Enzymatic Kinetic Resolution of Racemic 1-(Isopropylamine)-3-phenoxy-2-propanol: A Building Block for β-Blockers.

This study aimed to optimize the kinetic resolution of building blocks for the synthesis of β-blockers using lipases, which could be potentially used to synthesize enantiomerically pure β-blockers further. Reaction mixtures were incubated in a thermostated shaker. Qualitative and quantitative analyses of the reaction mixtures were performed using chiral stationary phases and the UPLC-IT-TOF system.

A New Approach in Lipase-Octyl-Agarose Biocatalysis of 2-Arylpropionic Acid Derivatives.

The use of lipase immobilized on an octyl-agarose support to obtain the optically pure enantiomers of chiral drugs in reactions carried out in organic solvents is a great challenge for chemical and pharmaceutical sciences. Therefore, it is extremely important to develop optimal procedures to achieve a high enantioselectivity of the biocatalysts in the organic medium. Our paper describes a new approach to biocatalysis performed in an organic solvent with the use of CALB-octyl-agarose support including the application of a polypropylene reactor, an appropriate buffer for immobilization (Tris base-pH 9, 100 mM), a drying step, and then the storage of immobilized lipases in a climatic chamber or a refrigerator.

Bio-Approach for Obtaining Enantiomerically Pure Clopidogrel with the Use of Ionic Liquids.

Clopidogrel is a chiral compound widely used as an antiplatelet medication that lowers the risk of blood clots, strokes, and heart attacks. The main aim of the study presented herein was to obtain ()-clopidogrel, which is commercially available in treatments, via the kinetic resolution of racemic clopidogrel carboxylic acid with the use of lipase from and a two-phase reaction medium containing an ionic liquid. For this purpose, the enantioselective biotransformation of clopidogrel carboxylic acid and chiral chromatographic separation with the use of a UPLC-MS/MS system were optimized.

Platelet inhibition with standard vs. lower maintenance dose of ticagrelor early after myocardial infarction (ELECTRA): a randomized, open-label, active-controlled pharmacodynamic and pharmacokinetic study.

Aims: Currently available data indicate that reduction of ticagrelor maintenance dose (MD) 1-3 years after acute myocardial infarction (AMI) not only provides sufficient platelet inhibition but also can improve ticagrelor's safety profile. The aim of this study was to compare the antiplatelet effect of reduced and standard ticagrelor MD in stable patients beginning 1 month after AMI.

Methods And Results: In a single-centre, randomized, open-label, active-controlled trial, on Day 30 following AMI, 52 patients (26 in each study arm) were assigned in a 1:1 ratio to receive either reduced (60 mg b.

METoclopramide Administration as a Strategy to Overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS-The METAMORPHOSIS Trial.

Extensive search for methods of overcoming morphine-related delay of the absorption and onset of action of oral P2Y inhibitors in patients presenting with acute coronary syndrome is on-going. The aim of the trial was to investigate whether metoclopramide co-administration could reduce this delay and improve the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ticagrelor and its active metabolite AR-C124900XX. Plasma concentration of both compounds and platelet reactivity were evaluated in nine pre-defined time points within 6 hours after administration of ticagrelor loading dose.

Impact of levosimendan on platelet function.

Levosimendan has been developed for treatment of severe heart failure. The favorable hemodynamic effect of levosimendan is related to its unique dual mechanism of action - increase of the contractile force of the myocardium caused by enhanced sensitivity of myofilaments to calcium combined with vasodilatation caused by the opening of adenosine triphosphate - dependent potassium channels. Due to the structural similarities to phosphodiesterase inhibitors it may partly exert its action via inhibition of phosphodiesterase inhibitors III.

Comparison of Ticagrelor Pharmacokinetics and Pharmacodynamics in STEMI and NSTEMI Patients (PINPOINT): protocol for a prospective, observational, single-centre study.

