Search Results (136)

Background: Pulmonary arterial hypertension is a rare but life-threatening condition in children, with hereditary forms often being linked to mutations in genes such as bone morphogenetic protein receptor type 2 (BMPR2), caveolin 1 (CAV1), and potassium channel subfamily K member 3 (KCNK3). Among these, CAV1 mutations are associated with severe disease phenotypes, though cases resulting from de novo heterozygous CAV1 mutations with multi-system involvement remain rarely reported. The CAV1 mutation (c.424C > T, p.Q142X) disrupts caveolin-1 function, leading to dysregulated pulmonary vascular remodeling and multi-system abnormalities. Methods: This was a retrospective case study of a pediatric patient with hereditary PAH. The patient was followed at our hospital from initial presentation until death. Clinical data were collected from medical records, including physical examinations, laboratory tests, echocardiography, chest X-ray, computed tomography pulmonary angiography (CTPA), and genetic analysis. The patient was treated sequentially with various PAH-targeted medications. This report also includes a review of the relevant literature on CAV1-associated PAH. Results: A female aged 3 years and 11 months was diagnosed with hereditary PAH associated with a de novo heterozygous CAV1 mutation (c.424C > T, p.Q142X). Both parents underwent genetic testing and were negative for the mutation, confirming its de novo origin. Clinical manifestations included special facial features, congenital telangiectasia, cutis marmorata (marbled skin), congenital cataract, hereditary lipodystrophy, and severe PAH. The patient presented with progressive exercise intolerance, syncope, and worsening dyspnea over nine years. Echocardiography revealed pulmonary hypertension with an estimated pulmonary artery systolic pressure of 69–105 mmHg, right heart enlargement, right ventricular hypertrophy, and moderate tricuspid regurgitation. Blood and urine metabolic screenings were normal. A chest X-ray showed progressive enlargement of the cardiac silhouette and bulging of the pulmonary artery segment. CTPA demonstrated pulmonary hypertension, secondary right heart dysfunction, decompensated right ventricular function, and mosaic perfusion in both lungs, suggestive of small arterial branch occlusion. Right heart catheterization was declined by the parents. Thus, the diagnosis of PAH was established based on clinical, echocardiographic, CTPA, and genetic findings. The patient was hospitalized four times and lost to follow-up from 2017 to 2023. She received sequential treatment with digoxin, hydrochlorothiazide, tadalafil, ambrisentan, selexipag, and treprostinil. Despite these therapies, pulmonary artery pressure continued to rise with progressive clinical deterioration. The patient ultimately died at 13 years of age due to a pulmonary hypertensive crisis and multiple organ failure following a severe episode of gastroenteritis. Conclusions: Despite aggressive treatment with multiple targeted reduced pulmonary artery pressure drug therapies, managing hereditary PAH caused by CAV1 mutations in children remains a significant challenge, with a high mortality rate. Early genetic diagnosis, regular follow-up, and individualized treatment are crucial. It requires the joint efforts of patients, parents, and healthcare providers. Full article

Gut microbiome composition influences cardiovascular drug efficacy and safety, yet its integration into heart failure (HF) management remains underexplored. Alterations in intestinal microbial communities have been linked to atherosclerosis, coronary artery disease, heart failure, and hypertension through multiple mechanisms. Dysbiosis disrupts the balance between commensal and pathogenic bacterial species, impairing gut barrier function and activating inflammatory pathways. The altered microbial ecosystem modulates the production of key metabolites—such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (BAs)—that directly impact cardiovascular function. This narrative review synthesizes current evidence on bidirectional interaction between heart failure pharmacotherapy and gut microbiome composition. Commonly used drugs in heart failure management show microbiome-dependent pharmacokinetics. Digoxin undergoes bacterial inactivation by Eggerthella lenta, while angiotensin converting enzyme inhibitors and beta-blockers demonstrate enhanced efficacy with specific Firmicutes populations. Conversely, certain probiotic strains attenuate drug-induced gut barrier injury and restore gut homeostasis. Sodium–glucose cotransporter 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists, and angiotensin receptor–neprilysin inhibitors exhibit beneficial microbiome-modulating effects beyond their primary cardiovascular actions. These findings underscore the potential for microbiome-informed precision medicine in heart failure. However, significant methodological challenges must be addressed, including lack of standardization in microbiome profiling, small sample sizes, and limited longitudinal data. Future research should focus on identifying specific microbial signatures that predict drug response, developing targeted probiotic interventions, and conducting prospective clinical trials to validate pharmacomicrobiomics approaches in heart failure management. Full article

