Search Results (13)

Oral anticoagulant therapy (OAT) for managing atrial fibrillation (AF) encompasses vitamin K antagonists (VKAs, such as warfarin), which was the mainstay of anticoagulation therapy before 2010, and direct-acting oral anticoagulants (DOACs, namely dabigatran etexilate, rivaroxaban, apixaban, edoxaban), approved for the prevention of AF stroke over the last thirteen years. Due to the lower risk of major bleeding associated with DOACs, anticoagulant switching is a common practice in AF patients. Nevertheless, there are issues related to OAT switching that still need to be fully understood, especially for patients in whom AF and heart failure (HF) coexist. Herein, the effective impact of the therapeutic switching from warfarin to DOACs in HF patients with AF, in terms of cardiac remodeling, clinical status, endothelial function and inflammatory biomarkers, was assessed by a machine learning (ML) analysis of a clinical database, which ultimately shed light on the real positive and pleiotropic effects mediated by DOACs in addition to their anticoagulant activity. Full article

Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44–111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85–147) ng/mL in the wild-type CC genotype vs. 110 (47–159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04–9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen. Full article

The development of novel anticoagulants requires a comprehensive investigational approach that is capable of characterizing different aspects of antithrombotic activity. The necessary experiments include both in vitro assays and studies on animal models. The required in vivo approaches include the assessment of pharmacokinetic and pharmacodynamic profiles and studies of hemorrhagic and antithrombotic effects. Comparison of anticoagulants with different mechanisms of action and administration types requires unification of the experiment scheme and its adaptation to existing laboratory conditions. The rodent thrombosis models in combination with the assessment of hemostasis parameters and hematological analysis are the classic methods for conducting preclinical studies. We report an approach for the comparative study of the activity of different anticoagulants in vivo, including the investigation of pharmacodynamics and the assessment of hemorrhagic effects (tail-cut bleeding model) and pathological thrombus formation (inferior vena cava stenosis model of venous thrombosis). The reproducibility and uniformity of our set of experiments were illustrated on unfractionated heparin and dabigatran etexilate (the most common pharmaceuticals in antithrombic therapy) as comparator drugs and an experimental drug variegin from the tick Amblyomma variegatum. Variegin is notorious since it is a potential analogue of bivalirudin (Angiomax, Novartis AG, Basel, Switzerland), which is now being actively introduced into antithrombotic therapy. Full article

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction. Full article

Aim: To determine the complementary effects of dabigatran etexilate (DE), exercise training (ET), and combination (DE + ET) on the development and stability of the atherosclerotic lesions in diabetic apoE knockout (apoE^−/−) mice. Methods: In 48 male apoE^−/− diabetic mice, streptozotocin (STZ) was induced for 5 consecutive days. Mice received a high-fat diet (HFD) for 8 weeks and then were randomized into four groups (1. Control/CG, 2. DEG: HFD with DE, 3. ETG: ET on treadmill, 4. DE + ETG: combination DE and ET treatment). At the end of the eighth week, all mice were euthanatized and morphometry of the aortic lesions at the level of aortic valve was obtained. Collagen, elastin, MCP-1, TNF-a, matrix metalloproteinases (MMP-2,-3,-9), and TIMP-1 concentrations within plaques at the aortic valve were determined. Results: All active groups had significantly smaller aorta stenosis (DEG:7.9 ± 2.2%, ETG:17.3 ± 5.3%, DE + ETG:7.1 ± 2.7%) compared to CG (23.3 ± 5.5% p < 0.05), reduced the relative intra-plaque content of MCP-1, macrophages, MMP-3, and MMP-9, and considerably increased collagen, elastin, and TIMP-1 (p < 0.05). Group 4 showed the most pronounced results (p < 0.05). Both DEG and DE + ETG significantly reduced MMP-2 and TNF-a concentrations compared to ETG and CG (p < 0.010). Conclusion: DE and ET treatment of diabetic apoE^−/− mice resulted in complementary amelioration of atherosclerotic lesions development and stability, mediated by the anti-inflammatory modulation of both DE and ET. Full article

