Search Results (659)

Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data. Methods: The 3- and 14-day effects of 40 mg/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARα). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age. Results: Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively. Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment. Full article

Background: Gastrointestinal (GI) bleeding is a recognised complication of long-term antithrombotic therapy. Whereas the overall bleeding risk associated with direct oral anticoagulants (DOACs) and low-dose aspirin has been extensively characterised, the anatomical distribution of bleeding lesions between these two pharmacological classes remains incompletely defined. Methods: We retrospectively analysed all consecutive adult patients admitted to the Emergency Department of San Carlo di Nancy Hospital (Rome, Italy) between January 2022 and March 2025 with a clinical diagnosis of acute GI bleeding. Patients were categorised as DOAC monotherapy or aspirin (ASA) monotherapy at presentation. The primary endpoint was the site of bleeding (upper vs. lower GI tract) by drug group. Secondary endpoints included site of bleeding by specific DOAC molecule and indicators of clinical severity (haemoglobin at admission, transfusion requirement, melena, hematochezia). Logistic and linear regression models were adjusted for age and sex. Because the number of transfused units is count data with a right-skewed distribution, the corresponding linear-regression estimate is reported as an exploratory approximation and interpreted with caution. As adjustment was limited to age and sex, all adjusted estimates are associative rather than causal and do not represent an independent effect of drug class. Results: The merged cohort comprised 316 patients; the head-to-head analysis included 179 patients on monotherapy (DOAC n = 100, ASA n = 79). Upper GI bleeding (UGIB) was equally distributed between groups (55% vs. 54%; OR 1.02, 95% CI 0.57–1.85; p = 1.00), whereas identified lower GI bleeding (LGIB) was numerically less frequent in DOAC monotherapy (34% vs. 49%; OR 0.53, 95% CI 0.29–0.97; p = 0.047), an association that was attenuated and no longer significant after adjustment for age and sex (p = 0.076). Restricting to patients who underwent oesophagogastroduodenoscopy (EGDS), the diagnostic yield was substantially lower in DOAC monotherapy (72% vs. 91%; adjusted OR 0.25, 95% CI 0.08–0.79; p = 0.018). DOAC-treated patients presented with lower haemoglobin (7.9 ± 2.4 vs. 9.3 ± 2.9 g/dL; adjusted β = −1.32 g/dL, p = 0.002) and required transfusion more frequently (68% vs. 49%; adjusted OR 2.50, 95% CI 1.29–4.83; p = 0.007). No statistically significant differences were detected among the four DOAC molecules for site of bleeding or specific lesion, although this analysis was substantially underpowered. Conclusions: In a real-world emergency cohort, DOAC and ASA monotherapy were associated with a comparable proportion of upper GI bleeding, while identified LGIB was numerically less frequent in DOAC users. DOAC users presented with lower haemoglobin and more frequently required transfusion, despite a lower diagnostic yield at EGDS. Among the four DOAC molecules, no significant differences emerged. In sensitivity analyses, the lower identified-LGIB frequency and the higher transfusion burden in DOAC users were attenuated and no longer statistically significant when the analysis was restricted to fully evaluated patients or when count-based and comorbidity-adjusted models were applied. Further studies are warranted to clarify the anatomical distribution of bleeding sources in DOAC users with negative initial endoscopy. Full article

Background/Objectives: Ibrutinib is an established treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but its use commonly occurs in older patients with polypharmacy, cardiovascular comorbidity and infection vulnerability. CYP3A-modifying drugs and antithrombotic agents are clinically actionable co-exposure domains because they may alter ibrutinib exposure, bleeding risk or the management of atrial arrhythmia. This study evaluated post-marketing reporting patterns for these co-exposures in FAERS. Methods: Adult FAERS reports through 25Q2 with ibrutinib exposure and CLL/SLL-compatible indications were analyzed after false-positive indication captures were removed. Co-exposures were defined at report level using prespecified drug dictionaries, and grouped adverse-event reporting was evaluated using reporting odds ratio, proportional reporting ratio, chi-square and an information-component-style two-by-two metric. Results: The final cohort comprised 20,878 adult CLL/SLL + ibrutinib reports. CYP3A modifier co-exposure was present in 1373 reports (6.6%), and antithrombotic co-exposure in 3701 reports (17.7%). Antithrombotic exposure increased with age, from 9.8% in reports aged 18–64 years to 23.2% in reports aged ≥75 years. CYP3A modifier exposure was associated with enriched reporting of infection and cytopenia phenotypes, particularly severe infection-like events with CYP3A inhibitors and inducers. Antithrombotic exposure showed consistent reporting enrichment for atrial arrhythmia, bleeding and major bleeding-like events, with the strongest grouped signals among anticoagulant-exposed reports. Overlap analyses showed that the co-exposure domains were not mutually exclusive. Conclusions: These findings should be interpreted as reporting disproportionality rather than incidence or causal risk, but they support prioritizing CYP3A-modifying drugs and antithrombotic therapy during medication reconciliation, interaction screening and risk mitigation in older patients receiving ibrutinib. Full article

