Effects Of Digoxin Research Articles

Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer

ABSTRACTSmall cell lung cancer (SCLC) is a malignant neuroendocrine tumor with very high mortality. Effective new therapy for advanced SCLC patients is urgently needed. By screening a FDA-approved drug library, we identified a cardiac glycoside (CG), namely digoxin (an inhibitor of cellular Na+/K+ ATPase pump), which was highly effective in inhibiting SCLC cell growth. Intriguing findings showed that NaCl supplement markedly enhanced the anti-tumor activities of digoxin in both in vitro and in vivo models of SCLC. Subsequent analysis revealed that this novel combination of digoxin/NaCl caused an up-regulation of intracellular Na+ and Ca2+ levels with an induction of higher resting membrane potential of SCLC cells. We also found that this combination lead to morphological shrinking of SCLC cells, together with high levels of cytochrome C release. Lastly, our data revealed that NaCl supplement was able to induce the expression of ATP1A1 (a Na+/K+ ATPase subunit), in which contributes directly to the increased sensitivity of SCLC cells to digoxin. Thus, this is the first demonstration that NaCl is a potent supplement necessitating superior anti-cancer effects of digoxin for SCLC. Further, our study suggests that digoxin treatment could need to be combined with NaCl supplement in future clinical trial of SCLC, particularly where low Na+ is often present in SCLC patients.

P2777Accumulating evidence for deleterious effects of digoxin in heart failure and atrial fibrillation: an updated meta-analysis

P2777Accumulating evidence for deleterious effects of digoxin in heart failure and atrial fibrillation: an updated meta-analysis

Cancer mortality does not differ by antiarrhythmic drug use: A population-based cohort of Finnish men

In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34–1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug.

High doses of digoxin increase the myocardial nuclear factor-kB and CaV1.2 channels in healthy mice. A possible mechanism of digitalis toxicity.

Toxic effects of digoxin may occur with normal therapeutic serum level. However, the underlying mechanisms are not fully understood. Nuclear factor kappa-B (NF-kB) is an important transcription factor in most organ systems and is often implicated in the harmful effects of cardiac injury. NF-kB promotes inflammatory responses, mediates adverse cardiac remodeling and has a function correlation with calcium. The voltage-gated L-type calcium channel CaV1.2 mediates the influx of Ca+2 into the cell in response to membrane depolarization. Our aim was to characterize the role of NF-kB during digoxin toxicity and to assess its correlation with Cav 1.2 in healthy mice in vivo. To address these questions, digoxin was administered in doses of 0.1, 1 or 5 mg/kg orally daily for seven days to the animals. Serum digoxin, serum calcium, atrial and ventricular calcium levels were measured. We, also, looked for NF-kB and CaV1.2 channel expression in cardiac muscle of mice. Digoxin at a dose of 0.1 mg/kg did not enhance serum, atrial, and ventricular Ca+2 levels, but were increased when digoxin dose of 1 and 5 mg/kg were administered. Histologically, myocardial necrosis and cellular infiltration on day 7 were significantly more severe in the 5 mg/kg/day digoxin group. Immunohistochemical studies showed more expression of both NF-kB and CaV1.2 in 1 and 5 mg/kg/day digoxin groups. These data suggest that NF-kB may be responsible for digoxin toxicity, at least partially via modulation of CaV1.2 and intracellular calcium homeostasis in the myocardium.

