Search Results (55)

Background: While anticoagulant and antiplatelet therapies are commonly combined in clinical settings, this combination increases the risk of hemorrhage. However, comparative data on the bleeding risks of different drug combinations remain limited. This study assesses hemorrhage risk associated with various anticoagulant–antiplatelet combinations using data from the USFDA Adverse Event Reporting System (AERS). Methods: Hemorrhage-related reports were extracted from the AERS database (March 2004–June 2024). Anticoagulants analyzed included warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, betrixaban, and acenocoumarol; antiplatelets included aspirin, clopidogrel, ticagrelor, cilostazol, prasugrel, and dipyridamole. Disproportionality analysis using frequentist and Bayesian approaches was conducted to detect hemorrhage signals. Results: Out of 160,715 hemorrhage reports, rivaroxaban, warfarin, and apixaban were the most frequently reported anticoagulants, while aspirin and clopidogrel were the top antiplatelets. Apixaban had the lowest reporting odds ratio for hemorrhage. The rivaroxaban-aspirin combination showed the highest hemorrhage risk, while combinations with cilostazol were the lowest. Apixaban, alone and in combination, was associated with reduced hemorrhage and mortality risks. Conclusions: Combining anticoagulants with antiplatelets increases hemorrhage and mortality risk. While our findings highlight potential safety signals related to hemorrhage with antithrombotic drug combinations, they remain hypothesis-generating and should not be interpreted as causal associations. Instead, they provide an initial basis for further validation in well-designed clinical cohorts where comorbidities can be adequately accounted for. Full article

Oral administration of dipyridamole (DIP) with acetylsalicylic acid (ACA) is recommended in thromboembolic conditions or for the treatment of myocardial infarction and stroke. The present study presents an alternative dosage form of these two active ingredients, consisting of a honey core and a dark chocolate coating. The composition masks the bitter taste, is palatable and ensures compliance of a wide range of patients, mainly pediatric. For the simultaneous quantitative determination of the analytes, a Diode Array Detector/Fluorescence Detector (HPLC-DAD/FLD) method was used with a C18 column (250 mm × 4.6 mm, 5 μm) and an isocratic two-phase system (A: H₂O 0.2% formic acid—B: Acetonitrile-H₂O 90:10 v/v) 65:35 v/v. The method was validated according to ICH guidelines (r² > 0.999, RSD < 2.3%, % Recovery > 95.4%), and a stability study of the two active ingredients as well as salicylic acid (SAL), which is a hydrolysis product of ACA, was followed. Finally, a digestion protocol (oral cavity–stomach–intestine) for edible materials was applied to determine the release rate of ACA, DIP and SAL in the gastrointestinal tract, while an in vitro permeability study (P_app) was subsequently performed in Franz cells. The results show satisfactory behavior of ACA and DIP and provide a trigger for further studies of the formulation. Full article

Introduction. Many pharmacological properties of dipyridamole (DIP) are associated with its ability to inhibit phosphodiesterases (PDEs). Actually, DIP has interesting properties like antiviral for influenza, SARS-2 COVID-19, and herpesviruses. Our research aimed to design and synthesize the dynamic combinatorial DIP derivatives with more pronounced inhibiting properties in relation to PDE and to carry out the HPLC analysis of the resulting combinatorial derivatives of DIP. This study is aimed at investigating the effect of the dynamic derivative of dipyridamole (DDD) on intestinal dysbiosis syndrome in mice caused by streptomycin against the background of cyclophosphamide-induced cellular immunodeficiency. Materials and methods. For the synthesis of a dynamic combinatorial derivative of dipyridamole, we used a molecular dynamic method for drug design and combinatorial acylation of dipyridamole by succinic and acetic anhydride in different molar ranges of acylation agents. Combinatorial derivatives were analyzed using gradient HPLC with a UV detector. Also, derivatives established the inhibition ability for phosphodiesterase by the spectrophotometric method. Also, we used an in vivo mouse model with immunodeficiency caused by cyclophosphamide for pharmacological study. Results and discussion. Molecular modeling suggests that 18 different dipyridamole derivatives can self-assemble into a stable supramolecular structure with lower total energy. Specific combinatorial molar ratios of the synthesis components were necessary to create a new supramolecular compound with enhanced pharmacological properties. The inhibition of phosphodiesterase in such a dynamic combinatorial derivative already appeared at a concentration of 0.05 μM. In mice with colitis caused by streptomycin treatment, the administration of DDD per os resulted in an antidiarrheal effect and prevention of the animals’ weight loss. Given the cyclophosphamide-induced immunosuppression and streptomycin-associated diarrhea, immunity was completely restored only under the action of DDD. Conclusions. The most effective dipyridamole derivative for phosphodiesterase inhibition was formed only if the number of different derivatives in solution was maximum and consisted of all 18 molecules. With other quantities of modifiers, there was no qualitative change in the inhibitory activity of the combinatorial mixture against phosphodiesterase. According to all parameters, DDD has been proven to be more effective than the pure dipyridamole reference product. Full article