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. Full article

Background and Objectives: Diazepam, a GABA_A receptor agonist with sympatholytic properties, is sometimes co-administered with antiarrhythmic agents in the emergency management of atrial fibrillation (AF), yet evidence supporting this practice is remarkably limited. Given the established role of sympathetic activation in the initiation and maintenance of AF, we investigated whether adjunctive diazepam influences treatment outcomes. Materials and Methods: This single-centre retrospective cohort study included 72 hemodynamically stable patients presenting with AF to the emergency department of University Hospital Centre Split, Croatia. Patients were stratified by treatment strategy into a rhythm control group (n = 33, receiving any Class IC/III antiarrhythmic) and a rate control only group (n = 39, beta-blockers and/or digoxin). Diazepam was administered orally at the physician’s discretion (median dose 5 mg). Primary outcomes were rhythm conversion and achievement of a heart rate < 110 bpm. Secondary outcomes included changes in heart rate, blood pressure, and time to therapeutic goal. Results: Diazepam was administered to 32 patients (44.4%). In the rate control stratum, spontaneous rhythm conversion was significantly higher with diazepam (40.0% vs. 9.5%; OR 6.33, 95% CI 1.06–37.78, p = 0.046), corresponding to a model-predicted increase in conversion probability from 8% to 33%. This effect was absent in the rhythm control group (64.3% vs. 64.7%; OR 0.98, p = 1.000). Diazepam increased the odds of achieving HR < 110 bpm by 3.46-fold (95% CrI 0.63–23.1, posterior probability of benefit 92%) in the rate control group. Diazepam-treated patients in the rate control group had longer median time to therapeutic goal (4.2 vs. 2.8 h, p = 0.005). In the rhythm control group, diazepam was associated with reduced variability in diastolic blood pressure response (p = 0.006). Conclusions: Adjunctive diazepam was associated with a significantly higher rate of spontaneous rhythm conversion in AF patients receiving rate control therapy only, consistent with sympatholysis removing a key factor sustaining the arrhythmia. This effect was not observed when Class IC/III antiarrhythmics were co-administered, suggesting that diazepam’s benefit is context-dependent. These hypothesis-generating findings warrant prospective validation, with attention to thromboembolic risk in patients who convert unexpectedly. Full article

Background/Objectives: Digoxin is a cardiotonic agent with a narrow therapeutic window and a high risk of toxicity. The current clinical use is based on an empirically FDA-recommended regimen which has wide dosing ranges, introducing the risk of inappropriate dosing and related adverse events. This study aims to develop a physiologically based pharmacokinetic (PBPK) model to characterize digoxin pharmacokinetics in adult and pediatric patients with heart failure, and then to evaluate the FDA-recommended regimen. Methods: The PBPK model was initially developed in healthy adults using PK-Sim^®. Then, it was translated to adults with heart failure by incorporating disease factors. Next, it was further translated to pediatrics by scaling age-related parameters. Finally, through two-step translations, the model was used to evaluate current dosing regimens to inform safety and effectiveness based on observing predicted trough concentrations at a steady state. Results: This PBPK model has strong predicting ability, where observed concentrations and key PK metrics (C_max, AUC_0-t) were within 0.5–2.0-fold of predictions in healthy adults, adults with heart failure, neonates, and infants. The model prediction work on the evaluation of recommended dosing regimens from the FDA shows that the current regimen may not achieve the lowest boundary of the therapeutic window (0.5–2 ng/mL) in neonates (0–30 days), whereas infants (1–2 months) and children (<18 years) are generally good within it. Conclusions: This PBPK model explained major physiological and pathological contributors to differences in digoxin pharmacokinetics across populations and showed good performance in pediatric extrapolation. It also pointed out the shortage of empirical dosing regimens for such a drug with a narrow therapeutic window. The model may assist in optimizing the pediatric dosing strategies of digoxin, and suggests that current neonatal dosing regimens need refinement. Full article

Cardenolides are an important group of steroidal natural products and have been used successfully for the treatment of cardiovascular diseases by targeting Na⁺/K⁺-ATPase (NKA) and found more recently to show potential anticancer activity. Biological investigations indicate that both the C-17 lactone unit and the C-3 saccharide moiety of these compounds play an important role in their interaction with NKA and in manifesting the resultant bioactivities. Interestingly, the crystal structures of several cardenolides show various conformations, due to a rotation of the C-3 saccharide moiety or the C-17 lactone unit. These rotation conformations could affect their binding to NKA and the resultant bioactivities, and thus docking profiles with NKA for several cardenolides, including cryptanoside A, digoxin and its aglycone, digoxigenin, and gitoxin, have been investigated in the present investigation. The results indicate that the binding poses of the rotation conformations of the cardenolides selected are different when they bind to NKA, as indicated by their docking scores calculated. For each compound, the rotation conformations observed could be in a dynamic equilibrium, of which each conformer may interact with NKA differentially, and these rotation conformers could act on NKA cooperatively to lead to a specific bioactivity. Full article