MONITORING OF SERUM DIGOXIN CONCENTRATION AND SAFETY OF THERAPY WITH DIGOXIN IN PATIENTS WITH ATRIAL FIBRILLATION

Background. Monitoring of serum digoxin concentration (SDC) is one of the approaches for controlling the safety of the long-term digoxin treatment, however, the benefits from SDC monitoring in paroxysmal arrhythmias have not been studied. Aim. To evaluate the potential benefits of digoxin laboratory monitoring at the initiation of digoxin therapy in patients with paroxysmal atrial fibrillation (AF). Material and methods. A retrospective analysis of SDC was performed in patients with paroxysmal or persistent (n=142) and permanent AF (n=48) who received digoxin therapy. Anthropometric features, comorbidity, anamnesis of the underlying disease, concomitant therapy, severity of signs of myocardial remodeling and the presence of cardiac rhythm and/or conduction disorders before and after the treatment were considered to analyze the results of treatment. SDC was measured in 20 hours after digoxin treatment initiation and after restoration of sinus rhythm, or in 1 week after the start of therapy if arrhythmia persisted. Results. During the first week after digoxin therapy initiation the rate of non-specific ECG repolarization abnormalities was 54%, the incidence of clinically significant conductivity disturbances – 28%. We found a relationship between SDC in the first week of treatment and the risk of high grade AVor SA-conduction abnormalities after the restoration of sinus rhythm (mean SDC 0.98Ѓ}0.72 ng/dL in the group of patients with complications and 0.45Ѓ}0.42 – in the group without them, p=0.015); these complications did not correlate with clinical signs of digitalization or intensity of digoxin therapy. The intake of digoxin was not an independent factor for the occurrence of cardiac rhythm disturbances. Comparison of the direct SDC measurements and the calculated values obtained with the valid calculators developed for the long-term digoxin use did not show reliable reproducibility of the calculated data. Conclusion. SDC monitoring may be used during the first week of therapy (before the establishment of a steady-state SDС) to minimize the risks of clinically significant adverse effects of digoxin on intracardiac conduction at the start of therapy. The existing empiric SDC calculators are not suitable as an alternative to the direct measurement. Further studies are needed to determine the clinically valid borderline values of the safe SDC in the condition of rapid digitalization.

Effect of digoxin in patients with heart failure and mid-range (borderline) left ventricular ejection fraction.

To evaluate the effects of digoxin in patients with the newly described phenotype of heart failure (HF) and mid-range ejection fraction (HFmrEF), attributed to mild left ventricular systolic dysfunction. We carried out a retrospective analysis of the Digitalis Investigation Group (DIG) trial which had 7788 patients available for analysis with a left ventricular ejection fraction (LVEF) ranging between 3% and 85%. We compared the effect of digoxin to placebo in three mutually exclusive groups of patients defined by LVEF category: <40% (HF with reduced LVEF, HFrEF, n = 5874), 40-49% (HFmrEF, n = 1195) and ≥50% (HF with preserved LVEF, HFpEF, n = 719). The primary outcome was the composite of cardiovascular death or HF hospitalisation. Patients with HFmrEF resembled patients with HFrEF, more than those with HFpEF, with respect to age, sex and aetiology but were more like HFpEF patients with respect to blood pressure and the prevalence of hypertension. Event rates in patients with HFmrEF were similar to those in HFpEF and much lower than in HFrEF. Digoxin reduced the primary endpoint in patients with HFrEF, mainly due to reduced HF hospitalisation: the digoxin/placebo hazard ratio (HR) for HF hospitalisation was 0.71 [95% confidence interval (CI) 0.65-0.77]. The digoxin/placebo HR for HF hospitalisation in patients with HFmrEF was 0.80 (95% CI 0.63-1.03) and 0.85 (95% CI 0.62-1.17) in those with HFpEF. The digoxin/placebo HR for the composite of HF death or HF hospitalisation was 0.74 (95% CI 0.68-0.81) in HFrEF, 0.83 (95% CI 0.66-1.05) in HFmrEF and 0.88 (95% CI 0.65-1.19) in HFpEF. In this study, event rates in patients with HFmrEF were closer to those in HFpEF than HFrEF. Digoxin had most effect on HF hospitalisation in patients with HFrEF, an intermediate effect in HFmrEF, and the smallest effect in HFpEF.

Successful Treatment of Heart Failure Due to Simultaneous Poisoning with Aluminum Phosphide and Zinc Phosphide: A Case Report

Introduction: Rodenticides are considered a global challenge to public health. Two major compounds in this category include aluminum phosphide and zinc phosphide. However, the simultaneous use of aluminum phosphide and zinc phosphide has not been reported in the literature. Case Presentation: We present the case of a 20-year-old female, who was poisoned with both a rice tablet and powdered rat poison. She was admitted to a university- affiliated hospital, Babol, Iran in July 2016. Resuscitative and supportive measures were applied, including prophylactic intubation, gastric lavage with a bicarbonate solution, and intravenous administration of N-acetylcysteine (NAC), magnesium sulfate, calcium gluconate, and bicarbonate compounds. In case of a blood sugar level above 100 mg/dL, regular insulin was infused. After the diagnosis of phosphine-induced cardiomyopathy, digitization with digoxin was prescribed for the patient. Conclusions: This case report presents the possible positive effects of digoxin, insulin, and antioxidant therapy on simultaneous poisoning with aluminum phosphide and zinc phosphide.

Comparative Action of Cardiotonic Steroids on Intracellular Processes in Rat Cortical Neurons.