Warfarin is a coumarin-derived oral anticoagulant widely used for the prevention and treatment of thromboembolic disorders, particularly in patients with mechanical heart valves. The drug exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, thereby impairing γ-carboxylation of vitamin K-dependent coagulation factors. Despite its clinical efficacy, warfarin therapy is associated with a narrow therapeutic index, substantial interindividual variability in dose response, numerous drug interactions, and significant hemorrhagic risk. Maternal warfarin therapy during pregnancy is strongly associated with fetal warfarin syndrome (FWS), a characteristic pattern of embryopathy resulting from in utero exposure to the drug. This review summarizes current knowledge regarding the physicochemical properties, pharmacological mechanisms, dose variability, toxicity, and developmental effects associated with warfarin exposure. Evidence from human clinical studies and vertebrate animal models is discussed to elucidate conserved developmental and molecular mechanisms underlying warfarin teratogenicity. The review also examines the signaling pathways disrupted by warfarin exposure, highlighting that its teratogenic effects extend beyond anticoagulation to the disruption of vitamin K-dependent developmental signaling. Inhibition of γ-glutamyl carboxylation, together with alterations in Gas6/TAM, PXR, Ras, and Wnt/β-catenin signaling pathways, impairs skeletal, vascular, and neural development, contributing to the characteristic abnormalities of fetal warfarin syndrome. Collectively, this review integrates clinical, molecular, and experimental findings to provide a comprehensive understanding of warfarin-induced developmental toxicity. Current knowledge is insufficient to fully elucidate the complex mechanisms underlying warfarin-induced embryopathy and fetal toxicity. Further investigations are warranted to identify safer anticoagulant regimens during pregnancy and to inform the development of novel therapeutic strategies that minimize fetal risk while maintaining maternal anticoagulation. Full article

Background: Warfarin remains widely used in specific clinical situations. Its management is complicated by multiple factors that affect anticoagulant response, particularly during the early period after hospital discharge. This study examined the prevalence, patterns, and factors associated with nontherapeutic international normalized ratio (INR) among patients discharged on warfarin from a tertiary-care hospital. Methods: Electronic health records of adult patients discharged home with warfarin who had at least one INR measurement within 90 days (N = 1222) were retrospectively analyzed. Nontherapeutic INR was defined as INR outside the therapeutic range: 2.5–3.5 for mitral valve replacement and 2.0–3.0 otherwise. All available INR measurements were included. Major warfarin potential drug–drug interactions (pDDIs) were defined as DDIs with major severity according to the Micromedex^® database. Factors associated with nontherapeutic INR were examined using repeated-measures generalized estimating equations (GEEs), with generalized linear mixed models (GLMMs) as confirmatory analyses. Results: Of 3704 INR measurements within 90 days after discharge, 49.4% were subtherapeutic, while 30.5% were therapeutic and 20.1% were supratherapeutic. The proportion of therapeutic INR values did not show a substantial improvement over time. In GEEs, discharge from surgical service (adjusted odds ratio (aOR) 1.24, 95%CI: 1.05–1.48, p = 0.014) and presence of major warfarin pDDIs at discharge (aOR 1.36, 95%CI: 1.11–1.67, p = 0.003) were associated with nontherapeutic INR. GLMM analyses produced consistent results with the GEE model. Conclusions: Suboptimal INR control was prevalent within 90 days post-discharge. Discharge from surgical services and presence of major warfarin pDDIs at discharge were associated with nontherapeutic INRs. Major warfarin pDDIs may serve as markers of medication complexity at discharge and may help identify patients requiring closer anticoagulation monitoring. Full article

