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.

     

Temperature dependence of turn-on time delay of semiconductor laser diode: Theoretical analysis

Temperature dependence of the turn-on time delay (t_on) of uncooled semiconductor laser diodes biased below and above threshold is analyzed in presence of data pattern effect. We show that even when the laser is biased at or slightly above threshold, the increase in temperature of operation will lead to increase in the threshold carrier (N_th) and consequently the laser diode will be biased below the threshold again and a significant value of t_on will be produced. Thus, knowledge about a value of dc-bias current required to achieve zero t_on within wide range of temperature degrees is important when considering uncooled laser diode in high-speed optical communication systems. The temperature dependence of t_on is calculated according to the temperature dependence of N_th and Auger recombination coefficient (C) and not by the well-know exponentional relationship of threshold current with temperature. The temperature dependence of N_th is calculated according to the temperature dependence of laser cavity parameters. Advanced analytical model is derived in term of carrier density, recombination coefficients and the injection current (I_inj). The validity of proposed model is confirmed by a numerical method. In addition, approximated models are included where under specified assumptions the proposed model reduces to the well-known approximate models of t_on. According to our typical values and at a specified value of modulation current, the dc-bias one (I_ib) should be increased from I_ib = I_th to I_ib ≈ 1.25 and 1.5I_th in order to achieve approximately zero t_on when the temperature increases from 25°C to 55°C and 85°C, respectively.     

The Synthesis of Mono- and Bi-Metallic Platinum(II) and/or (IV) Complexes Containing the Ligand Bis(diphenylphosphino) Methylamine

Complexes of the type [Pt R₂ (dppma-PP′)] (R─Me, Et, Ph, CH₂Ph, C₆H₄ Me-p, C₆H₄OMe-2, CH₂CMe₃, 1-naphthyl, C₆H₄Me-o, dppma = Ph₂PNMe PPh₂) have been prepared from [PtCl₂, (dppma-PP′)] and the corresponding alkyl-lithium or Grignard reagents. Equilibrium constants, k, for the conversion of [PtR₂ (dppma-PP′)] into cis-[PtR₂(dppma-P)₂] with dppma were studied using ³¹P NMR spectroscopy at room temperature. Equilibrium is rapidly established for R─C₆H₄-Me-o, at 20°C. Complex of the type cis-[PtR₂ (dppma-P)₂] was isolated R─C₆H₄ Me-o. The complexes [PtMe₂(dppma-P)₂] and [Pt(o-methoxyphenyl)₂(dppma-P)₂] were prepared, but unfortunately decomposed once isolated, the only evidence for its formation being from ³¹P-{¹H} NMZR spectroscopy. The o-tolyl or 1-naphthyl complexes exist as syn-anti mixtures in solution, due to restricted rotation around the platinum aryl bonds. Treatment of several complexes of the type [PtR₂(dppma-PP′)] with MeI gives [PtR₂Me(I)(dppma-PP′)] with trans addition of MeI. Treatment of [PtR₂(dppma-PP′)] with HCl gives [Pt Cl (R) (dppma-PP′)] for R─C₆H₂Me₃-2,4,6, C₆H₄-CH₃-2, C₆H₄-Me-4, Me, 1-naphthyl. The ¹H, ³¹P NMR parameters for these complexes are discussed. Attempted preparation of complexes of the type [PtR₂ (dppma-P)₂M] (R─C₆H₄-Me-2, Me CN-C₆H₄-Me-4); M─Pd, Pt, Au,) are reported.     

Synthesis and Antibacterial Activity of Some New S-Triazole Derivatives

Abstract

Alkylation of 4-anilino-5-phenyl-4H-1,2,4-triazole-3-thiol (1) with some halo compounds yielded the corresponding sulfides 2a–f. Some sulfides 2e,f were cyclized to give triazolothiadiazines 3 and 4. Triazolothiadiazoles 5 and 6 were prepared through the reaction of compound 1 with carbon disulfide or ethyl orthoformate, respectively. Treatment of compound 1 with ethyl chloroformate or phenyl isothiocyanate yielded triazolo-thiadiazole and triazole 9 and 10, respectively. Reaction of compound 1 with Lawesson's reagent gave triazolothiadiazaphosphole derivative 11. Also, compound 1 underwent cyclocondensation reactions with some bidentate reagents to give triazolothiazines 4, 12, and 13. Triazolo-thiazepines and triaziepine 14–16 were synthesized via the reaction of compound 1 with β-ketoesters or ethyl cyanoacetate. Tricyclic systems 19 and 20 were prepared through the reaction of compound 4 with the appropriate reagent. Some synthesized compounds were tested for antibacterial activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

SOME REACTIONS OF 3-AMINO-2-CARBOETHOXY-4,6-DIMETHYLTHIENO[2,3-b]-PYRIDINE. SYNTHESIS OF SOME NEW THIENOPYRIDOPYRIMIDINES

Abstract

Thienopyridine oxazinone (1) has been prepared and explored as a precursor by its reaction with some reagents namely, ammonium acetate, aliphatic amines, aromatic amines, hydrazine hydrate, thiosemicarbazide, and ethyl glycinate to give pyridothienopyrimidines (11-VII). The pyrimidinone compound (11) was converted to the 4-chloro derivative (X) by its reaction with excess POCl₃ Interaction of the 4-chlorocompound (X) with some reagents namely, hydrazine hydrate, methyl amine, aniline, sodium thiophenolate, ethyl glycinate, thiosemicarbazide and thiourea, yielded pyridothieno-pyrimidine derivatives (XI-XVII) substituted at 4-position, respectively.     

