A series of sixteen novel substituted piperidines and (2-methoxyphenyl)piperazines were synthesized, starting from the key intermediates 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine and 1-(2-methoxyphenyl)-4-[(piperidin-4-yl)methyl]piperazine. Biological evaluation of the synthesized compounds was illustrated by seven compounds, of which 1-(2-methoxyphenyl)-4-{[1-(2-nitrobenzyl)piperidin-4-yl]methyl}piperazine had the highest affinity for the dopamine D 2 receptor. For all seven selected compounds, docking analysis was performed in order to establish their structure-to-activity relationship.
Background: Preoperative use of platelet function tests contributes to the decrease of re-intervention rate due to bleeding and the necessity of transfusion in coronary artery bypass grafting (CABG) patients. The aim was to investigate the predictive value and to justify routine preoperative use of multiple electrode aggregometry in these patients. Methods: A prospective observational trial which included 416 consecutive patients subjected to elective isolated CABG was conducted. The Multiplate® test was used to assess platelet function. Platelet function test results, postoperative blood loss, and transfusion requirements were compared between high and low bleeding risk patients. Receiver operating characteristic analysis was performed to assess the sensitivity and specificity of the arachidonic acid (ASPI) and adenosine di-phosphate high sensitive (ADPHS) tests. Results: ADPHS and ASPI test results significantly predicted total bleeding > 1000 ml (AUC, 0.685, p < .001; 0.695, p = .039). Sensitivity and specificity were 62.9% and 40.0%, for ADPHS ≤602, and 70.8% and 41.8%, for ASPI ≤ 453. The sensitivity and specificity of cutoff values recommended by the manufacturer were 84.2% and 40.0% for ADPHS ≤ 500, while for ASPI < 600 the values were 54.7% and 62.2%. More platelets and cryoprecipitate were transfused in patients with ADPHS ≤ 602.5 (p < .001; p = .035). Patients with ADPHS ≤ 500 had a higher rate of red blood count, platelet and cryoprecipitate transfusion (p<.001p<.001; p = .013). The manufacturer's ASPI test cutoff values showed no statistically significant prediction for a higher transfusion rate. Conclusion: Preoperative platelet function tests should be conducted systematically for all elective CABG patients who were on dual antiplatelet therapy after adjusting test cutoff values for each population.
Despite the application of new antiplatelet drugs (prasugrel and ticagrelor), dual antiplatelet therapy with clopidogrel and aspirin remains the standard for patients with acute coronary syndrome undergoing percutaneous coronary intervention, especially in countries of low socioeconomic status. Regardless of the proven benefits, numerous studies have shown that certain groups of patients who receive standard doses of clopidogrel and aspirin do not respond adequately, and many of them also exhibit adverse cardiovascular events. Studies have shown that the risk of stent thrombosis and ischemic complications is higher in patients with: acute coronary syndrome, diabetes mellitus, thrombocytosis, reduced systolic function of the left ventricle with ejection fraction less than 30%, presence of multiple stents, longer and thinner stents, and renal failure. In these patients it is particularly important to assess the response to clopidogrel and selecting adequate antiplatelet therapy; this provides an impetus for platelet function tests. The second especially significant group to target for laboratory evaluation includes patients with increased risk of bleeding, such as elderly patients, patients with low body weight, anemia, thrombocytopenia, renal failure, past or current ventricular or duodenal ulcer, coagulopathy, or liver disease. The third important application of platelet function tests entails the preparation and evaluation of the time for surgical interventions or invasive diagnostic procedures in patients on antiplatelet therapy. These tests can also be helpful for monitoring the effects of therapy of bleeding due to platelet dysfunction. For high-risk patients the careful selection of optimal antiplatelet drug(s) on the basis of estimated individual risk of thrombosis and bleeding, pharmacodynamic characteristics of each drug, and patient̀s comorbidity remains essential.
A series of eight novel 5-substituted derivatives of benzimidazole was synthesized by condensation of the corresponding diamine with ethyl 4-[4--(2-chlorophenyl)piperazin-1-yl]butanoate in refluxing 4 M hydrochloric acid. In vitro antibacterial activity against ten strains, namely Bacillus subtilis, Clostridium sporogenes, Streptosporangium longisporum, Micrococcus flavus, Sarcina lutea, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis and Proteus vulgaris and antifungal activity against two fungal strains, namely Candida albicans and Saccharomyces cerevisiae, were evaluated. Of all the compounds screened for activity, 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-iodo-1H-benzimidazole and 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-methyl-1H-benzimidazole were associated with higher antifungal activity than commercial drugs.
The interactions of nine amino acid derivatives of tert-butylquinone with biomacromolecules were studied. SDS electrophoresis and mass spectrometry confirmed the absence of modifications of lysozyme by any of the synthesized compounds. Spectrophotometric studies demonstrated hyperchromism, i.e. existence of interactions between the quinones and CT-DNA. Determination of binding constant by absorption titration indicates weak interactions between quinone derivatives and CT-DNA. The quenching of fluorescence of intercalator ethidium bromide from EB-CT-DNA system and of minor groove binder Hoechst 33258 from H-CT-DNA system by the synthesized derivatives indicates interactions of compounds and CT-DNA. CD spectra demonstrate non-intercalative binding mode of quinone derivaties to CT-DNA. Molecular docking results confirm binding to the minor groove. Electrophoretic pattern showed no cleavage of pUC19 plasmid in the presence of any of the synthesized compounds. The ability of the derivatives to scavenge radicals was confirmed by DPPH test. All the presented results suggest that the DNA minor groove binding is the principal mechanism of action of the examined amino acid derivatives. [Projekat Ministarstva nauke Republike Srbije, br. 172055]
Introduction Hemorrhagic early death (HED) remains a major cause of treatment failure among patients with acute promyelocytic leukemia (APL). We aimed to investigate the prognostic potential of rotational thromboelastometry (ROTEM) for bleeding in patients with APL. Materials and Methods 31 newly-diagnosed APL patients (median age of 40 years; 14 female/17 male) that underwent treatment at the Clinic of Hematology UCCS from 2016-2020 with all-trans retinoic acid and anthracyclines were recruited. CBCs (complete blood count), conventional coagulation tests (CCTs), and ROTEM parameters obtained before treatment initiation were evaluated. Results All patients demonstrated at least one ROTEM parameter out of the reference range. ROTEM parameters associated with significant hemorrhage were EXTEM clotting time (CT) (P = 0.041) and INTEM amplitude 10 (A10) (P = 0.039), however, only EXTEM CT (P = 0.036) was associated with HED. Among CBCs and CCTs, only platelets were associated with significant bleeding (P = 0.015), while D-dimer was associated with both bleeding and HED (P = 0.001 and P = 0.002, respectively). Conclusion Our results indicate that ROTEM parameters may reveal hypocoagulability in APL patients and have the potential to improve current hemorrhage prognostic methods. Additionally, these results suggest the combination of ROTEM and CCTs might be useful in identifying patients at risk for HED.
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