Resorbable medical devices provide temporary functionality before degrading into safe byproducts. One application is absorbable inferior vena cava filters (IVCFs), which prevent pulmonary embolism in high-risk patients with contraindications to anticoagulants. However, current absorbable IVCFs are limited by radiolucency and local clot formation risks. This study aimed to develop radiopaque, drug-loaded resorbable IVCFs with enhanced imaging and therapeutic capabilities. Poly-p-dioxanone (PPDO) sutures were infused with gadolinium nanoparticles (GdNPs) and dipyridamole (DPA), an anti-thrombotic agent. GdNPs were synthesized with an average diameter of 35.76 ± 3.71 nm. Gd content was 371 ± 1.6 mg/g (PPDO-Gd) and 280 ± 0.3 mg/g (PPDO-Gd + DPA), while the DPA content was 18.20 ± 5.38 mg/g (PPDO-DPA) and 12.91 ± 0.83 mg/g (PPDO-Gd + DPA). Suture thickness (0.39–0.49 cm, p = 0.0143) and melting temperature (103.61–105.90, p = 0.0002) statistically differed among the different groups, while load-at-break did not (4.39–5.38, p = 0.2367). Although suture thickness and melting temperatures differed significantly, load-at-break was preserved and did not alter the mechanical and degradation properties of the various IVCFs. Micro-computed tomography revealed enhanced radiopacity for Gd-containing IVCFs (2713 ± 105 HU for PPDO-Gd, 1516 ± 281 HU for PPDO-Gd + DPA). Radiopacity decreased gradually over 10–12 weeks. Clot-trapping efficacy was maintained, and no hemolysis or cellular toxicity was observed. In conclusion, the GdNP- and DPA-infused PPDO IVCFs demonstrated improved radiopacity, anti-thrombotic potential, and compatibility with routine imaging, without compromising mechanical strength or safety. Full article

Background: Platelets have been shown to promote ovarian cancer; however, the mechanism is poorly understood. Previously, we demonstrated that platelets reduce the size and increase the density of multi-cellular ovarian cancer spheroids in cell cultures. The objectives of this study were to determine if platelet inhibitors could counteract these effects, and to explore the mechanisms involved. Methods: FDA-approved platelet inhibitors were screened for their abilities to alter platelet effects on ovarian cancer spheroids. Mass spectrometry was used to identify proteins significantly altered in cancer cells upon exposure to platelets. The effects of platelets and/or liver x receptor agonists or antagonists on LXR activity were measured using ES-2 ovarian cancer cells transduced with an LXR-reporter vector. Results: Eptifibatide, a GPIIB-IIIA integrin inhibitor, and dipyridamole, an adenosine reuptake inhibitor, reduced and enhanced platelet effects on ovarian cancer spheroids, respectively. Proteomic studies identified the LXR/RXR and integrin pathways as mediators of platelet effects on ovarian cancer, and downstream effectors of eptifibatide. Conclusions: Integrin pathways and their downstream LXR/RXR effectors are implicated in how platelets alter ovarian cancer spheroid morphology. These results support studying eptifibatide and LXR/RXR agonists as candidate drugs for repurposing as therapeutic strategies to counteract platelet promotion of ovarian cancer. Full article

