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There is uncertainty regarding the clinical effects of discontinuation of drugs for heart failure after long-term use. The withdrawal of long-term treatment can follow 1 of 4 distinct patterns: 1) loss of on-treatment effect with no observed changes following discontinuation (eg, prazosin); 2) attenuation or loss of on-treatment effect with rebound clinical worsening following discontinuation (eg, nitroprusside); 3) persistence of deleterious on-treatment effect followed by clinical worsening after discontinuation (eg, milrinone and flosequinan); and 4) persistence of favorable on-treatment effect followed by clinical worsening after discontinuation (eg, digoxin and sodium-glucose cotransporter 2 inhibitors). Persuasive evidence for persistence of efficacy has been demonstrated for the use of digoxin, diuretic agents, sodium-glucose cotransporter 2 inhibitors, and (to a limited extent) for angiotensin-converting enzyme inhibitors. Available evidence for worsening of clinical status following the withdrawal of neurohormonal antagonists largely consists of observational studies. However, their findings are difficult to interpret because of considerable confounding related to the fact that drugs were withdrawn for clinical reasons, which represented a more important contributor to the poor outcome of these patients than the withdrawal of an effective drug. Nevertheless, the totality of available evidence points to a meaningful clinical deterioration within a few weeks following the withdrawal for most drugs that have been evaluated for the treatment of heart failure. These findings suggests that that our current emphasis on the implementation of foundational drugs needs to include an equally important emphasis to avoid even short-term gaps in treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Key points We investigated acute effects of the Na+,K+‐ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K+] ([K+]a) and fatigue with intense exercise. In a randomised, crossover, double‐blind design, 10 healthy adults ingested 0.50 mg digoxin (DIG) or placebo (CON) 60 min before cycling for 1 min at 60% V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ then at 95% V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ until fatigue. Pre‐ and post‐exercise muscle biopsies were analysed for [3H]‐ouabain binding site content without (OB‐Fab) and after incubation in digoxin antibody (OB+Fab) and NKA α1‐2 and β1‐2 isoform proteins. In DIG, pre‐exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA–digoxin occupancy was 8.2%. Muscle OB‐Fab did not differ between trials, whereas OB+Fab was higher in DIG than CON (8.1%, treatment main effect, P = 0.001), whilst muscle NKA α1‐2 and β1‐2 abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [−7.7%, 2.90 (0.77) vs. 3.14 (0.86) min, respectively; P = 0.037]. [K+]a increased during exercise until 1 min post‐exercise (P = 0.001), and fell below baseline at 3–10 (P = 0.001) and 20 min post‐exercise (P = 0.022, time main effect). In DIG, [K+]a (P = 0.035, treatment effect) and [K+]a rise pre‐fatigue were greater [1.64 (0.73) vs. 1.55 (0.73), P = 0.016], with lesser post‐exercise [K+]a decline than CON [−2.55 (0.71) vs. −2.74 (0.62) mM, respectively, P = 0.003]. Preserved muscle OB‐Fab with digoxin, yet increased OB+Fab with unchanged NKA isoforms, suggests a rapid regulatory assembly of existing NKA α and β subunits exists to preserve muscle NKA capacity. Nonetheless, functional protection against digoxin was incomplete, with earlier fatigue and perturbed [K+]a with exercise. Intense exercise causes marked potassium (K+) shifts out of contracting muscle cells, which may contribute to muscle fatigue. Muscle and systemic K+ perturbations with exercise are largely regulated by increased activity of Na+,K+‐ATPase in muscle, which can be specifically inhibited by the cardiac glycoside, digoxin. We found that acute oral digoxin in healthy adults reduced time to fatigue during intense exercise, elevated the rise in arterial plasma K+ concentration during exercise and slowed K+ concentration decline post‐exercise. Muscle functional Na+,K+‐ATPase content was not reduced by acute digoxin, despite an 8.2% digoxin occupancy, and was unchanged at fatigue. Muscle Na+,K+‐ATPase isoform protein abundances were unchanged by digoxin or fatigue. These suggest possible rapid assembly of existing subunits into functional pumps. Thus, acute digoxin impaired performance and exacerbated plasma K+ disturbances with intense, fatiguing exercise in healthy participants. These occurred despite the preservation of functional Na+,K+‐ATPase in muscle. [ABSTRACT FROM AUTHOR]

