Computer-Assisted HPLC Method Development for Determination of Tolmetin and Possible Kinetic Modulators of Its Oxidative Metabolism in Vivo

Following administration of the acidic drug tolmetin (TOL) anaphylactic reactions occurred, which have been hypothesized to be related to the formation of reactive acyl glucuronides. Recently, glutathione adducts have been detected upon incubation of TOL with human liver microsomal preparations, which proved that oxidative activation might also be a pathway of formation of reactive—possibly toxic—glutathione metabolites of TOL. The aim of this work was to develop a new and robust HPLC method to investigate the in vivo effect of 2 coadministered drugs/nutritional supplements on the kinetics of TOL in rats (cimetidine; CIM) known to be a potent inhibitor of CYP3A4, an enzyme that catalyzes the oxidative metabolism and Quercetin; and QUE which induces UGT1A6, an enzyme involved in glucuronidation of acidic drugs. DryLab^®, a computer simulation software package, was used to assist in the development and optimization of the HPLC method used for separation of TOL and the two potential kinetic modulators together with three potential internal standards (zomepirac, carvedilol and fexofenadine). The method was validated in biological samples obtained from rats. Non-compartmental pharmacokinetic analysis of data obtained from plasma and rat liver tissue showed significantly higher concentrations of TOL in the presence of CIM; and significantly longer elimination half-life lives in presence of QUE, which implies that drugs or food components interacting with CYP3A4 cause alteration in the metabolic oxidative biotransformation of TOL in vivo leading to accumulation of TOL in the body through a decrease of its clearance. These findings might account for to the side-effects associated with TOL when co-administered with such kinetic modulators.

     

2-Keto-3-mercaptocinchoninic Acids as Precursors for Novel Thiazino[6,5-c]quinoline-1,5-dione Derivatives

2-Keto-3-mercaptocinchoninic acid derivatives 1a and b react with Schiff's bases 2a–d in toluene at refluxing temperature to give thiazino[6,5-c]quinoline derivatives 4a–h. Also, refluxing of 1a and b with arylazomalononitriles 5a–d in acetic acid afforded the thiazolo[6,5-c]quinoline derivatives 7a–d. The structure of all the newly synthesized products was confirmed based on elemental and spectral data.     

Synthesis and spectroscopic studies of CoII, NiII, FeIII and ThIV complexes derived from 2,2'-dihydroxy-3,3'-di(carboxymethyl)-1,1'-binaphthyl

The synthesis of 2,2'-dihydroxy-3,3'-di(carboxymethyl)-1,1'-binaphthyl (H2L) and its novel metal complexes with Co(II), Ni(II), Fe(III) and Th(IV) salts are reported. The ligand and its metal complexes have been characterized on the basis of analytical, conductance, spectral (IR, UV-vis, 1H NMR, mass) and magnetic susceptibility measurements. The M?ssbauer spectrum of the Fe(III) complex indicates a low-spin octahedral geometry around the Fe(III) ion. The IR and 1H NMR spectral data show that the ligand behaves in a dibasic bidentate fashion coordinating to two metal atoms through the two deprotonated naphthyl OH groups and acts in a dibasic tetradentate manner using both carbonyl oxygen's and the deprotonated naphthyl OH groups coordinating to two metal ions. Thermal studies (TGA, DTA) confirm the presence of solvents either inside or outside the coordination sphere and support the mechanism of the decomposition process. The value of [alpha]D20 for the ligand has been determined in DMSO.     

Effect of rare earth elements on the structural and optical properties of PMMA for possible uses in polymer optical communications

Rare-earth elements (REEs) as Tm⁺³, Er⁺³, Yb⁺³ and Nd⁺³ have a significant optical photon emission. Therefore, Films of PMMA doped with 5?wt.% of NdCl₃, TmCl₃, ErCl₃ or YbCl₃ were prepared using the casting technique. FTIR of the prepared films has been studied. The optical and dispersion behavior of all doped samples have been investigated. The reflectance (R) and the transmittance (T) were measured in the wavelength range of 200–2500?nm. FTIR of all PMMA reveals that, REEs addition to PMMA samples creates new transmission peaks C=O groups and a decrease in the intensity of the absorption band of C–O groups has been obtained. The results showed the dependency of the refractive index and energy gap on the REE electronic transitions nature. The obtained results suggest strongly the applicability of these PMMA derivatives in improving the performance of the polymer optical fiber (POF).     