A new molecularly imprinted polymer (MIP)-based disposable electrochemical sensor for dipyridamole (DIP) determination was obtained. The sensor was rapidly prepared by potentiodynamic electrochemical polymerization on a pencil graphite electrode (PGE) using curcumin (CUR) as a functional monomer and DIP as a template molecule. After the optimization of the conditions (pH, monomer–template ratio, scan rate, number of cyclic voltammetric cycles applied in the electro-polymerization process and extraction time of the template molecule) for MIP formation, DIP voltammetric behavior at the modified electrode (MIP_PGE) was investigated. DIP oxidation took place in a pH-dependent, irreversible mixed diffusion-adsorption controlled process. Differential pulse voltammetry (DPV) and adsorptive stripping differential pulse voltammetry (AdSDPV) were used to quantify DIP from pharmaceutical and tap water samples. Under optimized conditions (Britton–Robinson buffer at pH = 3.29), the obtained linear ranges were 5.00 × 10⁻⁸–1.00 × 10⁻⁵ mol/L and 5.00 × 10⁻⁹–1.00 × 10⁻⁷ mol/L DIP for DPV and AdSDPV, respectively. The limits of detection of the methods were 1.47 × 10⁻⁸ mol/L for DPV and 3.96 × 10⁻⁹ mol/L DIP for AdSDPV. Full article

The role of immune system components in the development of myocardial remodeling in chronic kidney disease (CKD) and kidney transplantation remains an open question. Our aim was to investigate the associations between immune cell subpopulations in the circulation of CKD patients and kidney transplant recipients (KTRs) with subclinical indices of myocardial performance. We enrolled 44 CKD patients and 38 KTRs without established cardiovascular disease. A selected panel of immune cells was measured by flow cytometry. Classical and novel strain-related indices of ventricular function were measured by speckle-tracking echocardiography at baseline and following dipyridamole infusion. In CKD patients, the left ventricular (LV) relative wall thickness correlated with the CD14++CD16− monocytes (β = 0.447, p = 0.004), while the CD14++CD16+ monocytes were independent correlates of the global radial strain (β = 0.351, p = 0.04). In KTRs, dipyridamole induced changes in global longitudinal strain correlated with CD14++CD16+ monocytes (β = 0.423, p = 0.009) and CD4+ T-cells (β = 0.403, p = 0.01). LV twist and untwist were independently correlated with the CD8+ T-cells (β = 0.405, p = 0.02 and β = −0.367, p = 0.03, respectively) in CKD patients, whereas the CD14++CD16+ monocytes were independent correlates of LV twist and untwist in KTRs (β = 0.405, p = 0.02 and β = −0.367, p = 0.03, respectively). Immune cell subsets independently correlate with left ventricular strain and torsion-related indices in CKD patients and KTRs without established CVD. Full article

This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies were conducted to select the oil, surfactant, and co-surfactant. Phase diagrams were constructed using the aqueous phase titration method. All the formulations were in nanoscale, and Formula (F2) (which contains oleic acid oil as the oil phase, a mixture of Surfactant Tween 80 and co-surfactant (ethanol) at a ratio of 1:2 in addition to distilled water as an aqueous phase in a ratio of 1:5:4, respectively) was the selected formula depending on the particle size, PDI, and zeta potential. Formula (F2) has the best ratio because it gives the smallest nanoemulsion globule size (particle size average of 167.1 nm), the best homogenicity (lowest PDI of 0.195), and the highest stability (higher zeta potential of −32.22). The selected formula was converted into a nanoemulgel by the addition of 0.5% (w/w) xanthan gum (average particle size of 172.7 nm) and the best homogenicity (lowest PDI of 0.121%) and highest stability (higher zeta potential of −28.31). In conclusion, the selected formula has accepted physical and chemical properties, which enhanced skin penetration. Full article

Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this context, the modulation of adenosine signaling pathways has emerged as a promising therapeutic option, encouraging osteoblast activation and tempering osteoclast differentiation. A literature review of the PubMed database with relevant keywords was conducted. The search criteria involved in vitro or in vivo models, with clear methodological descriptions. Only studies that included the use of indirect adenosine agonists, looking at the effects of bone regeneration, were considered relevant according to the eligibility criteria. A total of 29 articles were identified which met the inclusion and exclusion criteria, and they were reviewed to highlight the preclinical translation of adenosine agonists. While preclinical studies demonstrate the therapeutic potential of adenosine signaling in bone regeneration, its clinical application remains unrealized, underscoring the need for further clinical trials. To date, only large, preclinical animal models using indirect adenosine agonists have been successful in stimulating bone regeneration. The adenosine receptors (A₁, A_2A, A_2B, and A₃) stimulate various pathways, inducing different cellular responses. Specifically, indirect adenosine agonists act to increase the extracellular concentration of adenosine, subsequently agonizing the respective adenosine receptors. The agonism of each receptor is dependent on its expression on the cell surface, the extracellular concentration of adenosine, and its affinity for adenosine. This comprehensive review analyzed the multitude of indirect agonists currently being studied preclinically for bone regeneration, discussing the mechanisms of each agonist, their cellular responses in vitro, and their effects on bone formation in vivo. Full article

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC₅₀) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility. Full article

Three-dimensional printing (3DP) technology has revolutionized the field of the use of bioceramics for maxillofacial and periodontal applications, offering unprecedented control over the shape, size, and structure of bioceramic implants. In addition, bioceramics have become attractive materials for these applications due to their biocompatibility, biostability, and favorable mechanical properties. However, despite their advantages, bioceramic implants are still associated with inferior biological performance issues after implantation, such as slow osseointegration, inadequate tissue response, and an increased risk of implant failure. To address these challenges, researchers have been developing strategies to improve the biological performance of 3D-printed bioceramic implants. The purpose of this review is to provide an overview of 3DP techniques and strategies for bioceramic materials designed for bone regeneration. The review also addresses the use and incorporation of active biomolecules in 3D-printed bioceramic constructs to stimulate bone regeneration. By controlling the surface roughness and chemical composition of the implant, the construct can be tailored to promote osseointegration and reduce the risk of adverse tissue reactions. Additionally, growth factors, such as bone morphogenic proteins (rhBMP-2) and pharmacologic agent (dipyridamole), can be incorporated to promote the growth of new bone tissue. Incorporating porosity into bioceramic constructs can improve bone tissue formation and the overall biological response of the implant. As such, employing surface modification, combining with other materials, and incorporating the 3DP workflow can lead to better patient healing outcomes. Full article

Human serum alpha-1-acid glycoprotein (AAG) is an acute-phase plasma protein involved in the binding and transport of many drugs, especially basic and lipophilic substances. The sialic acid groups that terminate the N-glycan chains of AAG have been reported to change in response to numerous health conditions and may have an impact on the binding of drugs to AAG. In this study, we quantified the binding between native and desialylated AAG and seven drugs from different pharmacotherapeutic groups (carvedilol, diltiazem, dipyridamole, imipramine, lidocaine, propranolol, vinblastine) using microscale thermophoresis (MST). This method was chosen due to its robustness and high sensitivity, allowing precise quantification of molecular interactions based on the thermophoretic movement of fluorescent molecules. Detailed glycan analysis of native and desialylated AAG showed over 98% reduction in sialic acid content for the enzymatically desialylated AAG. The MST results indicate that desialylation generally alters the binding affinity between AAG and drugs, leading to either an increase or decrease in K_d values, probably due to conformational changes of AAG caused by the different sialic acid content. This effect is also reflected in an increased denaturation temperature of desialylated AAG. Our findings indicate that desialylation impacts free drug concentrations differently, depending on the binding affinity of the drug with AAG relative to human serum albumin (HSA). For drugs such as dipyridamole, lidocaine, and carvedilol, which have a higher affinity for AAG, desialylation significantly changes free drug concentrations. In contrast, drugs such as propranolol, imipramine, and vinblastine, which have a strong albumin binding, show only minimal changes. It is noteworthy that the free drug concentration of dipyridamole is particularly sensitive to changes in AAG concentration and glycosylation, with a decrease of up to 15% being observed, underscoring the need for dosage adjustments in personalized medicine. Full article