Natural products featuring a direct σ-bond between a cyclic monoterpene and an aromatic moiety provide a vast source of biological activities, such as antimicrobial, anticancer, antiviral, anticoagulant and cannabinoid regulatory, among others. Only few methods exist for synthetically accessing such hybrid structures and their analogs, all of which are prone to limitations, most notably the reliance on sensitive organometallic intermediates and the difficulty in furnishing certain stereoisomers. An efficient, three-stage synthetic methodology is described herein, that enables the production of hybrid structures featuring a C(sp³)-C(sp²) bond between six-membered cyclic monoterpenes and aromatic moieties. This process combines: enol triflate formation from a terpenoid ketone precursor, that introduces most of the stereochemical information; Suzuki–Miyaura C-C cross-coupling of the enol triflate with a pool of (hetero)arylboronic acids, to establish the terpene–aromatic link, initially in the form of a C(sp²)-C(sp²) bond; and a stereoselective hydrogenation of the resulting adducts to afford the target compounds, establishing the stereoconfiguration of the last chiral center. Enantiomeric terpenoid scaffolds derived from menthone and trans-tetrahydrocarvone have been combined with six (6) (hetero)arylboronic acids, including medicinally relevant moieties, such as methoxyphenyl, pyridine, quinoline and benzofuran. The power of this method, apart from circumventing the need for in situ-formed sensitive organometallic intermediates, resides in providing access, for the first time, to menthyl- and trans-tetrahydrocarvoneyl-type stereoisomers, that were unattainable by any previously described method. The resulting compound library members exhibit drug-like features, based on the computational assessment of 11 selected physicochemical parameters (molecular weight, polarity, aqueous solubility, degree of unsaturation, conformational flexibility, lipophilicity, BBB permeability, skin permeability, gastrointestinal absorption, P-glycoprotein substrate behavior and Lipinski compatibility), using the platforms SwissADME, ADMETLab 3.0 and pkCSM. A computational docking study employing AutoDock Vina further identified promising candidates for targeting the known binding sites of human cannabinoid receptors CB1 and CB2, with calculated binding affinities comparable to those of established ligands. Full article

Thromboembolism is a life-threatening complication of nephrotic syndrome, which is treated with oral anticoagulants (warfarin and direct oral anticoagulants [DOACs]) that possess a variety of pharmacokinetic characteristics. This narrative review focused on drug–drug interactions between oral anticoagulants and calcineurin inhibitors (CNIs) (e.g., tacrolimus, cyclosporine, and voclosporin) for the management of thromboembolism in nephrotic syndrome. While warfarin has less potential for interacting with CNIs, DOACs carry a risk of drug–drug interactions with CNIs owing to the inhibition of drug-metabolizing enzymes and transporters, including cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. Specifically, a significant increase in DOAC exposure was observed when DOACs were co-administered with cyclosporine, a more potent P-glycoprotein inhibitor than tacrolimus. Limited evidence suggests that more pronounced drug interactions occur in specific cases: (1) apixaban and CNIs in patients with renal impairment, (2) edoxaban combined with cyclosporine in patients with renal impairment, and (3) a combination of rivaroxaban with dual inhibitors of P-glycoprotein and CYP3A4 (e.g., cyclosporine and fluconazole). From a pharmacological viewpoint, CNI-induced nephrotoxicity and hypertension may increase the risk of critical bleeding in patients receiving DOACs. In addition, the variation factors of pharmacokinetic parameters, such as renal function, pharmacogenomic profiles, and pathophysiological changes directly caused by nephrotic syndrome, may vary between patients, which could potentially augment the magnitude of drug–drug interactions between oral anticoagulants and CNIs. Further studies are required to understand the clinical significance of drug interactions in patients with nephrotic syndrome. Full article

Oral administration of narrow therapeutic index anticoagulants like phenprocoumon (PHP) necessitates careful control of the kinetic release of the drug to avoid dose dumping and severe haemorrhagic effects. This study was carried out to prepare and characterize novel PHP delivery systems based on κ-carrageenan hydrogels, exploring the importance of potassium ion (K⁺) stabilization in controlling the release process. FT-IR, TG/DTG, and in vitro release studies were employed in combination with a new validated RP-HPLC assay. FT-IR and thermal analysis results showed that PHP is physically encapsulated into the polysaccharide matrix, where there are no chemical incompatibilities between them. Furthermore, potassium ions increase the stability and heat resistance of the polymer network. However, when K⁺ was considered for modelling the kinetic release using the Korsmeyer–Peppas equation, it was observed that PHP is released from the K⁺ stabilized matrix in a relaxation dominated diffusion-controlled transport. Ionic cross-linking effectively reduces the initial burst effect, demonstrating that these matrices are promising vehicles for the sustained delivery of phenprocoumon. Full article