Development of a colourimetric pH assay for the quantification of pyrethroids based on glutathione-S-transferase

Recombinant glutathione-S-transferases (GSTs) can be used as analytical tools for the development of simple insecticide quantification assays. This assay explores the ability of pyrethroids to promote inhibition of the GST-catalysing 1-chloro-2,4-dinitrobenzene (CDNB)/glutathione (GSH) conjugation reaction. The sensing scheme is based on the pH change occurring in a weak buffer system by the GST reaction, which is measured using a spectrophotometer and the dye indicator bromothymol blue (616 nm). Practical use depends on the recognition affinity of the GST for insecticides, inhibition kinetics, enzyme stability and compatibility with the detection assay. In this study we compared the recombinant GSTs AgGSTD1-6 and AdGSTD1-1 from the mosquito vectors Anopheles gambiae and Anopheles dirus, respectively, with high affinity for pyrethroids, for their suitability for detecting pyrethroids in vector disease control programmes. The results showed that AgGSTD1-6 was the most suitable enzyme with the best structural stability at higher temperatures (T _m = 57°C) and pH optima in the alkaline range (pH 7.7). Using the AgGSTD1-6, we subsequently developed a pH - change colourimetric assay for detecting pyrethroids. Linear calibration curves were obtained for deltamethrin (R ² = 0.99) with useful concentration ranges of 0–50 µg mL^?1. The effect of temperature in the range 25–40°C on the pyrethroid quantification assay was negligible. The assay was validated with extracts from insecticide sprayed surfaces and found to be reproducible and reliable compared with the standard reverse-phase high performance liquid chromatography (Rp-HPLC) method. The potential of the assay for monitoring insecticide residues in the frame of insecticide based malaria control interventions is discussed.     

Efficient Synthesis of Highly Substituted Furan,Thiophene, Pyrrole and 2‐Aminothiazole Derivatives

Ethyl cyanoacetate dimer (1) undergoes bromination with N‐bromosuccinimide (NBS) to afford 3‐amino‐4‐bromo‐2‐cyano‐pent‐2‐enedioic acid diethyl ester (2). This bromo derivative reacts with potassium carbonate, sodium hydrogen sulfide, aromatic amines, ammonium thiocyanate, thiourea, N‐phenylthiourea, and thiosemicarbazide to afford highly substituted furan, thiophene, pyrrole, and 2‐aminothiazole derivatives. Mechanistic explanations as well as structure elucidations are discussed.     

Calorimetric, optical and catalytic activity studies of europium chloride-polyvinyl alcohol composite system

Polyvinyl alcohol (PVA) films doped with europium chloride (EuCl₃) have been prepared by casting from their aqueous solutions. The phase transitions and thermal decomposition behavior of the prepared samples were investigated by thermal analysis and the interactions between the host PVA and Eu³⁺ were examined by FTIR spectroscopy. The optical absorption was recorded at room temperature in the range of 190-1000 nm. From the absorption edge studies, the values of the Urbach energy (E_e) were found to be 0.56 eV in case of the pure polymer; however, its value increased to be in the range of 1.21-1.75 eV. These energy values indicate that the model based on electronic transitions between localized states is not preferable and transitions are made between band tails. Optical parameters such as refractive index and complex dielectric constant have been determined. The dispersion of the refractive index is discussed in terms of the single-oscillator Wemple-DiDomenico model. Color properties of the prepared samples are discussed in the framework of CIE L?u*v* color space. The prepared samples have been used as catalysts in the photocatalytic degradation of p-nitrophenol (PNP) in aqueous solution under UV light irradiation using H₂O₂ as oxidizing agent. The catalytic activity of the Eu-polymer towards the photodegradation of PNP greatly increased after doping with Eu³⁺ ions. The highest catalytic activity was noticed at the optimum pH value of 5.5.     

A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross‐resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4‐trioxolane activity based protein‐profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi‐quantitatively, suggesting a common mechanism of action that raises concerns about potential cross‐resistance liabilities.     

Two-photon coincidence studies of highly-charged ion relaxation in solids

We studied the relaxation of hollow atoms by two-photon transitions during the stopping of slow (E=8.5q keV) highly charged Pb^q+ (q=53–58) ions in a thin Ta foil. The X-rays emitted during the relaxation process were detected in coincidence with two Si(Li) detectors. Particular attention was paid to the role of the internal dielectronic excitation (IDE) in the relaxation dynamics. We found a clear contribution to relaxation by the IDE process also for projectiles with initial M-shell vacancies and IDE speeds up relaxation of electrons from high Rydberg states by directly filling vacancies in the N-shell that is accompanied with the excitation of M-shell electrons. We discuss the relaxation mechanism, and present results for the fluorescence yield and the IDE probability of highly charged Pb ions in a solid.