Dabigatran etexilate, an oral prodrug, is often used to treat complications linked to thrombosis. Dabigatran (DAB, active form) does not need to be monitored. However, there are several conditions, such as reduced renal function, traumatic bleeding, emergency surgery, the need for thrombolytic therapy in acute stroke, or the requirement to use other forms of anticoagulation, where knowing the concentration of DAB in the blood is indispensable. Unfortunately, there are no convenient DAB-specific point-of-care tests available. To solve this problem, two disposable sensors were constructed and optimised in this work to detect the anticoagulant drug DAB using novel co-facing disposable electrodes, which allows a calibration-free quantitation of the electroactive mediator concentration. A trypsin-based sensor was evaluated. This sensor performed well in a 10 mM Tris buffer (pH 8.8) solution. However, trypsin was inhibited by alpha-1 antitrypsin when a plasma sample was introduced into the sensor. This problem was overcome by plasma filtration. This sensor showed a detection limit of 50.7 ng mL⁻¹ DAB in plasma and a quantification range of 177–500 ng mL⁻¹. A thrombin-based sensor was also constructed. This sensor performed well in ten-fold diluted plasma, overcoming the filtration problem observed with the trypsin-based sensor. This sensor showed a detection limit of 9.6 ng mL⁻¹ DAB in plasma and a quantification range of 11.5–140 ng mL⁻¹. Its extensive pH stability range, the possibility of working at physiological pH, low volume, low cost, and fast turnaround response (less than 20 s) make the calibration-free thrombin-based sensor a suitable point-of-care test to measure DAB concentration in the blood. Full article

In this study, a dabigatran etexilate edisylate (DBE) was prepared by the reaction crystallization of dabigatran etexilate (DBG) and edisilic acid. According to single crystal X-ray diffraction (SXRD), it was revealed that two DGB were combined with one edisylate and associated with one water for DBE monohydrate. Additionally, the hot stage microscopy showed that the DBE monohydrate was transformed to DBE amorphous solid and then finally shifted to the DBE anhydrate in solid-state. Using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and a hygroscopic test, it was confirmed that the phase transformation of DBE monohydrate to DBE anhydrate was irreversible. Additionally, any other crystal form of DBE anhydrate was not available because it was the most stable phase. Full article

Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate. Full article

Background and Purpose: Thrombophilic gene alterations are a major risk factor for cerebral sinus vein thrombosis (CSVT). Up to 30% of all patients with cerebral sinus vein thrombosis (CSVT) are found to have thrombophilic defects such as prothrombin mutation (PTM) or factor V Leiden (FVL). Their repercussions on the plasma levels of dabigatran etexilate are unclear. In this prospective case–control study, we aimed to investigate whether thrombophilia in CSVT has an influence on dabigatran peak-plasma levels. Methods: We monitored 10 patients over 12 months with acute CSVT, genetic thrombophilia with off-label use of dabigatran etexilate 150 mg twice a day and measured dabigatran peak-plasma levels and radiological outcome. We also monitored patients without genetic thrombophilia with dabigatran etexilate 150 mg twice a day and compared the efficiency and dabigatran peak-plasma levels. Results: Patients with homozygote PTM had significantly lower dabigatran peak concentration compared to patients with FVL or the control group (23 ± 4.2 vs. 152.3 ± 27.5 and 159.6 ± 63.08; p-value ≤ 0.05) There was no significant difference in dabigatran etexilate plasma levels between the heterozygote PTM group compared to patients with FVL or the control group (p = 0.29). There was no correlation between dabigatran peak concentration and delayed thrombus dissolution. Conclusions: Dabigatran peak concentration was stable in patients with heterozygote FVL and heterozygote PTM, but not in homozygote PTM, compared to controls. Genetic screening for thrombophilia in patients after CSVT may be useful to make patient tailored therapeutic decisions regarding oral anticoagulation and may decrease thrombotic events. Full article