Binding to Na+,K+-ATPase, cardiotonic steroids (CTS) activate intracellular signaling cascades that affect gene expression and regulation of proliferation and apoptosis in cells. Ouabain is the main CTS used for studying these processes. The effects of other CTS on nervous tissue are practically uncharacterized. Previously, we have shown that ouabain affects the activation of mitogen-activated protein kinases (MAP kinases) ERK1/2, p38, and JNK. In this study, we compared the effects of digoxin and bufalin, which belong to different subclasses of CTS, on primary culture of rat cortical cells. We found that CTS toxicity is not directly related to the degree of Na+,K+-ATPase inhibition, and that bufalin and digoxin, like ouabain, are capable of activating ERK1/2 and p38, but with different concentration and time profiles. Unlike bufalin and ouabain, digoxin did not decrease JNK activation after long-term incubation. We concluded that the toxic effect of CTS in concentrations that inhibit less than 80% of Na+,K+-ATPase activity is related to ERK1/2 activation as well as the complex profile of MAP kinase activation. A direct correlation between Na+,K+-ATPase inhibition and the degree of MAP kinase activation is only observed for ERK1/2. The different action of the three CTS on JNK and p38 activation may indicate that it is associated with intracellular signaling cascades triggered by protein-protein interactions between Na+,K+-ATPase and various partner proteins. Activation of MAP kinase pathways by these CTS occurs at concentrations that inhibit Na+,K+-ATPase containing the α1 subunit, suggesting that these signaling cascades are realized via α1. The results show that the signaling processes in neurons caused by CTS can differ not only because of different inhibitory constants for Na+,K+-ATPase.

Antitumoral effects of digoxin in the liver cancer cell line is mediated through induction of apoptosis and down regulation of HIF-A expression

Antitumoral effects of digoxin in the liver cancer cell line is mediated through induction of apoptosis and down regulation of HIF-A expression

Оптимизация дигиталисной терапии в клинической практике

In recent years there has been a marked decrease in cardiac glycosides use in patients with heart failure in sinus rhythm and atrial fibrillation. The results of published studies contradict each other. Some of them doubt the favorable effect of digoxin in patients with heart failure; others refute the increase in the lethality and frequency of hospitalizations associated with the use of digoxin. In this regard, we found it important to analyze these reports impartially and reflect modern views on the mechanisms of cardiac glycosides, the pharmacokinetics and the possibility of optimizing digitalis therapy in cardiac practice.

Differential Effects of Digoxin on Imiquimod-Induced Psoriasis-Like Skin Inflammation on the Ear and Back.

Differential Effects of Digoxin on Imiquimod-Induced Psoriasis-Like Skin Inflammation on the Ear and Back.

Study the toxicity of digoxin on liver and their transaminase enzymes level in rat

The current study was conducted at the college of veterinary medicine, university of basrah in the periods extended from 22/10/2016 to 22/1/2017. Digoxin is an important cause of poisoning. It is prescribed and widely used to patients with heart failure. Digoxin toxicity can emerge during long-term therapy as well as after an overdose and because it is metabolized and eliminated by liver. Therefore, the study is designed to determine the toxic effects of digoxin on liver histologically and biochemically by measuring liver transaminase enzymes level in the serum. Maximum toxic dose determined by using 2 rats dosed orally until clinical signs of toxicity became prominent at 30mg for each rat and considered as MTD. The chronic toxicity study was carried out on 48 adult rats divided into 4 groups. Control (G1) receive distilled water, Low dose (G2) dosed with (1.5mg/kg), Intermediate dose (G3) dosed with (3mg/kg) and High dose (G4) dosed with (6mg/kg) of digoxin by oral gavage for 90 days. At the end of experiments all animals were sacrificed and blood sample were collected for estimation of biochemical parameter of rat. Result reveals histopathological changes as sever periportal fibrosis, bile duct proliferation and aggregation of mononuclear cells specially with high (G4) group. There is a significant (P≤0.05) increase in serum AST &amp; ALT level in high (G4) group when compared with other study groups. We conclude that high dose digoxin has a toxic effect on liver tissue.