Introduction: The most common classification of acute myocardial infarction (AMI) is based on electrocardiographic findings and distinguishes ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). Both types of AMI differ concerning their epidemiology, clinical approach and early outcomes. Ticagrelor is a P2Y12 receptor inhibitor, constituting the first-line treatment for STEMI and NSTEMI.

Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina. A pharmacokinetic/pharmacodynamic study.

Oral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina.

Which platelet function test best reflects the in vivo plasma concentrations of ticagrelor and its active metabolite? The HARMONIC study.

Aim of this study was assessment of the relationship between concentrations of ticagrelor and its active metabolite (AR-C124910XX) and results of selected platelet function tests. In a single-centre, cohort study, patients with myocardial infarction underwent blood sampling following a 180 mg ticagrelor loading dose intake (predose, 1, 2, 3, 4, 6, 12, 24 hours postdose) to perform pharmacokinetic and pharmacodynamic assessments. Platelet reactivity was evaluated using the VASP-assay, the VerifyNow device and the Multiplate analyzer.

Ligand fishing using new chitosan based functionalized Androgen Receptor magnetic particles.

Superparamagnetic nanoparticles with chemically modified chitosan has been proposed as a potential support for the immobilization of the androgen receptor (AR). The study involved comparison of different AR carriers like commercially available magnetic beads coated with silica (BcMag) and chitosan coated nanoparticles with different amount of amino groups. The immobilization was carried out through covalent immobilization of the AR through the terminal amino group or through available carboxylic acids.

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial.

Aims: The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction.

Methods And Results: In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor.

Alpha-methylacyl-CoA racemase and hepsin as urinary prostate cancer markers.

Background: Because of the numerous limitations of prostate-specific antigen (PSA), α-methylacyl-CoA racemase (AMACR) and hepsin have recently been suggested as potential biomarkers in prostate cancer (PC). This report presents a comparison study of the presence of AMACR and hepsin in urine collected before and after digital rectal examination (DRE) as a previously suggested diagnostic marker for PC.

Methods: Seventy-six urine samples (38 before and 38 after prostate massage) from patients with benign prostate hyperplasia (BPH) and 66 urine samples (33 before and 33 after prostate massage) from patients with PC were analyzed.

High enantioselective Novozym 435-catalyzed esterification of (R,S)-flurbiprofen monitored with a chiral stationary phase.

Lipases form Candida rugosa and Candida antarctica were tested for their application in the enzymatic kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification. Successful chromatographic separation with well-resolved peaks of (R)- and (S)-flurbiprofen and their esters was achieved in one run on chiral stationary phases by high-performance liquid chromatography (HPLC). In this study screening of enzymes was performed, and Novozym 435 was selected as an optimal catalyst for obtaining products with high enantiopurity.

Siderophore-drug complexes: potential medicinal applications of the 'Trojan horse' strategy.

The ability of bacteria to develop resistance to antimicrobial agents poses problems in the treatment of numerous bacterial infections. One method to circumvent permeability-mediated drug resistance involves the employment of the 'Trojan horse' strategy. The Trojan horse concept involves the use of bacterial iron uptake systems to enter and kill bacteria.

Kinetic resolution of profens by enantioselective esterification catalyzed by Candida antarctica and Candida rugosa lipases.

Profens (2-arylpropionic acids) are known as one of the major nonsteroidal antiinflammatory drugs (NSAIDs) used in the treatment of inflammation associated with tissue injury. The inflammatory activity of profens is mainly due to their (S)-enantiomer, whereas they are commercially available not only as pure enantiomers, but as racemates as well. There are several methods widely used in order to obtain enantiomerically pure compounds, however, the kinetic resolution with the application of lipases as biocatalysts may have an added advantage in the production of optically pure active pharmaceutical ingredients, such as milder reaction conditions, reduced energy requirements, and production costs.

Engrailed-2 protein as a potential urinary prostate cancer biomarker: a comparison study before and after digital rectal examination.

