternal liver cells degeneration, necrosis and intrahepatic cholestasis. Placental Abcb1a/Abcb1b/HIF-1α mRNA and P-gp/HIF-1α protein expression were determined by real-time quantitative PCR and western-blot. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay. ResultsThe ICP group showed higher levels of maternal plasma ALT, AST, TB, DBIL, γ-GT, LDH, ALP and TBA concentrations, reduction in fetal survival rates, lower placental and fetal weights, and typical liver cells degeneration, necrosis and intrahepatic cholestasis. The placental Abcb1a mRNA and P-gp expression of ICP group were significantly elevated, while transplacental digoxin transfer rates were significantly decreased. Both placental HIF-1α mRNA and protein expression was significantly elevated in the ICP group, and there was a positive correlation between Abcb1a mRNA and HIF-1α mRNA. Conclusions17α-ethynylestradiol induced ICP could up-regulate placental P-gp expression and reduce transplacental digoxin transfer rate in mice, which might be partly associated with higher expression of HIF-1α.

Label-Free Detection of Digoxin Using Localized Surface Plasmon Resonance-Based Nanobiosensor

The scientific community finds gold nanoparticles particularly interesting due to their great applications, especially in SPR-based analysis. So far, no contributions have been made on detecting digoxin in which GNPs and LSPR technique have been used. In the present investigation, the localized surface plasmon resonance (LSPR) property of gold nanoparticles (GNPs) was utilized to develop a novel optical biosensor for the detection of digoxin. GNPs were synthesized using the sodium citrate reduction method and then made functional using the 11-mercaptoundecanoic acid (11-MUA) ligand. The carboxyl-functionalized GNPs reacted with a monoclonal antibody of digoxin through the EDC/NHS method. To characterize each processing step in the nanobiosensor preparation, UV-Vis spectrophotometry, X-ray diffraction, field emission scanning electron microscopy (FESEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR), and zeta potential tests were performed. The nanobiosensor’s performance was evaluated in the presence of different concentrations of digoxin in PBS and FBS. The synthesized GNPs size was estimated as 11.2 nm and present a LSPR peak at 520 nm. The size of 11-MUA-functionalized GNPs was 13.2 nm. The FTIR results revealed that 11-MUA ligand are linked to GNPs through thiol groups (Au-S-). The surface charge of 11-MUA and the monoclonal antibody-conjugated gold nanoparticles were −29.45 and −11.69, respectively. The limit of detection (LOD) of this LSPR-based nanobiosensor was 2 ng/ml. We have developed the new LSPR-based optical biosensor for direct and inexpensive detection of digoxin. This optical biosensor is easy to fabricate and the operation procedure has become more convenient.

A pharmacokinetic study of digoxin holiday dosing practice in Egypt: A prospective-randomized trial

BackgroundBecause of the narrow therapeutic index of digoxin, most cardiologists in Egypt give digoxin holiday for atrial fibrillation and heart failure, it is not clear if the interrupted digoxin regimens are effective since serum digoxin concentrations might fall below the therapeutic range. ObjectiveTo evaluate and compare the digoxin serum concentration and patient’s quality of life in the continuous versus interrupted digoxin dosing regimens. MethodsPatients were randomized to receive one of four regimens: regimen 1: 0.25mg daily except Friday (N=17); regimen 2: 0.25mg daily except Thursday and Friday (N=17); regimen 3: 0.125mg daily (N=17); and regimen 4: a tailored dose was calculated based on renal function and given daily (N=23). After reaching steady state in the two holiday regimens, two plasma samples were collected (preholiday and post holiday trough concentrations); in the other two groups one trough plasma sample was collected. Quality of life questionnaire for atrial fibrillation (QLAF), was administered to all patients at baseline and then after at least one month of digoxin therapy. ResultsThere was a statistically significant difference between the preholiday trough concentration and the trough steady state concentration across the four regimens (p=0.002). There was no significant difference in the QLAF questionnaire domains, total scores at baseline, or after the follow up between the four regimens. ConclusionOnce daily tablet (0.25mg) was suitable in maintaining digoxin serum concentration in the recommended therapeutic range, fluctuation in digoxin serum concentration did not affect quality of life for atrial fibrillation patients.

Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)

abstractContext: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes. Objective: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given. Materials and methods: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations. Results: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 μg/L) (range: 2.3–11.2 nmol/L) and 5.3 mmol/L (range: 2.9–9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and ≥3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration. Conclusions: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.

Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein.

Drug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

Digoxin Effectively Decreased Proliferation of Liver Cancer Cell Line

Introduction: Cardiac glycosides such as digoxin have been considered recently as anticancer drugs based on some epidemiological evidences. However, controversies results have been obtained in several experimental and clinical researches following using them. Therefore, in the present study the antiproliferative properties of digoxin and its mechanisms on the liver cancer cell line have been studied. Methods: HepG2 cell line was cultured with different concentrations of digoxin for 6, 12, 24 and 48 hrs. The cell proliferation and viability were determined with MTT assay and trypan blue respectively. Also, hematoxilin staining was applicated for nucleus morphology. Results: Cell proliferation and viability were decreased after treatment of the cells with digoxin in all groups compared to control. Colony formation decreased significantly in groups received digoxin. Also, nucleus morphology showed apoptotic changes in the cells after digoxin especially after 48 h. Conclusions: Digoxin decreases the cell proliferation and viability in liver cancer cell line. It is suggested that digoxin exerts its antitumor properties through antiproliferative properties and apoptosis. Since, digoxin is cytotoxic on the cells, finding the doses that have the minimum toxicity in the patients are necessary. In vivo studies in future help us to know more about the mechanisms involve in antitumoral effects of glycosides.

Management of digoxin toxicity.

Digoxin toxicity can emerge during long-term therapy as well as after an overdose. It can occur even when the serum digoxin concentration is within the therapeutic range. Toxicity causes anorexia, nausea, vomiting and neurological symptoms. It can also trigger fatal arrhythmias. There is a range of indications for using digoxin-specific antibody fragments. The amount ingested and serum digoxin concentration help to determine the dose required, but are not essential. Digoxin-specific antibody fragments are safe and effective in severe toxicity. Monitoring should continue after treatment because of the small risk of rebound toxicity. Restarting therapy should take into account the indication for digoxin and any reasons why the concentration became toxic.

A New Method for Individualized Digoxin Dosing in Elderly Patients.

Digoxin is a frequently prescribed drug in the elderly population. Estimated glomerular filtration rate is widely used to adjust dosages. The HUGE value is a tool for differentiating the presence or absence of chronic kidney disease in elderly patients. We aimed to investigate the usefulness of the HUGE value to predict the initial dose of digoxin in patients aged older than 70 years. We reviewed retrospectively the medical records of patients aged older than 70 years with serum digoxin concentrations (SDCs) monitored over a 6-month period (63 patients). A linear regression relating the patient's SDC, maintenance dose of digoxin and the HUGE value was estimated to generate a dosage equation. This equation was validated retrospectively (33 patients) and prospectively (35 patients) in comparison with two existing methods based on creatinine clearance. An equation (HUGE_DIG) was generated to calculate the initial digoxin dose to reach a specific target SDC. Thus, to achieve a SDC of 0.8 ng/mL: Digoxin (mg/day) = 0.091 - 0.006 x HUGE. After retrospective validation, the calculated digoxin doses with this equation were administered in the prospective phase and we did not observe statistical differences between measured and desired SDCs. Moreover, the predictive performance of our equation was better than that obtained with the compared methods. We offer a new validated digoxin dosing equation for elderly patients. Our results support the need to perform digoxin dosing in elderly people, bearing in mind the changes in renal physiology secondary to ageing and not merely the estimated glomerular filtration rate.