Digoxin Benefit Varies by Risk of Heart Failure Hospitalization: Applying the Tufts MC HF Risk Model

BackgroundDigoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization. Methods and ResultsWe conducted a post hoc analysis of the Digitalis Investigator Group (DIG) studies, randomized controlled trials of digoxin vs placebo in participants with heart failure and left ventricular ejection fraction ≤45% (main DIG study, n = 6800) or >45% (ancillary DIG study, n = 988). Using a previously derived multistate model to risk-stratify DIG study participants, we determined the differential treatment effect on hospitalization and mortality outcomes. There was a 13% absolute reduction in the risk of any heart failure hospitalizations (39% vs 52%; odds ratio 0.58; 95% confidence interval 0.47-0.71) in the digoxin vs placebo arms in the highest-risk quartile, compared with a 3% absolute risk reduction for any heart failure hospitalization (17% vs 20%; odds ratio 0.84; 95% confidence interval, 0.66-1.08) in the lowest-risk quartile. There were 12 fewer total all-cause hospitalizations per 100 person-years in the highest-risk quartile compared with an increase of 8 hospitalizations per 100 person-years in the lowest-risk quartile. There was neutral effect of digoxin on mortality in all risk quartiles and no interaction between baseline risk and the effect of digoxin on mortality (P = .94). ConclusionsParticipants in the DIG study at higher risk of hospitalization as identified by a multistate model were considerably more likely to benefit from digoxin therapy to reduce heart failure hospitalization.

Anti-proliferative effect of digoxin on breast cancer cells via inducing apoptosis.

Digoxin is a kind of plant-derived cardiac glycoside that is mainly used to treat heart diseases, especially in congestive heart failure or arrhythmia. However, its potentiality presented in anti-tumor remains unexplored. The purpose of this study was designed to investigate the beneficial pharmacological activity of digoxin on breast cancer cell line (MDA-MB-231, MM231). The methyl thiazolyl tetrazolium (MTT) assay was utilized to detect the proliferation of the breast cancer MM231. The apoptotic cell numbers were determined by the flow cytometry analysis. The expressions of Bcl-2 (B-cell lymphoma-2) and Bax (Bcl2-associated X protein) were detected by Western blot analysis. Digoxin dose-dependently blocked the cell growth of the breast cancer MM231 through MTT assay, whereas the apoptotic numbers were significantly elevated as reflected in acridine orange staining and flow cytometry analysis. In addition, findings from Western blotting method indicated that digoxin intervention showed reduced Bcl-2 expression and elevated Bax level in MM231 cells, characterized by increased Bax/Bcl-2 ratio. Digoxin plays a potential anti-tumor role in breast cancer in vitro, possibly by inducing mitochondria-dependent apoptosis.

Digoxin enhances radiation response in radioresistant A549 cells by reducing protein phosphatase 2A.

Protein phosphatase 2A (PP2A) is a ubiquitous multifunctional enzyme usually known as a tumor suppressor. Recent studies have reported that although inhibition of PP2A leads to acceleration of cell growth, it also induces damaged cells to pass through the cell cycle and renders them sensitive to radiotherapy. Here, we investigated the radiosensitizing effects of digoxin as a PP2A inhibitor in two non-small-cell lung cancer (NSCLC) cell types (H460 and A549) with differential sensitivity to radiation. Digoxin inhibited the proliferation of H460 and A549 cells in a dose-dependent fashion and was especially effective on radioresistant A549 cells. Interestingly, the radiosensitizing effect of digoxin was only present in the radioresistant A549 cells and xenografts. The combination of digoxin and ionizing radiation (IR) significantly reduced clonogenic survival and xenograft tumor growth (P<0.001), compared with IR alone. Digoxin suppressed PP2A protein expression and prevented IR-induced PP2A expression in A549 cells. Digoxin treatment combined with IR allowed the damaged cell to progress through the cell cycle via suppression of cell cycle-related proteins (p53, cyclin D1, cyclin B1, CDK4, and p-cdc2). Moreover, digoxin enhanced IR-induced DNA damage through reduction in levels of repair proteins and elevation of p-ATM foci formation up to 24 h (P<0.001). In conclusion, digoxin has a novel function as a PP2A inhibitor, and combined with IR produces a synergistic effect on radiosensitizing cells, thereby indicating a potentially promising therapeutic approach to radioresistant lung cancer treatment.

Digoxin Toxicity presented with Right Bundle Branch Block: A Case report of Drug- Drug Interaction

Digoxin, one of the digitalis glycosides has specific effects on the myocardium. The effects of Digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. It is the most common drug used in treatment of congestive heart failure and tachy-arrhythmias. It is used in treatment of arrhythmias but when arrhythmias occur in a patient on maintenance dose of Digoxin, its toxicity should be suspected. Here we report a case of Digoxin toxicity with the therapeutic dose confirmed by elevated Serum Digoxin levels. This occurrence could be due to Digoxin itself or this adverse effect could be predisposed by a suspected drug –dug interaction (SDDI) with the concomitant drugs this patient was prescribed.

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin

Background: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. Methods: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. Results: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). Conclusions: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors.

