Comparative bioavailability of two zolpidem hemitartrate formulations in healthy human Brazilian volunteers using high-performance liquid chromatography coupled to tandem mass spectrometry

To assess the bioequivalence of two zolpidem hemitartrate formulations in 30 healthy volunteers. Plasma samples were obtained over a 24 h period. Plasma concentrations of zolpidem were analyzed by liquid chromatography coupled to tandem mass spectrometry with positive ion electrospray ionization using multiple reaction monitoring. Values of peak concentration (C_max), area under curve (AUC), half-life, elimination constant, volume of distribution and clearance showed statistically significant differences when comparing women (604.34 ng h/ml, 127.36 ng/ml, 4.4 h, 0.18 1/h, 50.56 L and 8.55 L/h, respectively) and men (276.1 ng h/ml, 70.9 ng/ml, 3.3 h, 0.26 1/h, 91.42 L and 24.34 L/h, respectively), receiving the same dose (5 mg), respectively. The geometric means with corresponding 90% confidence interval for Test/Reference percentage ratios were 99.73% (CI 93.69–106.16) for C_max, 97.44% (90% CI = 91.85–103.37%) for area under curve of plasma concentration until the last concentration observed (AUC_last) and 98.30% (90% CI = 92.48–104.49) for the area under curve between the first sample (pre-dosage) and infinity (AUC_0–inf). Since the 90% CI for AUC_last, AUC_0–inf and C_max ratios were within the 80–125% interval proposed by the US Food and Drug Administration, it was concluded that zolpidem hemitartrate formulation (5 mg orodispersible tablet) is bioequivalent to the zolpidem hemitartrate formulation (Patz SL 5 mg sublingual tablet) with regard to both the rate and the extent of absorption. A new formulation of zolpidem 2.5 mg may be useful in women for the same clinical benefits as the 5 mg formulation in men.     

Assessment of pharmacokinetic interaction between piracetam and l‐carnitine in healthy subjects

A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d‐8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one‐step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high‐performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC‐MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5–50 µg/mL (r > 0.99). This LC‐MS‐MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l‐carnitine (Piracar®; 270/330 mg tablet) and piracetam (Nootropil®; 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 – 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 – 104.51) for AUC_inf/dose. The limit of quantitation of 0.5 µg/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar®; 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil®; 800 mg tablet) formulation with regard to both the rate and the extent of absorption. Copyright © 2015 John Wiley & Sons, Ltd.     

Seeking (and finding) Lagrangians

It is well known that for any second-order ordinary differential equation (ODE), a Lagrangian always exists, and the key to its construction is the Jacobi last multiplier. Is it possible to find Lagrangians for first-order systems of ODEs or for higher-order ODEs? We show that the Jacobi last multiplier can also play a major role in this case.     

Ubiquitous symmetries

We review some of our recent work devoted to the problem of quantization with preservation of Noether symmetries, finding hidden linearity in superintegrable systems, and showing that nonlocal symmetries are in fact local. In particular, we derive the Schrödinger equation for the isochronous Calogero goldfish model using its relation to Darwin equation. We prove the linearity of a classical superintegrable system on a plane of nonconstant curvature. We find the Lie point symmetries that correspond to the nonlocal symmetries (also reinterpreted as λ-symmetries) of the Riccati chain.     

Theoretical derivation of the conservation equations for single phase flow in porous media: a continuum approach

This paper deals with the theoretical derivation of the conservation equations for single phase flow in a porous medium. The derivation is obtained within the framework of the continuum mechanics and classical thermodynamics. The adopted procedure provides the conservation equations of mass, momentum, mechanical energy, total energy, internal energy, entropy, temperature, enthalpy, Gibbs free energy and Helmholtz free energy. The obtained results highlight the connection between the basic equations of fluid mechanics and of fluid flow in porous media, as well as the restrictions and the limitations of Darcy’s law and Richards’ equation.     

Phosphate Assisted Proton Transfer in Water and Sugar Glasses: A Study Using Fluorescence of Pyrene-1-carboxylate and IR Spectroscopy