Background: Inflammation and angiogenesis are two main mechanisms that act as mutual pathways in rheumatoid arthritis (RA). This work aimed to study the efficacy of digoxin as an adjunct therapy to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in active RA patients. Methods: In a randomized, double-blinded, placebo-controlled study, 60 adult patients with active RA received a placebo or digoxin (0.25 mg every other day) combined with csDMARDs for 6 months. The American College of Rheumatology (ACR) 20, ACR50, and ACR70 response rates and the disease activity score (DAS28) were assessed for patients. Flow cytometric analysis of Th17 cells and serum concentrations of IL-17A, IL-23, HIF-1α, and VEGF were evaluated before and after three and 6 months of therapy. Results: Following three and 6 months of digoxin therapy combined with csDMARDs, significant differences were detected in laboratory and clinical parameters relative to the control group. After 6 months, 83.3% of patients in the digoxin group, compared to 56.7% in the control group, achieved an ACR20 response (p = 0.024). The digoxin group had a significantly higher percentage of patients who achieved DAS28 remission after 6 months (p = 0.024). Notable improvements in the Health Assessment Questionnaire Disability Index, ACR50, and ACR70 were detected in the digoxin group. Conclusion: Digoxin was well tolerated and exerted profound immunomodulatory and anti-inflammatory effects in RA patients, and may also exhibit anti-angiogenic properties, indicating that it might be an effective adjunct to csDMARDs in treating RA. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04834557. [ABSTRACT FROM AUTHOR]

In muscle, digoxin inhibits Na+,K+‐ATPase (NKA) whereas acute exercise can increase NKA gene expression, consistent with training‐induced increased NKA content. We investigated whether oral digoxin increased NKA isoform mRNA expression (qPCR) in muscle at rest, during and post‐exercise in 10 healthy adults, who received digoxin (DIG, 0.25 mg per day) or placebo (CON) for 14 days, in a randomised, double‐blind and cross‐over design. Muscle was biopsied at rest, after cycling 20 min (10 min each at 33%, then 67% V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_2}{\mathrm{peak}}}}$), then to fatigue at 90% V̇O2peak${{\dot{V}}_{{{{\mathrm{O}}}_2}{\mathrm{peak}}}}$ and 3 h post‐exercise. No differences were found between DIG and CON for NKA α1–3 or β1–3 isoform mRNA. Both α1 (354%, P = 0.001) and β3 mRNA (P = 0.008) were increased 3 h post‐exercise, with α2 and β1–2 mRNA unchanged, whilst α3 mRNA declined at fatigue (−43%, P = 0.045). In resting muscle, total β mRNA (∑(β1+β2+β3)) increased in DIG (60%, P = 0.025) and also when transcripts for each isoform were normalised to CON then either summed (P = 0.030) or pooled (n = 30, P = 0.034). In contrast, total α mRNA (∑(α1+α2+α3), P = 0.348), normalised then summed (P = 0.332), or pooled transcripts (n = 30, P = 0.717) did not differ with DIG. At rest, NKA α1–2 and β1–2 protein abundances were unchanged by DIG. Post‐exercise, α1 and β1–2 proteins were unchanged, but α2 declined at 3 h (19%, P = 0.020). In conclusion, digoxin did not modify gene expression of individual NKA isoforms at rest or with exercise, indicating NKA gene expression was maintained consistent with protein abundances. However, elevated resting muscle total β mRNA with digoxin suggests a possible underlying β gene‐stimulatory effect. Highlights: What is the central question of this study?Na+,K+‐ATPase (NKA) in muscle is important for Na+/K+ homeostasis. We investigated whether the NKA‐inhibitor digoxin stimulates increased NKA gene expression in muscle and exacerbates NKA gene responses to exercise in healthy adults.What is the main finding and its importance?Digoxin did not modify exercise effects on muscle NKA α1–3 and β1–3 gene transcripts, which comprised increased post‐exercise α1 and β3 mRNA and reduced α3 mRNA during exercise. However, in resting muscle, digoxin increased NKA total β isoform mRNA expression. Despite inhibitory‐digoxin or acute exercise stressors, NKA gene regulation in muscle is consistent with the maintenance of NKA protein contents. [ABSTRACT FROM AUTHOR]

Aims: Digoxin is the oldest drug in cardiovascular (CV) medicine, and one trial conducted >25 years ago showed a reduction in heart failure (HF) hospitalizations but no effect on mortality. However, later studies suggested that the dose of digoxin used in that trial (and other studies) may have been too high. The DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) trial will examine the efficacy and safety of low‐dose digoxin in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with a background of contemporary HF treatment. Methods: The DECISION trial is a randomized, double‐blind, parallel‐group, placebo‐controlled event‐driven outcome trial which will investigate the efficacy and safety of low‐dose digoxin in patients with chronic HF and LVEF <50%. Both patients with sinus rhythm and atrial fibrillation will be enrolled and will be randomized (1:1) to low‐dose digoxin or matching placebo. To maintain a target serum digoxin concentration of 0.5–0.9 ng/ml, dose adjustments are made throughout follow‐up based on serum digoxin measurements with dummy values for the placebo group. The primary endpoint is a composite of CV mortality and total HF hospitalizations or total urgent hospital visits for worsening HF, and all endpoints are adjudicated blindly by a Clinical Event Committee. The estimated sample size was 982 patients who will be followed for a median of 3 years, and in December 2023 enrolment was completed after 1002 patients. Conclusions: The DECISION trial will provide important evidence regarding the effect of (low‐dose) digoxin on CV mortality and total HF hospitalizations and urgent hospital visits when added to contemporary HF treatment of patients with reduced or mildly reduced LVEF. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03783429. [ABSTRACT FROM AUTHOR]