Bleeding is one of the most common and feared complications after coronary angiography and percutaneous coronary intervention (PCI). It is associated with longer hospital stays, higher mortality, and worse clinical outcomes. As the number of patients at high bleeding risk (HBR) continues to grow, preventing bleeding has become an important part of PCI management. This practical review summarizes current evidence on how to assess bleeding risk and reduce bleeding before, during, and after PCI. Several tools, including the BARC classification, ARC-HBR criteria, PRECISE-DAPT, and DAPT scores, help identify patients who may benefit from tailored treatment. Current strategies include the use of radial access, optimized anticoagulation, appropriate selection of antiplatelet therapy, newer-generation drug-eluting stents, and shorter durations of dual antiplatelet therapy in selected HBR patients. We also discuss the management of patients with atrial fibrillation requiring oral anticoagulation, as well as those with anemia or thrombocytopenia. Although significant progress has been made, several questions remain unanswered, particularly regarding transfusion thresholds, antithrombotic therapy in complex patients, and the best balance between bleeding and ischemic risks. Ongoing clinical trials are expected to provide further evidence and help improve the management of patients undergoing PCI. Full article

Background/Objectives: Alcohol consumption and medication use have increased among older population, potentially increasing the risk of alcohol–drug interactions and adverse outcomes. Biological sex differences may further influence these effects. This study aimed to assess sex-related differences in medication use, comorbidities, and hepatic biomarkers among older adults with risky alcohol consumption. Methods: A cross-sectional, multicenter study was conducted in 455 adults aged ≥65 years. Sociodemographic and clinical characteristics, medication prescriptions, and hepatic biomarkers were collected. Results: Of the participants, 41% were women, with a mean age of 71 years. The median weekly alcohol consumption was 7 standard drink units. Overall, 90% were taking at least one medication, with antihypertensives being the most prescribed (62%). Significant sex differences were observed (p ≤ 0.01): men showed higher use of antidiabetic drugs (24%), anticoagulants (8%), and nitrates (4%), whereas women more frequently used anxiolytics (35%), non-steroidal anti-inflammatory drugs (22%), and antidepressants (18%). Although risky alcohol consumption was more prevalent among men, women had a higher overall medication use. Significant differences were also observed in hepatic biomarkers, with higher gamma-glutamyl transferase levels and a higher prevalence of elevated FIB-4 values among men (p ≤ 0.01). Conclusions: These findings highlight the importance of routinely assessing alcohol consumption and medication use in older adults and support incorporating a sex-specific perspective into clinical practice and future research. Full article

Factor Xa (FXa) remains an important target in the development of anticoagulant and antithrombotic agents. In this study, twenty isosteviol-derived oxime ether analogs previously reported as FXa inhibitors were used to develop a predictive QSAR model. The compounds were geometry-optimized at the B3LYP/6-311++G(d,p) level, and Dragon molecular descriptors were calculated from the optimized structures. After descriptor filtering, Random Forest-based supervised preselection and correlation-based pruning were applied. Several models of increasing complexity were evaluated, including multiple linear regression, additive MARSplines, and constrained second-order MARSplines models. The final model employed four active basis functions involving R6p+, C-025, ATSC7e, and Mor31p and demonstrated excellent calibration and cross-validated predictive ability (R² = 0.929 and Q²_LOO = 0.865). Based on this model, twenty new isosteviol-derived analogs were designed and their activities were predicted after DFT optimization and descriptor calculation. Eight representative compounds were subsequently subjected to molecular docking against human factor Xa (PDB ID: 2P16), molecular dynamics simulations, MM/GBSA binding free energy calculations, and preliminary SwissADME/pkCSM profiling. Docking protocol validation yielded a redocking RMSD of 0.953 Å. Although ISV-M20 was the highest-ranked compound according to the QSAR model, subsequent receptor-based analyses identified ISV-M19, ISV-M04, and ISV-M06 as the derivatives with the most favorable combination of structural stability, persistent protein–ligand interactions, and binding free energies. The ADMET/toxicity screen further refined this prioritization: ISV-M19, ISV-M04, and ISV-M06 showed the most favorable preliminary toxicity balance among the prioritized derivatives, whereas ISV-M20 displayed additional developability liabilities, including very high lipophilicity, poor predicted solubility, P-gp substrate status, and a predicted hERG II alert. Overall, the results demonstrate that integrating interpretable QSAR modeling with receptor-based simulations and early ADMET/toxicity filtering provides a more balanced strategy for the rational design and prioritization of novel isosteviol-derived FXa inhibitors than any single computational approach alone. Full article