Background: The role of digoxin in atrial fibrillation, particularly in patients with heart failure, has long been debated. Observational studies reporting higher mortality have fueled skepticism, yet growing evidence suggests that these findings largely reflect prescription bias, confounding by indication, and inadequate adjustment for serum-level rather than intrinsic toxicity. Objective: To reassess digoxin’s role in atrial fibrillation with heart failure using contemporary evidence and to propose a physiology-based, personalized monitoring framework. Evidence review: We reevaluated the studies that initially linked digoxin to excess mortality and reassessed these associations through three analytic pillars: randomized evidence, bias deconstruction, and exposure–response relationships. Across datasets, low serum digoxin concentrations were consistently associated with stable resting rate control without increasing mortality. Key findings: Low-dose, continuously administered digoxin is a viable second-line option for atrial fibrillation rate control in patients who are hypotensive or intolerant of β-blockers. Safety is concentration-dependent; adverse outcomes increase at higher serum digoxin concentration (≥1.2 ng/mL). Resting heart rate can serve as a contextual surrogate of exposure: persistent HR > 100 bpm in stable patients usually reflects underexposure rather than digoxin toxicity, whereas bradycardia should prompt immediate serum digoxin concentration testing. Proposal: A probability-based monitoring model that integrates heart rate, renal function, dosage, electrolytes, and drug–drug interactions to guide when serum digoxin concentration measurement is warranted. As a future direction, a supervised “pill-in-the-pocket” supplemental dose strategy could be evaluated for transient tachycardia in selected, stable patients. Conclusions: When properly dosed and contextually monitored, digoxin remains a safe, effective, and individualized rate-control option in atrial fibrillation with heart failure. Prospective validation of probability-guided monitoring and evaluation of a “pill-in-the-pocket” approach could simplify digoxin management while maintaining safety. Full article

Gut microbiota, through both its species composition and its metabolites, impacts expression and activity of intestinal drug transporters. This phenomenon directly affects absorption process of orally administered drugs and contributes to the observed inter-individual variability in pharmacotherapeutic responses. This review summarizes mechanistic evidence from in vitro and animal studies and integrates clinical observations in which alterations in gut microbiota are associated with changes in oral drug exposure, consistent with potential regulation of key intestinal drug transporters—such as P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2), MRP2/3 proteins (ABCC2/3), and selected Organic Anion-Transporting Polypeptides (OATPs, e.g., SLCO1A2, SLCO2B1)—by major bacterial metabolites including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan-derived indoles. The molecular mechanisms involved include activation of nuclear and membrane receptors (PXR, FXR, AhR, TGR5), modulation of transcriptional and stress-response pathways (Nrf2, AP-1) with simultaneous suppression of pro-inflammatory pathways (NF-κB), and post-translational modifications (e.g., direct inhibition of P-gp ATPase activity by Eggerthella lenta metabolites). The review also highlights the pharmacokinetic implications of, e.g., tacrolimus, digoxin, and metformin. In conclusion, the significance of “drug–transporter–microbiome” interactions for personalized medicine is discussed. Potential therapeutic interventions are also covered (diet, pre-/probiotics, fecal microbiota transplantation, modulation of PXR/FXR/AhR pathways). Considering the microbiota as a “second genome” enables more accurate prediction of drug exposure, reduction in toxicity, and optimization of dosing for orally administered preparations. Full article

