LC�CMS�CMS Method for the Analysis of New Non-Imidazole Histamine H3 Receptor Antagonist 1-[3-(4-tert-Butylphenoxy)propyl]piperidine in Rat Serum��Application to Pharmacokinetic Studies

A sensitive and specific liquid chromatography electrospray ionisation-tandem mass spectrometry method for determination of new non-imidazole histamine H(3) receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (DL76) in rat serum has been developed and validated. Chromatography was performed on a XBridge? C18 analytical column (2.1?×?30?mm, 3.5?μm, Waters, Ireland) with gradient elution using a mobile phase containing acetonitrile and water with an addition of 0.1% of formic acid. Detection was achieved by an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 2000 triple quadrupole mass spectrometer. Electrospray ionization (ESI) was used for ion production. The limit of detection in the SRM mode was found to be 0.5?ng?mL(-1). The limit of quantification was 1?ng?mL(-1). The precision and accuracy for both intra- and inter-day determination of DL76 ranged from 1.65 to 15.09% and from 88.74 to 113.43%. The results of this analytical method validation allow to carry out pharmacokinetic studies in rats. The method was used for the pilot study of the pharmacokinetic behavior of DL76 in rats after intravenous administration.     

Molecular dynamics study of the hydration of the hydroxyl radical at body temperature

Classical molecular dynamics (MD) simulation of ˙OH in liquid water at 37 °C has been performed using flexible models of the solute and solvent molecules. We derived the Morse function describing the bond stretching of the radical and the potential for ˙OH-H(2)O interactions, including short-range interactions of hydrogen atoms. Scans of the potential energy surface of the ˙OH-H(2)O complex have been performed using the DFT method with the B3LYP functional and the 6-311G(d,p) basis set. The DFT-derived partial charges, ±0.375e, and the equilibrium bond-length, 0.975 ?, of ˙OH resulted in the dipole moment of 1.76 D. The radical-water radial distribution functions revealed that ˙OH is not built into the solvent structure but it rather occupies distortions or cavities in the hydrogen-bonded network. The solvent structure at 37 °C has been found to be the same as that of pure water. The hydration cage of the radical comprises 13-14 water molecules. The estimated hydration enthalpy -42 ± 5 kJ mol(-1) is comparable with the experimental value -39 ± 6 kJ mol(-1) for 25 °C. Inspection of hydrogen bonds showed the importance of short-range interaction of hydrogen atoms and indicated that neglect of the angular condition greatly overestimates the number of the H-acceptor radical-water bonds. The mean number ?n = 0.85 of radical-water H-bonds has been calculated using geometric definition of H-bond and ?n = 0.62 has been obtained when the energetic condition, E(da)≤-8 kJ mol(-1), was additionally considered. The continuous lifetimes of 0.033 ps and 0.024 ps have been estimated for the radical H-donor and the H-acceptor bonds, respectively. Within statistical uncertainty the radical self-diffusion coefficient, (2.9 ± 0.6) × 10(-9) m(2) s(-1), is the same as (3.1 ± 0.5) × 10(-9) m(2) s(-1) calculated for water in solution and in pure solvent. To the best of our knowledge, this is the first study of the ˙OH(aq) properties at a biologically relevant body temperature.     

The Applicability of Essential Oils in Different Stages of Production of Animal-Based Foods

Essential oils (EOs) have been used for centuries, and interest in these compounds has been revived in recent years. Due to their unique chemical composition as well as antimicrobial, immunostimulatory, anti-inflammatory and antioxidant properties, EOs are used in pharmacology, cosmetology and, increasingly, in animal breeding and rearing, and processing of animal raw materials. Essential oils have become a natural alternative to preservatives, taste enhancers and, most importantly, antibiotics, because the European Union banned the use of antibiotics in metaphylaxis in animal husbandry in 2006. In the animal production chain, EOs are used mainly as feed additives to improve feed palatability and increase feed intake, improve animal resistance and health status, and to prevent and treat diseases. Recent research indicates that EOs can also be applied to sanitize poultry houses, and they can be used as biopesticides in organic farming. Essential oils effectively preserve meat and milk and, consequently, improve the safety, hygiene and quality of animal-based foods. Novel technologies such as encapsulation may increase the bioavailability of EOs and their application in the production of food and feed additives.     

Promising Antimicrobial Properties of Bioactive Compounds from Different Honeybee Products

Bee products have been known for centuries for their versatile healing properties. In recent decades they have become the subject of documented scientific research. This review aims to present and compare the impact of bee products and their components as antimicrobial agents. Honey, propolis, royal jelly and bee venom are bee products that have antibacterial properties. Sensitivity of bacteria to these products varies considerably between products and varieties of the same product depending on their origin. According to the type of bee product, different degrees of activity were observed against Gram-positive and Gram-negative bacteria, yeasts, molds and dermatophytes, as well as biofilm-forming microorganisms. Pseudomonas aeruginosa turned out to be the most resistant to bee products. An analysis of average minimum inhibitory concentration values for bee products showed that bee venom has the strongest bacterial effectiveness, while royal jelly showed the weakest antibacterial activity. The most challenging problems associated with using bee products for medical purposes are dosage and safety. The complexity and variability in composition of these products raise the need for their standardization before safe and predictable clinical uses can be achieved.     

