We characterized our institution's experience with supratherapeutic digoxin levels (> 2.0 mcg/L) which is reported to occur in 0.8-4% of treated patients. Children < 18 years with a measured digoxin level between January 2014 and December 2024 were included. Data were obtained from the electronic health record including digoxin dose, indication, renal function, and clinical interventions. Descriptive patient-level analyses were performed in children with supratherapeutic levels. Laboratory sample-level analyses were performed using all measured digoxin levels comparing high (> 2.0mcg/L) verses low accounting for repeated measurements within patients. Multivariable models report adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). Overall, 604 digoxin levels were obtained in 283 patients, of which 63 levels (10.4%) were > 2.0 mcg/L in 42 (14.8%) patients. Among patients with elevated levels, median age was 16-months (interquartile range [IQR]: 4-37) and 42% had documented clinical symptoms. Digoxin indications included heart failure (38%), interstage management (38%), and arrhythmia (17%). Median elevated digoxin level was 2.5mcg/L (IQR: 2.2-3.1) and dose was 7.9 mcg/kg/day (IQR: 6.1-9.9). Most patients (76%) were on interacting medications, 25% had moderate/severe renal dysfunction and clinical interventions occurred in 93%. At the sample-level, independent associations with higher odds of supratherapeutic levels included renal dysfunction (severe aOR 6.1, 95%CI 1.4-26.2]; moderate 4.3 [1.2-15.6], mild 2.9 [1.0-8.0] versus normal) and higher daily dose (1.2 mg/kg [1.0-1.3]). Outpatient samples were associated with lower odds of supratherapeutic levels. Supratherapeutic digoxin levels were common, frequently prompting clinical intervention, and associated with renal dysfunction and higher doses, supporting closer monitoring and dose adjustment in high-risk patients.

Thevetia peruviana (yellow oleander) is an ornamental shrub found in tropical and subtropical regions, including tropical America. All parts of the plant are toxic due to cardiac glycosides, which can cause severe cardiotoxicity and arrhythmias. Poisoning is associated with significant mortality, often due to deliberate self-harm. This report describes a case of accidental ingestion of Thevetia peruviana seeds by a patient who believed that they could treat benign prostatic hyperplasia (BPH). The patient presented to the emergency department within 30 minutes of ingesting yellow oleander seeds with nausea, vomiting, and abdominal cramps. Although initial vital signs were stable, he developed sinus bradycardia and symptoms of cardiac glycoside toxicity, including dizziness, tachypnea, and visual disturbances. Lab results later showed a serum digoxin level of 4.04 ng/mL, and the poison control center recommended digoxin immune fab (DigiFab). He received a total of 15 vials intravenously, resulting in marked clinical improvement. He was monitored on continuous telemetry in the cardiac unit and discharged in stable condition after four days. Although DigiFab is not approved by the U.S. Food and Drug Administration for oleander poisoning, it remains the most effective reported antidote, and timely administration is crucial for successful management. Given the limited reports of oleander toxicity in the United States, this case highlights the risks of unregulated herbal remedies and the clinical presentation and management of oleander toxicity, underscoring the need for public education about oleander toxicity and the dangers of unregulated herbal remedies.

Background/Objectives: Digoxin, a positive inotropic agent with a narrow therapeutic window, is used in heart failure but carries toxicity risks. This study aims to characterize the profile of digoxin-associated adverse drug reactions reported in the EudraVigilance database, focusing on drug-drug interactions, dosing errors, and off-label use. Methods: Descriptive and disproportionality analyses were performed on Individual Case Safety Reports (ICSRs) until 25 January 2026. Digoxin was compared with other inotropic agents by calculating the Reporting Odds Ratio and 95% confidence intervals. Results: Digoxin recorded 11,426 ICSRs, with a predominance in patients aged 65-85 years (46.4%) and over 85 years (25.1%). Higher reporting probabilities were identified for the terms "Drug interaction" and "Overdose" compared to other inotropes. Fatal outcomes were reported in 19 cases related to drug interactions and 41 cases related to overdose. Consistent disproportionality signals were found for gastrointestinal, renal, and nervous system disorders. Off-label use was reported in 0.8% of cases and was associated with unfavorable clinical outcomes. Risks are exacerbated by polypharmacy and renal decline in elderly patients. Conclusions: Digoxin toxicity and cardiac complications are the primary drivers of reported morbidity. This risk profile highlights the need for the rigorous clinical monitoring, precise dose adjustments and heightened vigilance regarding drug-drug interactions.

