Determination of plasma topiramate concentration using LC-MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers

A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.     

Spectroscopic studies on the effect of temperature on pH-induced folded states of human serum albumin

Human serum albumin (HSA) is a very important multi-domain transporter protein in the circulatory system responsible for carriage of various kinds of ligands within the physiological system. HSA is also known to undergo conformational transformation at different pH(s) and temperatures. In this report we have studied the binding interactions of a photosensitizing drug, protoporphyrin IX (PPIX) with various conformers of HSA at different temperatures using picosecond time-resolved fluorescence spectroscopy. Also, using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy we have followed the structural transition of various conformers of HSA at different temperatures. Ensuring the intact binding of PPIX to various conformers of HSA at different temperatures as revealed through time-resolved fluorescence anisotropy decay and significant spectral overlap of emission of Trp214 residue (donor) in domain-IIA and absorption of PPIX (acceptor) bound to domain-IB of HSA, we have applied F?rster's resonance energy transfer (FRET) technique to determine the interdomain separation under various environmental conditions. The alkali-induced conformer of HSA shows almost no change in donor-acceptor distance in contrast to the native and acid-induced conformers of HSA, which show a decrease in distance with increase in temperature. Through this study the non-covalently bound PPIX is shown to be an efficient FRET probe in reporting the different temperature-induced folded states of HSA in buffer solutions of widely differing pH values.     

The investigation of industrial plant processes using radiotracer techniques

Additional plant has been commissioned at the Springfields Works of BNFL to obtain increased production of uranium tetrafluoride. A programme of investigational work was undertaken during production to improve our understanding of the process. This paper describes some of the radiometric techniques used in the project, including passive gamma and neutron measurements and experiments using radioactive tracers.     

Chemical composition and antifungal activity of essential oils of Thuja sutchuenensis, a critically endangered species endemic to China

The essential oils from leaves, twigs and stems of large trees and shrub-like trees of Thuja sutchuenensis were extracted by hydrodistillation and supercritical fluid extraction, and analyzed by GC and GC-MS. The essential oil composition differed significantly among the three organs, as well as between large trees and shrub-like trees. Furthermore, consistent with the eastern Asia-North American disjunct distribution of the genus, many differences in the essential oil composition between T. sutchuenensis and other Thuja species were apparent. The essential oils exhibited a certain degree of antifungal activity against six strains of human pathogenic fungi.     

Versatile multilayer thin film preparation using hydrophobic interactions, crystallization, and chemical modification of poly(vinyl alcohol)

Multilayer thin film coatings were prepared on silicon substrates. Poly(vinyl alcohol) was adsorbed from aqueous solution to propyldimethylsilyl-modified silicon wafers. This thin semicrystalline coating was chemically modified using acid chlorides to form thicker, hydrophobic coatings. The products of the modification reactions allowed adsorption of a subsequent layer of poly(vinyl alcohol) that could subsequently be hydrophobized. This two-step process (adsorption/chemical modification) allows layer-by-layer deposition to prepare coatings with thickness, chemical structure, and wettability control.     

Enzyme Design from the Bottom Up: An Active Nickel Electrocatalyst with a Structured Peptide Outer Coordination Sphere

Catalytic, peptide‐containing metal complexes with a well‐defined peptide structure have the potential to enhance molecular catalysts through an enzyme‐like outer coordination sphere. Here, we report the synthesis and characterization of an active, peptide‐based metal complex built upon the well‐characterized hydrogen production catalyst [Ni(P^Ph₂N^Ph)₂]²⁺ (P^Ph₂N^Ph=1,3,6‐triphenyl‐1‐aza‐3,6‐diphosphacycloheptane). The incorporated peptide maintains its β‐hairpin structure when appended to the metal core, and the electrocatalytic activity of the peptide‐based metal complex (≈100,000 s^?1) is enhanced compared to the parent complex ([Ni(P^Ph₂N^APPA)₂]²⁺; ≈50,500 s^‐1). The combination of an active molecular catalyst with a structured peptide provides a scaffold that permits the incorporation of features of an enzyme‐like outer‐coordination sphere necessary to create molecular electrocatalysts with enhanced functionality.     

21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer Greatly Expands Mass Spectrometry Toolbox

We provide the initial performance evaluation of a 21 Tesla Fourier transform ion cyclotron resonance mass spectrometer operating at the Environmental Molecular Sciences Laboratory at the Pacific Northwest National Laboratory. The spectrometer constructed for the 21T system employs a commercial dual linear ion trap mass spectrometer coupled to a FTICR spectrometer designed and built in-house. Performance gains from moving to higher magnetic field strength are exemplified by the measurement of peptide isotopic fine structure, complex natural organic matter mixtures, and large proteins. Accurate determination of isotopic fine structure was demonstrated for doubly charged Substance P with minimal spectral averaging, and 8158 molecular formulas assigned to Suwannee River Fulvic Acid standard with root-mean-square (RMS) error of 10 ppb. We also demonstrated superior performance for intact proteins; namely, broadband isotopic resolution of the entire charge state distribution of apo-transferrin (78 kDa) and facile isotopic resolution of monoclonal antibody under a variety of acquisition parameters (e.g., 6 s time-domains with absorption mode processing yielded resolution of approximately 1 M at m/z?=?2700).

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Nickel‐Catalyzed Cross‐Coupling of Redox‐Active Esters with Boronic Acids

A transformation analogous in simplicity and functional group tolerance to the venerable Suzuki cross‐coupling between alkyl‐carboxylic acids and boronic acids is described. This Ni‐catalyzed reaction relies upon the activation of alkyl carboxylic acids as their redox‐active ester derivatives, specifically N‐hydroxy‐tetrachlorophthalimide (TCNHPI), and proceeds in a practical and scalable fashion. The inexpensive nature of the reaction components (NiCl₂?6 H₂O—$9.5 mol^?1, Et₃N) coupled to the virtually unlimited commercial catalog of available starting materials bodes well for its rapid adoption.     

The preparation of 2,6-diaminopyrazine, 2,6-diazidopyrazine and some of their derivatives

A much improved synthesis of the heretofore difficultly obtainable 2,6-diaminopyrazine (4) was afforded by the low-pressure catalytic hydrogenation (palladium on carbon) of 2,6-diazido-pyrazine (2) ; reaction of 2,6-dichloropyrazine (1) and sodium azide gave 2 in 84% yield. The outcome of the reduction was found to be solvent dependent: 1,2-dimethoxyethane containing aqueous ammonia gave 4 in 83% yield; 1,2-dimethoxyethane alone gave 5-aminotetrazolo[1,5-a]-pyrazine (3) in 26% yield. Additional alternative syntheses of 3 and 4 are described. A number of acyl and azo derivatives of 4 were prepared. Reactions of 2 with dimethyl acetylenedicarboxylate and ethyl acetate (base catalyzed) leading to vic-triazole derivatives are also described.     

Metal---metal bond formation promoted by steric effects: The structural chemistry of μ-dichlorobis(di-t-butyl-p-tolylphosphine)tetracarbonyldiruthenium(I)

The bulky teratiary phosphines P-t-Bu₂Ph and P-t-Bu₂-p-tol, provide binuclear ruthenium(I) complexes. An X-ray analysis of [Ru₂Cl₂(CO)₄(P-t-Bu₂-p-tol)₂] shows the RuCl₂Ru bridge to be non-planar and to have an Ru---Ru distance of 2.632Å.