This study was designed to compare and evaluate the presence of engrailed-2 (EN2) protein in urine collected before and after prostate massage as a diagnostic marker for prostate cancer (PCa). We analysed and compared 76 urine samples (38 before and 38 after prostate massage) from the benign group (BPH) and 66 urine samples (33 before and 33 after prostate massage) from patients with PCa confirmed by prostate biopsy. EN2 levels from the PCa and men with BPH (age range 50-82) were related to the tumour stage, Gleason score and prostate-specific antigen.

Tropomyosin-1 protects endothelial cell-cell junctions against cigarette smoke extract through F-actin stabilization in EA.hy926 cell line.

The aim of the study was to estimate the effect of cigarette smoke extract (CSE) on EA.hy926 endothelial cells in culture in the context of maintenance of cell-cell junctions through the structural stabilization of the actin cytoskeleton. In the present study, F-actin was stabilized by the overexpression of tropomyosin-1, which is known to stabilize actin filaments in muscle and non-muscle cells.

Ionic liquids as mobile phase additives for feasible assay of naphazoline in pharmaceutical formulation by HPTLC-UV-densitometric method.

A specific and reliable high-performance thin layer chromatography method with densitometry detection has been developed for the determination of naphazoline nitrate in nasal drops. The best separation of the basic analyte, without spot tailing, was achieved by using a mobile phase composed of acetonitrile-water (60:40, v/v), adding 1.5 % (v/v) imidazolium-class ionic liquid and covering the plates with a stationary phase based on RP-18 with F254S (10 × 20 cm).

Importance of retention data from affinity and reverse-phase high-performance liquid chromatography on antitumor activity prediction of imidazoacridinones using QSAR strategy.

Quantitative structure-activity relationships (QSAR) studies for prediction of cytotoxic and antitumor activity of imidazoacridinones (IA) based on experimentally obtained high-performance liquid chromatography (HPLC) retention data and calculated parameters using computational (molecular modeling) medicinal chemistry methods were proposed. The RP-HPLC and affinity-HPLC chromatographic techniques with four diversified HPLC systems applying columns with octadecylsilanes (C18), phosphatidylcholine (IAM), as well as α(1)-glycoprotein (AGP) and albumin (HSA) were used for the determination of the retention constants logk and logk(w) which characterize lipophilicity and protein affinity of IA. Moreover, molecular modeling studies were performed using HyperChem and Dragon software's, and structural descriptors were calculated and subsequently used.

Magnetic beads method for determination of binding of drugs to melanin.

Binding to melanin is considered to be a reason for several adverse effects of drugs and should be known to reduce the failure rate due to inappropriate pharmacokinetics in search for better pharmaceuticals. A new, reliable and convenient method of determination of affinity of drugs and drug candidates to melanin has been proposed employing magnetic beads. For that aim the reaction conditions to effectively covalently immobilize melanin on surface of superparamagnetic beads have been determined.

A new approach to determine camptothecin and its analogues affinity to human serum albumin.

A novel and fast method for the determination of the binding kinetic data of ligand to protein has been developed. A new tool including human serum albumin-coated magnetic beads (HSA-MB) was used to determine the affinity of camptothecin (CPT) and its analogues to HSA. From the biological activity point of view, these compounds have potential anticancer activity.

Contribution of artificial intelligence to the knowledge of prognostic factors in Hodgkin's lymphoma.

Hodgkin's lymphoma is one of the most curable malignancies and most patients achieve a lasting complete remission. In this study, artificial neural network (ANN) analysis was shown to provide significant factors with regard to 5-year recurrence after lymphoma treatment. Data from 114 patients treated for Hodgkin's disease were available for evaluation and comparison.

A protein-coated magnetic beads as a tool for the rapid drug-protein binding study.

A simple and fast method for the determination of the association constant (K(a)) of ligand to human serum albumin (HSA) has been developed by using human serum albumin-coated magnetic beads (HSA-MB). To date, magnetic beads (MB) have been increasingly used as a bioseparation tool, especially for DNA, RNA, protein, enzyme and cell isolation or purification. In this study, HSA-MB were used as a new tool to determine the affinity of known ligands to HSA.