Imlunestrant is a next-generation, oral, selective estrogen receptor degrader approved for treating adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced/metastatic breast cancer. Imlunestrant is metabolized partly by cytochrome P450 (CYP)3A4 oxidation and conjugation with glucuronic acid and sulfate; thus, pharmacokinetic and drug-drug interaction (DDI) studies for treatments utilizing similar pathways are essential for clinical development. Three open-label, phase 1 studies enrolled 182 healthy females of nonchildbearing potential to assess the tolerability, safety, and pharmacokinetics of imlunestrant as monotherapy or coadministered with other drugs. Drug concentrations were quantified by validated liquid chromatography-mass spectrometry. Participants tolerated imlunestrant at 200-800-mg doses, alone or with a CYP3A inhibitor (itraconazole), CYP3A inducer (carbamazepine), P-glycoprotein (P-gp) inhibitor (quinidine), and substrates of CYP2C8 (repaglinide), CYP2C19 (omeprazole), CYP2D6 (dextromethorphan), CYP3A (midazolam), P-gp (digoxin), and BCRP (rosuvastatin). Frequent treatment-related adverse events included headache (range, 4%-20%), diarrhea (2%-20%), and constipation (0%-16%). In the presence of imlunestrant, exposures (AUC0-∞) increased for dextromethorphan 1.33-fold (90% CI, 1.22-1.46), digoxin 1.39-fold (1.22-1.59), and rosuvastatin 1.49-fold (1.14-1.97). Imlunestrant exposure (AUC0-∞) decreased in combination with quinidine (CYP2D6 inhibitor) 0.87-fold (90% CI, 0.76-1.00) and carbamazepine (CYP3A4 inducer) 0.58-fold (0.49-0.69), but increased in combination with itraconazole (CYP3A4 inhibitor) 2.11-fold (1.77-2.53). Imlunestrant had no DDIs with CYP2C8 (repaglinide), CYP2C19 (omeprazole), and CYP3A4 (midazolam) substrates, or a P-gp inhibitor (quinidine), but weakly inhibited dextromethorphan (CYP2D6 substrate), digoxin (P-gp substrate), and rosuvastatin (BCRP substrate) clearance. Thus, considerations should be taken when imlunestrant is coadministered with strong CYP3A4 inhibitors, strong CYP3A4 inducers, and CYP2D6 and P-gp substrates where small changes in exposure may lead to toxicities.

Digoxin, a cardiac glycoside historically used for rate control in atrial arrhythmias and symptom relief in chronic heart failure, possesses a narrow therapeutic index and is highly susceptible to pharmacokinetic and pharmacodynamic disruption in critically ill patients. Its use in acute decompensated heart failure and cardiogenic shock is therefore controversial. We present the case of a 75-year-old woman with chronic heart failure with reduced ejection fraction who developed progressive bradycardia and cardiogenic shock after treatment with digoxin and amiodarone for 2:1 atrial flutter. Her hospital course was complicated by acute kidney injury, severe hyperkalemia, ischemic hepatitis, and persistent bradycardia following electrical cardioversion. Serum digoxin levels were supratherapeutic early in the intensive care unit course and subsequently normalized, though bradyarrhythmias persisted. The patient's presentation and clinical trajectory were consistent with BRASH (bradycardia, renal failure, AV-nodal blockade, shock, and hyperkalemia) syndrome , with amiodarone-digoxin interaction and systemic hypoperfusion likely amplifying myocardial digoxin sensitivity. She improved with supportive therapy, correction of metabolic derangements, withdrawal of AV-nodal-blocking agents, and cardioversion, without administration of digoxin-specific antibody fragments. This case highlights the importance of early recognition of BRASH physiology, cautious use of AV-nodal blockers in low-output states, and prioritization of underlying physiologic correction over reliance on serum drug levels alone in critically ill patients.