Anticancer Effects of Propolis Extracts Obtained with the Cold Separation Method on PC-3 and DU-145 Prostate Cancer Cell Lines

Plant extracts are increasingly tested for their biological activity and interactions with neoplastic cells. One of such sources of biologically active substances is propolis. This product has been known for thousands of years and is widely used in alternative, folk medicine. Articles describing its effects on the metabolism and cell signaling pathways of neoplastic cells derived from different organs are also published more and more frequently. The purpose of our study was to evaluate the biological activity of propolis extract produced with the cold separation method into hormone-dependent and hormone-independent prostate cancer cell lines. In our study, the propolis extracts showed at least an inhibitory effect on the growth of PC-3 and DU-145 neoplastic cells. Our results suggest that propolis extracts obtained with the cold separation method may be considered as promising compounds for the production of health-promoting supplements.     

A Modular Approach to Atropisomeric Bisphosphines of Diversified Electronic Density on Phosphorus Atoms

The series of C₂-symmetric biaryl core-based non-racemic bisphosphines possessing substituents of different electronic properties: both EDG and EWG were obtained in a short sequence of good yielding transformations, started from commercial 1,3-dimethyl-2-nitrobenzene. Several different approaches leading to the desirable ligands were practically evaluated. Notably, the synthesis of the entire series of ligands could be performed with the utilization of a single early-stage precursor DIDAB (6,6′-diiodo-2,2′,4,4′-tetramethylbiphenyl-3,3′-diamine), which could be easily obtained in enantiomerically pure form. The obtained compounds at concentrations of 50 and 200 µM showed various biological activity against normal human dermal fibroblast, ranging from inactivity through time-dependent action and ending up with high toxicity.     

Diastereoselective addition of vinylmagnesium halides to variously N-mono- and N,N-diprotected l-alaninals

Diastereoselective C₂-elongation processes of N-mono- 1a-c and N,N-diprotected 1d-fl-alaninals, using vinylmagnesium bromide and chloride, are described. A substantial difference between effects of the N-protecting groups replacing either one or two amino protons was observed.     

Voltammetric study of gold-supported lipid membranes in the presence of perfluorooctanesulphonic acid

The effect of perfluorooctanesulphonic acid (PFOS) on lipid membranes was studied using supported 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer as the model membrane. Phospholipid bilayer was deposited on gold electrode using a combination of the Langmuir–Blodgett and Langmuir–Schaefer (LB/LS) techniques. Electrodes were modified with two different types of membranes: DMPC bilayers initially containing PFOS and pure DMPC bilayers later exposed to the PFOS solutions. Such approach allowed studying both the changes in membrane characteristic imposed by the perfluorinated compound present in the model membrane and the process of its incorporation into the membrane. Studies with anticancer drug doxorubicin revealed that PFOS inhibits drug transport through the phospholipid bilayer and its effect can be compared to that of cholesterol. Moreover, the different trends observed in the changes in electron transfer rate constant (k_s) calculated for ferricyanides and in peak current of hexaamineruthenium chloride showed that electrostatic interactions between electroactive probes and PFOS molecules incorporating into phospholipid bilayers play an important role and should be taken into account while explaining the interactions of perfluorooctanesulphonic acid with model biological membranes.     

Systems of Inclusions Involving Fredholm Operators of Nonnegative Index and Nonconvex-Valued Maps

We study the existence of solutions to a system of two inclusions involving Fredholm operators of nonnegative (Fredholm) index and the so-called c-admissible maps: upper semicontinuous maps with values being continuous images of cell-like sets. The presented approach resembles the substitution technique, i.e. applies the so-called solution map. The appearance of the ‘dimension defect’ reflecting the nonnegativity of Fredholm indices requires the use of algebraic tools based on the cohomotopy theory, different from the usual homological ones present in the fixed point theory. An application to boundary value problems is provided as well as the brief exposition of basic facts from the cohomotopy theory. Mathematics Subject Classifications (2000) 47H04, 47A53, 55M20, 55Q55, 34A60.     

Remarks on the r and Δ convolutions

In this paper we study the properties of the r–deformation introduced in [B1]. We observe that the associated convolution coming from the conditionally free convolution is associative only for r = 1 and r = 0. We give the realization of some r–Gaussian random variables and obtain Haagerup–Pisier–Buchholz type inequalities. We also study another convolution defined with the use of the r–deformation through a moment–cumulant formula [KY1] and show that it is associative and in general not positive. Partially sponsored with KBN grant no 2P03A00723 and RTN HPRN-CT-2002-00279.