Background: Small-cell lung cancer (SCLC) is an aggressive malignancy marked by rapid progression, early metastasis, and frequent relapse despite chemotherapy. Due to its genetic complexity, targeted therapies have limited success. Autophagy, a lysosome-dependent cellular degradation process, plays a key role in SCLC, yet effective autophagy-targeting strategies are lacking. This study evaluates Tat-SP4, an autophagy-targeting stapled peptide, for its anti-proliferative effects in SCLC. Method: We assessed Tat-SP4′s impact on autophagy in SCLC cells by measuring p62 and LC3 levels. Mitochondrial function was evaluated via mitochondrial membrane potential (Δψm) and oxygen consumption rate (OCR). Anti-proliferative effects were determined using cell viability assays in vitro and xenograft models in vivo. Cellular uptake mechanisms were investigated using Ca²⁺ imaging and pharmacological inhibitors. Result: Tat-SP4 induced a strong autophagic response and triggered autosis, a form of autophagy-dependent necrotic cell death, impairing SCLC cell proliferation. It also caused mitochondrial dysfunction with impaired oxidative phosphorylation (OXPHOS). Tat-SP4 entered cells predominantly via macropinocytosis, triggering extracellular Ca²⁺ influx measurable by live-cell imaging. Digoxin, an Na⁺, K⁺-ATPase inhibitor, partially reversed the effect of Tat-SP4 on Ca²⁺ influx, cell death, and OXPHOS activity. Lastly, Tat-SP4 inhibited tumor growth in a xenograft-based animal model for SCLC. Conclusions: The autophagy-targeting stapled peptide Tat-SP4 inhibited the proliferation of SCLC cells in vitro and inhibited the growth of the SCLC tumor in vivo. Macropinocytosis facilitates cell entry for Tat-SP4, which can be monitored by influx of extracellular Ca²⁺. By exploiting macropinocytosis for cell entry and converting the pro-survival autophagy process into a death pathway, Tat-SP4 represents a novel therapeutic strategy against SCLC. Full article

Bufadienolides exert broad-spectrum pharmacological activities relevant to cardiology and novel cancer treatments. Their efficacy, toxicity, and pharmacokinetic profiles are significantly affected by modifications at carbon-3 (C3) of the steroid core. We have applied molecular dynamics simulations to characterize the consequences of (i) variations in size of the substituent at C3, (ii) the type of linker at C3 (ether vs. N-methoxy), and (iii) stereochemistry (C3β vs. C3α) for derivatives’ interactions with Na⁺,K⁺-ATPase. The model compounds included bufalin, bufalin-N-glucose, bufalin-O-glucose as well as digoxigenin, digoxigenin monodigitoxoside and digoxin. It was shown that the optimal size of the substituent is a trade-off between the ability to form stabilizing interactions and steric and entropic interferences. The former is strongly affected by the nature of the linker due to its impact on the spatial position of the ligand: N-methoxy linker imposes rotational restrictions and places the core into a less favorable position compared to an ether bond. Similarly, the change from β- to α-anomer delocalizes the substituent precluding contacts with amino acid residues of the binding site. The presented mechanistic model of bufadienolide interactions with Na⁺,K⁺-ATPase helps to anticipate the consequences of modifications while designing derivatives with high anticancer activity but reduced cardiotoxicity. Full article

Background: Heart failure (HF), as the end stage of various cardiac diseases, alters blood flow to key organs responsible for drug clearance. This can lead to unpredictable and often suboptimal drug exposure, creating a critical need for quantitative tools to guide precise dosing in this vulnerable population. Methods: This study aimed to establish a whole-body physiologically based pharmacokinetic (PBPK) model for characterizing drug pharmacokinetics in both healthy subjects and patients across the HF severity spectrum. Eight commonly used drugs (digoxin, furosemide, bumetanide, torasemide, captopril, valsartan, felodipine and midazolam) for treating HF and its comorbidities were selected. Following successful validation against clinical data from healthy subjects, the PBPK model was extrapolated to HF patients. Pharmacokinetics of the eight drugs in 1000 virtual HF patients were simulated by replacing tissue blood flows and compared using clinical observations. Results: Most of the observed concentrations were encompassed within the 5th–95th percentiles of simulated values from 1000 virtual HF patients. Predicted area under the concentration–time curve and maximum plasma concentration fell within the 0.5~2.0-fold range relative to clinical observations. Sensitivity analysis demonstrated that intrinsic renal clearance, unbound fraction in blood, muscular blood flow, and effective permeability coefficient significantly impact plasma exposure of digoxin at a steady state. Oral digoxin dosing regimens for HF patients were optimized via the validated PBPK model to ensure that steady-state plasma concentrations in all HF patients remain below the toxicity threshold (2.0 ng/mL). Conclusions: A PBPK model was successfully developed to predict the plasma concentration–time profiles of the eight tested drugs in both healthy subjects and HF patients. Furthermore, this model may also be applied to guide digoxin dose optimization for HF patients. Full article