Cardiac glycosides are Na+ /K+ -ATPases inhibitors used to treat congestive heart failure and cardiac arrhythmias. Epidemiological studies indicate that patients on digitalis therapy are more protected from cancer. Evidence of a selective cytotoxicity against cancer cells has suggested their potential use as anticancer drugs. The effect on angiogenesis of clinically used cardiac glycosides has not been extensively explored. We studied the effect of digoxin, digitoxin and ouabain on early events of the angiogenic process in HUVECs. We determined HUVEC viability, proliferation, migration and differentiation into capillary tube-like structures. We also tested drug activity using an in vivo angiogenesis model. Activation of protein tyrosine kinase 2 (FAK) and signalling proteins associated with the Na+ /K+ -ATPase signalosome was determined by Western blotting. Digitoxin and ouabain (1-100nM) inhibited HUVEC migration, concentration-dependently, without affecting cell viability, while digoxin induced apoptosis at the same concentrations. Digitoxin antagonized growth factor-induced migration and tubularization at concentrations (1-25nM) within its plasma therapeutic range. The anti-angiogenic effect of digitoxin was confirmed also by in vivo studies. Digitoxin induced Src, Akt and ERK1/2 phosphorylation but did not affect FAK autophosphorylation at Tyr397 . However, it significantly inhibited growth factor-induced FAK phosphorylation at Tyr576/577 . Therapeutic concentrations of digitoxin inhibited angiogenesis and FAK activation by several pro-angiogenic stimuli. These novel findings suggest a potential repositioning of digitoxin as a broad-spectrum anti-angiogenic drug for diseases where pathological angiogenesis is involved.

Comparison of Digitalis Sensitivities of Na+/K+-ATPases from Human and Pig Kidneys.

Digitalis drugs are selective inhibitors of the plasma membrane Na+/K+-ATPase. There are many studies on molecular mechanisms of digitalis interaction with purified pig kidney enzyme, with the tacit assumption that it is a good model of human kidney enzyme. However, previous studies on crude or recombinant human kidney enzymes are limited, and have not resulted in consistent findings on their digitalis sensitivities. Hence, we prepared comparably purified enzymes from human and pig kidneys and determined inhibitory constants of digoxin, ouabain, ouabagenin, bufalin, and marinobufagenin (MBG) on enzyme activity under optimal turnover conditions. We found that each compound had the same potency against the two enzymes, indicating that (i) the pig enzyme is an appropriate model of the human enzyme, and (ii) prior discrepant findings on human kidney enzymes were either due to structural differences between the natural and recombinant enzymes or because potencies were determined using binding constants of digitalis for enzymes under nonphysiological conditions. In conjunction with previous findings, our newly determined inhibitory constants of digitalis compounds for human kidney enzymes indicate that (i) of the compounds that have long been advocated to be endogenous hormones, only bufalin and MBG may act as such at kidney tubules, and (ii) beneficial effects of digoxin, the only digitalis with extensive clinical use, does not involve its inhibitory effect on renal tubular Na+/K+-ATPase.

Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines.

Digoxin, a cardiac glycoside used for the treatment of heart failure, was reported to inhibit the retinoid-related orphan receptor gamma t (RORγt) and attenuate the severity of experimental autoimmune encephalomyelitis and arthritis in mice. However, the effects of digoxin in a mice model of inflammatory bowel disease have not been elucidated. Colitis was induced in severe combined immunodeficiency mice by adoptive transfer of CD45RB CD4 T cells. Digoxin or a vehicle was injected into mice with colitis intraperitoneally every other day and changes in body weight were evaluated. After 6 to 8 weeks, the treated mice were killed and evaluated for histological score, T-cell subset, and cytokine messenger RNA (mRNA) expression in the colonic tissue. Wasting disease and histological damage were significantly attenuated in digoxin-treated mice with colitis compared with those in the vehicle-treated mice. In addition, the mRNAs of Th17-related cytokines were downregulated, whereas those of interleukin-10 were upregulated in the colonic mucosa of digoxin-treated mice. However, unexpectedly, the mRNA expression level of tumor necrosis factor alpha did not decrease in the colonic mucosa of digoxin-treated mice with colitis. This observation suggests that digoxin may ameliorate colitis by a tumor necrosis factor alpha-independent pathway. This study has shown for the first time that treatment with digoxin can ameliorate murine experimental colitis. This finding suggests that the suppression of Th17 using reagents such as digoxin could be effective in treating Crohn's disease refractory to anti-tumor necrosis factor alpha therapy.