The role of water’s H-bond percolation network in acid-assisted proton transfer was studied in water and glycerol solutions and in sugar glasses. Proton transfer rates were determined by the fluorescence of pyrene-1-carboxylate, a compound with a higher pK in its excited state relative to the ground state. Excitation of pyrene-1-COO⁻ produces fluorescence from pyrene-1-COOH when a proton is accepted during the excited singlet state lifetime of pyrene-1-COO⁻. The presence of glycerol as an aqueous cosolvent decreases proton transfer rates from phosphoric and acetic acid in a manner that does not follow the Stokes relationship on viscosity. In sugar glass composed of trehalose and sucrose, proton transfer occurs when phosphate is incorporated in the glass. Sugar glass containing phosphate retains water and it is suggested that proton transfer requires this water. The infrared (IR) frequency of water bending mode in sugar glass and in aqueous solution is affected by the presence of phosphate and the IR spectral bands of all phosphate species in water are temperature dependent; both results are consistent with H-bonding between water and phosphate. The fluorescence results, which studied the effect of cosolvent, highlight the role of water in assisting proton transfer in reactions involving biological acids, and the IR results, which give spectroscopic evidence for H-bonding between water and phosphate, are consistent with a mechanism of proton transfer involving H-bonding. The possibility that the phosphate-rich surface of membranes assists in proton equilibration in cells is discussed.     

Electrical impedance spectroscopy of epoxy systems: The case of 1,4-butanediol diglycidyl ether/cis-1,2-cyclohexanedicarboxylic anhydride and triethylamine as initiator

A series of epoxy cured samples, with different molar composition of 1,4-butanediol diglycidyl ether (EP), cis-1,2-cyclohexanedicarboxylic anhydride (CH) and triethylamine (TEA) as initiator, was studied by Electrical Impedance Spectroscopy (EIS) in the frequency range 10⁻²-10⁵ Hz. The resistivity of the system was evaluated by using the complex impedance analysis method. Resistivity values in the range between 10⁷ and 10¹³ Ω cm were obtained and related to the composition (molar fraction x_EP or x_CH) of the epoxy system. The gel formation characteristics of the samples were obtained as theoretically described by Flory.     

Mapping the hydration dynamics of ubiquitin

The nature of water's interaction with biomolecules such as proteins has been difficult to examine in detail at atomic resolution. Solution NMR spectroscopy is potentially a powerful method for characterizing both the structural and temporal aspects of protein hydration but has been plagued by artifacts. Encapsulation of the protein of interest within the aqueous core of a reverse micelle particle results in a general slowing of water dynamics, significant reduction in hydrogen exchange chemistry and elimination of contributions from bulk water thereby enabling the use of nuclear Overhauser effects to quantify interactions between the protein surface and hydration water. Here we extend this approach to allow use of dipolar interactions between hydration water and hydrogens bonded to protein carbon atoms. By manipulating the molecular reorientation time of the reverse micelle particle through use of low viscosity liquid propane, the T(1ρ) relaxation time constants of (1)H bonded to (13)C were sufficiently lengthened to allow high quality rotating frame nuclear Overhauser effects to be obtained. These data supplement previous results obtained from dipolar interactions between the protein and hydrogens bonded to nitrogen and in aggregate cover the majority of the molecular surface of the protein. A wide range of hydration dynamics is observed. Clustering of hydration dynamics on the molecular surface is also seen. Regions of long-lived hydration water correspond with regions of the protein that participate in molecular recognition of binding partners suggesting that the contribution of the solvent entropy to the entropy of binding has been maximized through evolution.     

Electro-initiated cationic polymerizations-VI: Anodic electrochemical behaviour and direct electropolymerization of anethole in 1,2-dichloroethane

A study has been made of the cationic electropolymerization of trans-anethole initiated by a direct electron transfer mechanism at a Pt anode in 1,2-dichloroethane solution with tetrabutylammonium perchlorate as supporting electrolyte. The electrochemical behaviour of the system has been preliminarily investigated by voltammetry at rotating and stationary Pt electrode and also by chronoamperometry. The results are consistent with an ECE oxidation process of anethole with formation first of a radical cation and finally of a dication. Polymerization experiments by electrolysis at the oxidation potential of the monomer have been also carried out both under continuous electrolysis and with short initial pulses of current. The results have been analysed and some kinetic parameters of the system have been evaluated.     

Coupled motion in proteins revealed by pressure perturbation

The cooperative nature of protein substructure and internal motion is a critical aspect of their functional competence about which little is known experimentally. NMR relaxation is used here to monitor the effects of high pressure on fast internal motion in the protein ubiquitin. In contrast to the main chain, the motions of the methyl-bearing side chains have a large and variable pressure dependence. Within the core, this pressure sensitivity correlates with the magnitude of motion at ambient pressure. Spatial clustering of the dynamic response to applied hydrostatic pressure is also seen, indicating localized cooperativity of motion on the sub-nanosecond time scale and suggesting regions of variable compressibility. These and other features indicate that the native ensemble contains a significant fraction of members with characteristics ascribed to the recently postulated "dry molten globule". The accompanying variable side-chain conformational entropy helps complete our view of the thermodynamic architecture underlying protein stability, folding, and function.