Heparin, the naturally occurring, highly sulfated glycosaminoglycan drug, acts as a regulator of diverse biological processes by interacting with diverse specific proteins through a variety of sulfated structural motifs with varying degrees of affinity. Despite its rarity, 3-O-sulfation of glucosamine plays a key role in several biological activities, especially anticoagulant activity mediated by interaction with antithrombin (AT), a mechanism that has been extensively studied. The present work primarily focuses on sequences containing 3-O-sulfated glucosamine that are not involved in anticoagulant activity, analysing their relative abundance and structural environments in heparins derived from distinct animal origins. Three heparin samples derived from bovine, ovine and porcine intestinal mucosa (BMH, OMH and PMH) were fractionated by affinity chromatography on AT-Sepharose into no affinity (NA) and high affinity (HA) fractions. Parent heparins and derived NA and HA fractions were enzymatically depolymerised using either a cocktail of heparinases I, II and III or heparinase II alone, and the resulting mixtures of di- and oligosaccharides were analysed by liquid chromatography coupled with mass spectrometry. Digestion with heparinase II, which preserves heparin sequences containing 3-O-sulfated glucosamine, produced a series of 3-O-sulfated trisaccharides containing two glucosamine residues either side of a uronic acid, located at the non-reducing end (NRE) of heparin chains. Treatment with a heparinase cocktail, which cleaves these trisaccharides, released NRE glucosamine monosaccharides, including 3-O-sulfated species. Notably, both the number of NRE trisaccharide species and the overall proportion of 3-O-sulfated monosaccharides were markedly higher in OMH compared to BMH or PMH. Using ¹H/¹³C bi-dimensional nuclear magnetic resonance spectroscopy, the higher proportion of NRE 3-O-sulfated glucosamine in ovine heparin relative to bovine and porcine heparins was found to be preferentially located in chains lacking affinity for AT. These results offer new insights into the localisation of most 3-O-sulfated heparin sequences that are not associated with anticoagulant activity and, importantly, also reveal a possible structural marker that indicates the ovine origin of heparin. Additionally, a tetrasaccharide species was detected that may be indicative of a highly sulfated AT-binding site in BMH. Full article

Glycosaminoglycans (GAGs) are the carbohydrate portion of proteoglycans (PGS), a family of complex biomacromolecules ubiquitously found in the extracellular matrix and on cell surfaces that play critical roles in a plethora of physiological and pathological processes. In the present work, chondroitin sulfate (CS) and dermatan sulfate (DS) were extracted and purified from the head (GCB) and skin (GDB) of blue runner fish (Caranx crysos) to explore their structural features and biological properties. GCB and GDB were purified by ion-exchange chromatography with yields of 0.82% and 0.61%, respectively. Chemical and structural analysis showed that GCB and GDD demonstrated quite similar sulfation degrees (4.45% and 4.24%, respectively). The molecular weight values obtained for GCB and GDB as estimated by high-performance size exclusion chromatography coupled with a triple detector array (HP-SEC-TDA) were 48.9 and 28.54 KDa, respectively. Structural features were elucidated using FT-IR and 2D NMR spectroscopy. GCB was mainly identified as chondroitin sulfate, containing 82% GlcA and minor proportions of IdoA and IdoA2S (scoring 18% dermatan-like structures). In contrast, GDB was predominantly dermatan sulfate, with a higher unsulfated IdoA content (54%) and a lower GlcA percentage (17%). In vitro anticoagulant activity, evaluated using APTT and PT assays, demonstrated that both GAGs exhibit significant anticoagulant potential. In addition, both fractions exhibited no antiplatelet activity, suggesting that the isolated glycosaminoglycans selectively target the coagulation cascade without affecting platelet aggregation. Furthermore, hemolytic assays confirmed that neither GCB nor GDB showed any hemolytic activity at the tested concentrations. Cytotoxicity assessment in HEK293 and HUVEK cell lines further confirmed the absence of detectable toxicity even at high concentration. Overall, these marine-derived GAGs present promising therapeutic potential as a source of anticoagulant drugs. Full article