Digitalis glycosides are among the oldest therapies for heart failure (HF) with reduced ejection fraction, yet their contemporary role remains debated. Clinical data now indicate that the predominant clinical benefits of digitalis appear to derive from autonomic and neurohormonal modulation (enhanced vagal activity, attenuation of sympathetic drive, and suppression of renin-angiotensin-aldosterone activation) rather than from classical positive inotropy. At low serum concentrations, these effects translate into improved rate control, reduced congestion, and fewer decompensations with a lower risk of toxicity, whereas higher "inotropic" levels are associated with proarrhythmia and excess mortality. This review summarises the mechanistic and pharmacokinetic differences between digoxin and digitoxin, appraises evidence from PROVED, RADIANCE and DIG, and integrates emerging outcome data from DIGIT-HF, which showed that low-dose digitoxin added to contemporary guideline-directed therapy reduces the composite of death or HF hospitalisation. Finally, this review also provides valuable insights from a 2025 survey of Portuguese HF specialists into real-world clinical practice regarding digitalis use. With 55 experts responding, the survey highlights a predominant, selective application of digitalis glycosides, primarily after optimization of foundational HF therapies, consistent with guideline recommendations. Perceived benefits focus on rate control and symptom relief, while concerns about toxicity, the need for monitoring, and gaps in modern trial evidence continue to restrict broader adoption. Together, current data support a repositioning of digitalis as a low-dose, concentration-guided, neurohormonal modulator and rate-control agent for carefully selected patients with HF with reduced ejection fraction, an approach that ongoing and future trials should further refine.

Paroxysmal atrial tachycardia (PAT) with atrioventricular (AV) block is a rare arrhythmia that can be easily misdiagnosed, yet correct identification is crucial for effective management. This report presents two cases illustrating different etiologies. The first patient, a 78-year-old man on digoxin for heart failure, presented with symptoms including tachycardia and dizziness, with elevated digoxin levels confirming toxicity. Following the withdrawal of digoxin and supportive treatment, sinus rhythm was restored without further intervention. The second case involves a 52-year-old man with hypertension who developed PAT with AV block and hypokalemia following excessive alcohol intake. Treatment with intravenous potassium normalized his rhythm, and he remained arrhythmia-free at follow-up. These cases highlight the importance of identifying underlying causes, such as digitalis toxicity and hypokalemia, in managing PAT with AV block. Accurate diagnosis and individualized therapy are essential for preventing complications and achieving optimal patient outcomes.

Chronic neuroinflammation contributes to neuronal damage through oxidative stress and inflammatory mediators, highlighting the need for novel therapeutic strategies. This study evaluated the cytotoxicity and neuroprotective effects of BD-8, a digoxin-derived cardiosteroid, in vitro and in vivo. BD-8 showed lower cytotoxicity than digoxin, with CC50 values of 7.4 µM in SH-SY5Y cells and 8.5 µM in BV-2 cells, while digoxin presented a CC50 of 33 nM in SH-SY5Y cells. In vivo, BD-8 did not alter cardiac, hepatic, or renal biochemical markers, supporting its systemic safety profile. In the open-field test, BD-8 prevented LPS-induced locomotor impairment, significantly increasing total crossings at 0.56 mg/kg (62.07 ± 3.269; P < 0.05) and 1.12 mg/kg (66.31 ± 5.282; P < 0.001) compared to the LPS group. BD-8 also reduced lipid peroxidation levels in the cortex at 0.56 mg/kg (14.38 ± 0.5568; P < 0.001) and 1.12 mg/kg (13.94 ± 0.8372; P < 0.001), and in the hippocampus at 1.12 mg/kg (14.04 ± 0.5223; P < 0.001). Additionally, BD-8 modulated antioxidant enzyme activities, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), in both the cortex and hippocampus and reduced IL-6 levels in these brain regions without altering BDNF (Brain Derived Neurotrophic Factor) levels. These findings support BD-8 as a promising candidate for neuroinflammatory disorders.