Purpose: Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults. Methods: This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100 mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextromethorphan metabolite (dextrorphan) was assessed in participants with functional CYP2D6 genes in Arm 2. Results: The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (Cmax) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37-48% and of 100% in Cmax. There was no increase in the primary PK parameters (AUCs and Cmax) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥ 2, or deaths. Conclusion: Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults. [ABSTRACT FROM AUTHOR]

Background and Aims: Cardiac glycosides (CGs), traditionally used for heart failure, have shown potential as anti‐cancer agents. This study aims to explore their multifaceted mechanisms in cancer cell biology using proteome integral solubility alteration (PISA), focusing on the interaction with key proteins implicated in cellular metabolism and mitochondrial function. Methods: We conducted lysate‐based and intact‐cell PISA assays on cancer cells treated with CGs (Digoxin, Digitoxin, Ouabain) to analyze protein solubility changes. This was followed by mass spectrometric analysis and bioinformatics to identify differentially soluble proteins (DSPs). Molecular docking simulations were performed to predict protein‐CG interactions. Public data including gene expression changes upon CG treatment were re‐analyzed for validation. Results: The PISA assays revealed CGs' broad‐spectrum interactions, particularly affecting proteins like PKM2, ANXA2, SLC16A1, GOT2 and GLUD1. Molecular docking confirmed stable interactions between CGs and these DSPs. Re‐analysis of public data supported the impact of CGs on cancer metabolism and cell signaling pathways. Conclusion: Our findings suggest that CGs could be repurposed for cancer therapy by modulating cellular processes. The PISA data provide insights into the polypharmacological effects of CGs, warranting further exploration of their mechanisms and clinical potential. [ABSTRACT FROM AUTHOR]

Futibatinib, an inhibitor of fibroblast growth factor receptor 1–4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug–drug interaction study, the effects of futibatinib on P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates, and of P‐gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18–55 years. In part 1, 20 participants received digoxin (P‐gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10‐day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3‐day washout, quinidine (P‐gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment‐emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P‐gp or BCRP substrates and that the effect of P‐gp inhibition on futibatinib PK is not clinically relevant. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Stone heart syndrome has a complex interaction with digoxin toxicity, where, theoretically, the administration of intravenous calcium can worsen a patient's condition. Research on this subject is conflicting, so it is imperative to approach it cautiously. [ABSTRACT FROM AUTHOR]

Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro , followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC 50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types. • Patient-derived 3D models of dedifferentiated endometrial carcinoma (DDEC) were subjected to drug repurposing screen. • The drug screen identified digoxin as an effective anti-cancer drug in suppressing DDEC tumor growth. • DDEC displayed greater sensitivity to digoxin compared to non-DDEC endometrial cancer cells in vitro. • Digoxin significantly inhibited patient-derived DDEC tumor growth in vivo. • These results provide compelling preclinical evidence for the use of digoxin as systemic therapy for DDEC. [ABSTRACT FROM AUTHOR]

Aims: Common genetic variations in the nitric oxide synthase‐1 adaptor protein (NOS1AP) gene are associated with QT‐interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT‐interval shortening in digoxin users. As QT‐interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. Methods: We included 11 377 individuals from the prospective population‐based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time‐dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose‐dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non‐users. Results: The median baseline age of the total study population was 62 (interquartile range [IQR] 58–71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow‐up of 11.5 (IQR 6.5–17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38–3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98–8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37–5.04] in the heterozygous TG and 2.56 [95%CI: 1.70–3.86] in the homozygous TT genotype groups. Compared to low‐ and moderate‐dose, high‐dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34–23.47]). Conclusions: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin‐associated risk of SCD in a population of European ancestry. [ABSTRACT FROM AUTHOR]

Introduction: Mortality benefit of digoxin prescription in patients suffering from heart failure has been questioned many time. We evaluated these effects among admitted symptomatic heart failure patients. Methods: We retrospectively divided our patients into two groups: group A (n=205) were digoxin prescribed, and group B (n=96) were digoxin naïve patients. Both groups' medical records were gathered for one year, and the study endpoints were compared between the two groups. Results: The mean age was 62.3±12.1 years and 54.8 % were male. All-cause mortality and readmission occurred in 26.7% and 31.7% of individuals, respectively, without significant differences between the two groups. However, in subgroup analysis, there was a significant relationship between in-hospital mortality and the presence of cardiovascular risk factors. Conclusion: Digoxin might increase in-hospital mortality in patients with underlying cardiovascular risk factors. [ABSTRACT FROM AUTHOR]