Factor Xa (FXa) remains a clinically validated and chemically tractable anticoagulant target despite the therapeutic role of direct oral FXa inhibitors. Contemporary FXa inhibitor literature, however, is heterogeneous in scaffold design, endpoint reporting, assay consistency, translational depth, and suitability for computer-aided drug design (CADD). This review evaluates published series of small-molecule FXa inhibitors through a framework that combines translational structure–activity relationships (SARs), assay-aware data quality, and QSAR-readiness. A structured narrative synthesis focused mainly on post-2014 studies reporting discrete small-molecule or semisynthetic FXa inhibitors. Eligible series were classified as fully synthetic or natural-product-derived/semisynthetic chemotypes, and extraction covered scaffold architecture, potency endpoints, assay context, selectivity, clotting or antithrombotic readouts, PK/ADME, structural clarity, translational context, and extraction confidence. QSAR-readiness was assessed using analog density, congenericity, endpoint quality, assay comparability, activity range, structural interpretability, and curation burden. Fully synthetic chemotypes, particularly anthranilamide-derived and related scaffolds, provided the most coherent and modellable FXa datasets, whereas natural-product-derived and semisynthetic series expanded structural diversity. Many exploratory series, however, were limited by small analog sets, heterogeneous endpoints, incomplete translational characterization, narrow activity ranges, or higher curation burden. The practical value of published FXa inhibitor series, therefore, depends not only on potency but also on whether chemical and biological information can be reconstructed with confidence for reproducible SAR interpretation, local QSAR modeling, AI/ML-enabled CADD reuse, and clinical benchmark-aware prioritization. The QSAR-readiness framework is a critical triage tool, not a substitute for formal validation, distinguishing datasets suitable for curated local modeling from those better suited to qualitative SAR, scaffold inspiration, or translational hypotheses. Full article

Background/Objectives: As population aging increases the prevalence of atrial fibrillation (AF), the use of direct oral anticoagulants (DOACs) has expanded for thromboembolism prevention. Although DOACs offer advantages over vitamin K antagonists (VKAs), gastrointestinal bleeding (GIB) remains the most common extracranial adverse event. Current guidelines address global bleeding risk but provide limited guidance on site-specific gastrointestinal risk assessment and prevention. This narrative review aims to summarize current evidence on the mechanisms, etiologies, and risk factors for DOAC-associated gastrointestinal bleeding and to propose a pragmatic, risk-based framework to support clinicians in individualized bleeding prevention. Methods: A narrative review of studies published between 2004 and 2025 was conducted, including randomized clinical trials, real-world evidence, meta-analyses, and major society guidelines. Evidence addressing DOAC safety profiles, gastrointestinal bleeding etiologies, patient-level risk factors, medication interactions, and preventive strategies was analyzed. Results: Gastrointestinal bleeding in patients treated with DOAC is strongly influenced by underlying gastrointestinal pathology, comorbid conditions, and concomitant medications. Established risk factors include prior gastrointestinal hemorrhage, Helicobacter pylori infection, gastrointestinal malignancy, diverticulosis, and angiodysplasia, as well as the use of nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet therapy, or selective serotonin reuptake inhibitors (SSRIs). DOACs differ in gastrointestinal safety: apixaban consistently demonstrates the most favorable profile, whereas rivaroxaban and high-dose dabigatran show higher GIB rates. Preventive strategies such as H. pylori testing and eradication, proton pump inhibitor use in high-risk individuals, avoidance of NSAIDs and unnecessary antiplatelet therapy, and individualized DOAC selection may help reduce bleeding risk. Conclusions: Gastrointestinal bleeding risk in patients receiving DOAC therapy should be assessed using a site-specific and dynamic approach. A structured strategy integrating baseline risk evaluation, correction of modifiable factors, tailored anticoagulant selection, and risk-adapted follow-up may improve the safety of anticoagulation. The proposed framework may provide a pragmatic approach to individualized bleeding risk mitigation while preserving the benefits of DOAC therapy; however, prospective validation is required before its routine implementation can be recommended. Full article