Herbal medicinal products are increasingly used alongside conventional medicines, raising the risk of potential interactions such as pharmacodynamic drug–herb interactions (PD-DHIs) that can cause serious adverse drug reactions (ADRs). This review aims to present available pharmacological, clinical and pharmacoepidemiological literature regarding potential DHIs associated with serotonin syndrome or cardiac arrhythmias. Furthermore, it assesses the current evidence using the Oxford Centre for Evidence-Based Medicine (CEBM) 2009 framework. Serotonin syndrome most often results from combining serotonergic herbs (e.g., St. John’s wort) with antidepressants like serotonin reuptake inhibitors (SSRIs), as supported by repeated case reports and mechanistic plausibility (CEBM Level 3, Grade C). Other herbs such as black cohosh, ginseng, Syrian rue, turmeric, rhodiola, ashwagandha, and L-tryptophan/5-HTP have been linked to serotonin syndrome when used with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), but evidence is limited (Levels 4–5, Grade D). For cardiac arrhythmias, PD-DHIs arise when herbs interact with drugs that alter cardiac electrophysiology—such as QT-prolonging agents, psychotropics, antiarrhythmics or digoxin—thereby amplifying arrhythmogenic risk. Ephedra with sympathomimetics is strongly associated with arrhythmias (Level 2–3, Grade B). Licorice may potentiate digoxin and QT-prolonging drugs via hypokalemia (Level 4, Grade C). Other related PD-DHIs include aconite with antiarrhythmics, bitter orange or caffeine with QT-prolonging psychotropics, yohimbine with cardiovascular agents, and aloe or senna with digoxin. Overall, the evidence for PD-DHIs varies from moderate to weak but large-scale pharmacoepidemiological data is scarce. Future approaches, including artificial intelligence with explainable machine learning and network pharmacology, may integrate mechanistic, clinical, and real-world data to improve early detection or prediction of PD-DHIs. However, several specific challenges must be addressed. Therefore, it is crucial for healthcare providers in both clinical and community settings to increase their awareness of these interactions and ADRs to ensure the safe use of herbal remedies alongside conventional therapies. Full article

Heart Failure (HF) remains a major cause of mortality despite the advances in pharmacological treatment. Anticoagulation therapies, including Clopidogrel, Aspirin, Warfarin, and novel oral anticoagulants (NOACs) such as Apixaban, Rivaroxaban, Edoxaban, and Dabigatran, are frequently administered to HF patients to prevent thromboembolism and adverse, life-threatening outcomes (e.g., stroke and myocardial infarction). In these settings, drug resistance and variability in responsivity to therapeutic approaches are challenging issues. Recent studies suggest that non-coding RNAs, particularly microRNAs (miRs) may play a modulatory role in HF therapy context, affecting drug efficacy. Specific miRs have been associated with resistance to Clopidogrel (e.g., miR-223 and miR-26a), Aspirin (e.g., miR-19b-1-5p and miR-92a) and Warfarin (e.g., miR-133 and miR-137). Moreover, Digoxin, a cardiac glycoside acting also over bleeding risk, upregulates miR-132, which is involved in HF-associated cardiac alteration and hypertrophy. Evidence linking miR expression to NOAC pharmacodynamics, cardiac remodeling and regulation of the coagulation is growing. These findings highlight the need of deeply harnessing the potential of miRs as predictive biomarkers or therapeutic targets in HF. Improving the knowledge on the relationship between miR and anticoagulant drugs in HF patients will contribute to personalization of the anticoagulant therapies, aimed at enhancing patient responsivity and minimizing adverse effects, ultimately improving patient life quality. Full article

(1) Chronic heart failure (CHF) is a typical component of the polymorbid profile of an elderly patient. The aim of this systematic review was to search for data from pharmacokinetic (PK) studies of any drugs in patients with CHF to systematize information on changes in PK parameters depending on the physicochemical properties (PCPs) of the drug and route of its administration. (2) A systematic review of PK studies in patients with CHF was performed using Elibrary.ru, United States National Library of Medicine (PubMed), China National Knowledge Infrastructure (CNKI), and Directory of Open Access Journals (DOAJ). The final number of included articles was 106. A descriptive and correlation analysis of PK data and PCPs of drugs included in the study was carried out. Inclusion criteria: PK study, available PK parameters, demographic data, and diagnosed CHF. Risk of bias was assessed using ROBINS-I. (3) Evaluation of correlations between PCPs of drugs and their PK revealed a link between (i) plasma protein binding (PPB) and volume of distribution for lipophilic drugs; (ii) PCPs, half-life, and clearance for drugs with high PPB; and (iii) PPB and clearance for hydrophilic and amphiphilic drugs. (4) Hypoalbuminemia associated with CHF may lead to an increased volume of distribution of lipophilic drugs; lipophilic drugs used in CHF patients may be associated with prolongation of the half-life period and reduction in clearance; highly protein-bound drugs may manifest with reduced clearance. PK characteristics identified in this review should guide modifications to dosing regimens in CHF patients receiving medications from different groups. Full article