Highlighting its pivotal role in modern pharmacology, the gut microbiome is emerging as a key determinant of drug efficacy, toxicity, and bioavailability. This review proposes the Gut Microbiome Dependency Continuum, a four-layer framework describing progressively deeper levels of microbiome involvement in drug discovery and therapeutic function. The first layer, intact functional microbiome-dependent therapeutics and includes interventions such as faecal microbiota transplantation and defined microbial consortia. The second layer, microbiome-modulated approved drugs include widely used therapeutics whose pharmacokinetics or pharmacodynamics are strongly influenced by microbial metabolism. Examples include metformin, irinotecan, levodopa, and digoxin, where gut microbial interactions influence efficacy, toxicity, and inter-individual variability in treatment outcomes. The third layer, microbiota-transformable natural products, encompasses dietary and plant-derived compounds such as polyphenols, ginsenosides, alkaloids, fibres, isoflavones, lignans, and glucosinolates. Their biological activity depends on microbial biotransformation into bioactive metabolites. The fourth layer, engineered microbiome therapeutics, includes synthetic biology approaches such as programmable microbial systems, engineered probiotics, CRISPR-based microbiome editing, and microbiome-responsive drug delivery systems. It also includes synthetic microbial consortia, enabling targeted sensing, therapeutic delivery, and ecological reprogramming of gut microbial communities. Altogether, these layers define a continuum in which the gut microbiome evolves from a passive modulator to an essential metabolic organ and ultimately a programmable therapeutic platform. The article provides an integrated framework for microbiome-informed drug discovery. It also supports the development of precision, ecology-aware, and engineered microbial therapeutics.

Cardiac glycosides have undergone one of the most paradoxical trajectories in cardiovascular therapeutics, evolving from foundational heart failure therapy to near abandonment in the modern era. Although the Digitalis Investigation Group (DIG) trial demonstrated substantial reductions in worsening heart failure hospitalizations, the absence of mortality benefit and subsequent toxicity concerns-particularly in women exposed to greater serum concentrations-led to therapeutic disrepute. Contemporary evidence now supports a more disciplined reassessment. Recent randomized trials, including Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure (DIGIT-HF) and Digoxin Evaluation in Chronic Heart Failure: Investigational Study in Outpatients in the Netherlands (DECISION), together with a contemporary meta-analysis, demonstrate consistent directional reductions in worsening heart failure events with low-dose digitalis therapy, without excess mortality when serum concentrations are carefully controlled. These findings suggest that the historical toxicity narrative largely reflected excessive drug exposure rather than intrinsic biologic hazard. Digitalis glycosides should not be viewed as mortality-reducing "foundational" therapy but rather as complementary agents for selected patients with persistent residual risk despite optimized guideline-directed therapy, particularly those with recurrent decompensation or concomitant atrial fibrillation.

Background: Thrombotic disorders remain one of the leading causes of global mortality, necessitating the discovery of anticoagulants with broader therapeutic windows and multi-target efficacy. This study aimed to identify FDA-approved drugs capable of simultaneously inhibiting three critical nodes of the coagulation cascade: Factor X (F10), Proteinase-activated receptor 1 (PAR1) and Prothrombin (F2). Methods: High-confidence 3D structures of coagulation cascade proteins were established using AlphaFold2 and validated via MolProbity (Favored regions > 91%). A library of 1657 compounds from the Zinc database was screened using PyRx, followed by rigorous ADMET profiling to evaluate pharmacokinetic viability. The structural integrity and binding kinetics of the top candidate drugs were further analyzed through Molecular Dynamics simulation for 100 ns. Results: Virtual screening and downstream analysis identified 30 multi-target drugs. Avodart and Naldemedine were observed to have superior pharmacokinetic equilibrium. Compared to the other two drugs (Digoxin and Ledipasvir), Avodart and Naldemedine showed high affinity, higher adherence to drug likeness, lower metabolic inhibition risks and lack of acute toxicity, and were therefore the most suitable candidates. The 100 ns MD simulations revealed Avodart and Naldemedine to have the highest level of interaction stability and favorable MM-GBSA energies with Factor X, whereas Ledipasvir and Digoxin exhibited significant structural instability. Conclusions: The study proposes Avodart and Naldemedine as promising candidates for drug repurposing in antithrombotic therapy. This study provides a computational blueprint for the development of next-generation, broad-spectrum anticoagulants.