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood. Full article

Dabigatran is a novel oral anticoagulant that directly inhibits free and fibrin-bound thrombins and exerts rapid and predictable anticoagulant effects. While the use of this reagent has been associated with an increased risk of gastrointestinal bleeding, the reason why dabigatran use increases gastrointestinal bleeding risk remains unknown. We investigated the cytotoxicity of dabigatran etexilate and tartaric acid, the two primary components of dabigatran. The cytotoxicity of dabigatran etexilate and tartaric acid was measured in a cell viability assay. Intracellular mitochondrial reactive oxygen species (mitROS) production and lipid peroxidation were measured using fluorescence dyes. Cell membrane viscosity was measured using atomic force microscopy. The potential of ascorbic acid as an inhibitor of dabigatran cytotoxicity was also evaluated. The cytotoxicity of dabigatran etexilate was higher than that of tartaric acid. Dabigatran etexilate induced mitROS production and lipid peroxidation and altered the cell membrane viscosity. Ascorbic acid inhibited the cytotoxicity and mitROS production induced by dabigatran etexilate. Therefore, we attributed the cytotoxicity of dabigatran to dabigatran etexilate, and proposed that the cytotoxic effects of dabigatran etexilate are mediated via mitROS production. Additionally, we demonstrated that dabigatran cytotoxicity can be prevented via antioxidant treatment. Full article

Patients on anticoagulant therapy for the prevention of cardiovascular accidents present an increased risk of bleeding following dental and oral surgery. Four recently introduced non-vitamin K antagonist oral anticoagulants, namely dabigatran etexilate (direct thrombin inhibitor), rivaroxaban, apixaban, and edoxaban (Xa factor direct inhibitor), are widely spreading for convenience of use compared to the older drug class. Dental management of patients taking these drugs has substantial differences compared to patients on vitamin K antagonist therapy. Anticoagulation is not assessed directly through a hematological test, but indirectly by renal function. The interventions must be scheduled at the time of minimum blood concentration of the drug. Bleeding can occur even after several days following the surgery. The interaction with drugs administered for dental care must be carefully evaluated. The peri-operative diet can influence the risk of bleeding. Local measures favoring coagulation must be adopted. The interventions with higher risk must be divided into multiple less invasive interventions. Although antidotes exist for these drugs, their use does not seem necessary for dental interventions that have been planned optimally. Furthermore, in this review of the literature a decision protocol is proposed for the evaluation of the suspension of the anticoagulant drug before oral surgery. Cessation of any anticoagulant should only be made in consultation with the patient’s general practitioner/cardiologist, who will weigh up the risk of bleeding from the proposed procedure with the risk of thrombosis/stroke in each individual patient. Full article

Dabigatran etexilate is a direct oral anticoagulant (thrombin inhibitor) used for the prevention of stroke and systemic thromboembolic events in patients with permanent atrial fibrillation; prevention of venous thromboembolic events and deep veins thrombosis; treatment and prevention of pulmonary embolism. Dabigatran is a relatively new drug, and as a result, its interactions with other medications and their significance are not fully known. A 72 years old male, having a medical history of heart and renal failure, was hospitalized for pneumonia treatment. The patient was taking several drugs, including dabigatran 150 mg twice daily and ranolazine 750 mg twice daily. His creatinine clearance was 45.22 mL/min, International Normalized Ratio (INR)—7.03. Dabigatran was discontinued. After 9 days, INR decreased to 1.33, and after 6 days, creatinine clearance increased to 64.39 mL/min. The patient was taking an adequate dosage of dabigatran, thus dabigatran was thought to be overdosed due to its interaction with ranolazine because dabigatran is a p-glycoprotein substrate, whereas ranolazine is the inhibitor of this transporter. Dabigatran and ranolazine should be used with caution in patients with renal failure. It is recommended to use smaller doses of both medications and observe coagulation parameters if needed. Full article