Synthesis of Novel Semiconducting Aromatic Polyesteramids Containing Pyridine: Characterization of Nanometer-Sized Rod-Like Analogues and their Copper (II) Complexes

In this paper, new thermally stable isomeric unsubstituted polyesteramides have been successfully prepared by condensation of aromatic acids chlorides namely; isophthaloyl, pyridine-3,5-dicarbonyl and pyridine-2,6-pyridine-dicarbonyl dichlorides with the aminophenol isomers in NMP. Conducting the reaction in NMP/H₂O (90/10 v/v) followed by centrifugal separation furnished the desired polymers as rod-like nanoparticles. The morphology of obtained nanoparticles were studied by SEM. Mixing NMP with H₂O was essential for controlling the particles morphology and as a reaction accelerator.

Pyridine-containing polymers exhibit semi-conducting nature as their conductivities increase with increasing temperature, while no variation of the conductivity with the temperature was observed for their corresponding phenylene analogues. Introduction of the nitro group into the polymer backbone led to a red shift in the absorption and the obtained polymers have a bright yellow color, which is unusual with this polymer group. Copper (II) ions were complexed the polyesteramides-containing nitro group in a (1:1) ratio. Complexes of pyridine-containing polymers exhibit semiconducting nature changed to metallic characters on heating and their conductivities increased tens of magnitudes than their corresponding ligands. These new types of polymeric materials and their nano-sized rods may have numerous applications in nanotechnology and their properties can be tuned for specific applications such as conducting adhesives and coating materials.     

Synthesis,characterisation and supramolecular interaction of Rh-biphenylic-imidazole-phenanthroline with antibiotics

A novel rhodium biphenylic imidazole phenanthroline metal-organic complex (BIP-MC) has been synthesised and characterised as a stable supramolecule. The structure of compound was established on the basis ESI, ¹H NMR and UV–vis spectroscopic data. The selectivity of BIP-MC as a new fluorescent chemosensor for various antibiotics has been explored. The supramolecular interaction of amoxicillin with BIP-MC enhanced the fluorescence activity of BIP-MC. A linear response of the sensor was observed in the measuring ranges of excitation 240–298 nm and emission 290–360 nm with detection limits of up to 10 μg/ml at an optimum pH 8.0. Based on the observations made here, a new quantitative method for the determination of this drug in synthetic samples without the use of separation of matrix is developed. It is also inferred that the possible fluorescence enhancement is due to the formation of exciplex between the BIP-MC and amoxicillin. These finding will thus help in pharmacokinetics studies of drugs. The sensor was used for the direct assay of amoxicillin antibiotic in commercial pharmaceutical preparations.     

pTSA-catalyzed condensation of xylenols and aldehydes under solvent-free conditions: One-pot synthesis of 9H-xanthene or bisphenol derivatives

A simple and efficient procedure for the synthesis of 9H-xanthene or bisphenol derivatives has been developed by one-pot condensation of xylenols with aromatic aldehydes in the presence of p-toluenesulfonic acid (pTSA) as a catalyst under solvent-free conditions at 100 °C. It is noteworthy that the condensation reaction of 3,5-xylenol with aldehydes produces 9H-xanthene derivatives, while the reaction with other xylenols leads to the corresponding bisphenol derivatives. Different types of aromatic aldehydes are used in the reaction and in every case the products were obtained in good to excellent yields. The structures of these compounds were established on the basis of IR, ¹H NMR, ¹³C NMR and CHN data.     

Synthesis of novel di-Se-containing thymidine and Se-DNAs for structure and function studies

The selenium derivatization of nucleic acids and nucleic acid-protein complexes has provided a powerful tool to solve phase problem in X-ray crystallography.Selenium atoms in the nucleotides can serve as fine scattering centers in crystal diffraction.Towards the synthesis of multiple selenium atom-containing nucleotides,which offers strong phasing power to facilitate crystal structure determination,we report here the synthesis of the thymidine analogue containing two Se atoms in one nucleobase.The novel Se-containing nucleoside and oligonucleotide DNAs were synthesized and found with the red-shifted UV spectrum and yellow color.Their unique properties are useful in phase determination,nucleic acid-based detection as well as spectroscopic studies of nucleic acids and nucleic acid-protein complexes.     

In vitro surface biocompatibility of high-content silicon-substituted calcium phosphate ceramics

The present work investigates surface biocompatibility of silicon-substituted calcium phosphate ceramics. Different silicon-substituted calcium phosphate ceramic bodies were prepared from co-precipitated powders by sintering at 1300°C. The in vitro bioactivity of the ceramics was assessed in simulated body fluid (SBF) at 37°C for periods up to 4 weeks. The changes in the surface morphology and composition were determined by scanning electron microscopy (SEM) coupled with electron probe microanalysis and energy dispersive spectrometer (EDX). Inductively coupled plasma optical emission spectroscopy (ICP-OES) was used to observe the change in ionic concentration of SBF after removal of the samples. The bioactivity of the ceramics increased with an increasing silicate ion substitution in a systematic way. The surface of ceramics with 2.23% silicon substitution was partially covered with apatite layer after one week, while ceramics with 8.1% silicon substitution were completely covered with apatite in the first week. The porous microstructure of high-concentration Si-substituted ceramics helps the dissolution of surface ions and the leaching process. This allows SBF to reach supersaturation in a short time and accelerate the deposition of apatite layer.