To improve the efficacy over antiplatelet monotherapy, dual antiplatelet therapy (DAPT) has been increasingly adopted in the management of non-cardioembolic stroke. For minor ischemic stroke and high-risk transient ischemic attack, the aspirin–clopidogrel combination is now recommended for acute short-term treatment, whereas aspirin–ticagrelor combination may be considered in selected patients, especially those with resistance to clopidogrel. For long-term stroke prevention, aspirin–dipyridamole combination has been used as an alternative to antiplatelet monotherapy, and aspirin or clopidogrel combined with cilostazole may be prescribed for added protection in high-risk patients. In this paper, we review the development of DAPT from a historical perspective and describe the findings from major clinical trials published up until the end of 2023. Using the 2021 American Heart Association guideline for secondary stroke prevention as a basis for our recommendations, we further discuss areas of controversy and more recent developments to provide an updated review for clinicians to consider in their daily practice. Full article

Background and Objectives: Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder characterized by glucose intolerance during pregnancy. The triglyceride glucose (TyG) index, a marker of insulin resistance, and coronary flow reserve (CFR), a measure of coronary microvascular function, are emerging as potential indicators of cardiovascular risk. This study aims to investigate the association between CFR and the TyG index in GDM patients. Materials and Methods: This cross-sectional study of 87 GDM patients and 36 healthy controls was conducted. The participants underwent clinical assessments, blood tests, and echocardiographic evaluations. The TyG index was calculated as ln(triglycerides × fasting glucose/2). CFR was measured using Doppler echocardiography during rest and hyperemia induced by dipyridamole. Results: The study included 87 individuals in the GDM group and 36 individuals in the control group. There was no significant difference in age between the two groups (34.1 ± 5.3 years for GDM vs. 33.1 ± 4.9 years for the control, p = 0.364). The TyG index was significantly higher in the GDM group compared to the controls (p < 0.001). CFR was lower in the GDM group (p < 0.001). A negative correlation between the TyG index and CFR was observed (r = −0.624, p < 0.001). Linear regression revealed the TyG index as an independent predictor of reduced CFR. Conclusions: The study findings reveal a significant association between the TyG index and CFR in GDM patients, suggesting their potential role in assessing cardiovascular risk. Full article

The article examines the regularities of structure formation of ultrafine fibers based on poly-3-hydroxybutyrat under the influence of technological (electrical conductivity, viscosity), molecular (molecular weight), and external factors (low-molecular and nanodispersed substances of different chemical natures). Systems with polar substances are characterized by the presence of intermolecular interactions and the formation of a more perfect crystalline fiber structure. Changes in technological and molecular characteristics affect the fiber formation process, resulting in alterations in the morphology of the nonwoven fabric, fiber geometry, and supramolecular fiber structure. Polymer molecular weight, electrical conductivity, and solution viscosity influence fiber formation and fiber diameter. The fiber structure is heterogeneous, consisting of both crystalline and non-equilibrium amorphous phases. This article shows that with an increase in the molecular weight and concentration of the polymer, the diameter of the fiber increases. At the same time, the increase in the productivity of the electrospinning process does not affect the fiber geometry. The chemical structure of the solvent and the concentration of polar substances play a decisive role in the formation of fibers of even geometry. As the polarity of the solvent increases, the intermolecular interaction with the polar groups of poly-3-hydroxybutyrate increases. As a result of this interaction, the crystallites are improved, and the amorphous phase of the polymer is compacted. The action of polar molecules on the polymer is similar to the action of polar nanoparticles. They increase crystallinity via a nucleation mechanism. This is significant in the development of matrix-fibrillar systems for drug delivery, bioactive substances, antiseptics, tissue engineering constructs, tissue engineering scaffolds, artificial biodegradable implants, sorbents, and other applications. Full article