Analysis of five HMG-CoA reductase inhibitors-- atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin: pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies

A specific, accurate, precise and reproducible high-performance liquid chromatographic (HPLC) method was developed and validated for the simultaneous quantitation of five 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, viz. atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin, in pharmaceutical formulations and extended the application to in vitro metabolism studies of these statins. Ternary gradient elution at a flow rate of 1 mL/min was employed on an Intertisl ODS 3V column (4.6 x 250 mm, 5 microm) at ambient temperature. The mobile phase consisted of 0.01 m ammonium acetate (pH 5.0), acetonitrile and methanol. Theophylline was used as an internal standard (IS). The HMG-CoA reductase inhibitors and their metabolites were monitored at a wavelength of 237 nm. Drugs were found to be 89.6-105.6% of their label's claim in the pharmaceutical formulations. For in vitro metabolism studies the reaction mixtures were extracted with simple liquid-liquid extraction using ethyl acetate. Baseline separation of statins and their metabolites along with IS free from endogenous interferences was achieved. Nominal retention times of IS, atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin were 7.5, 17.2, 21.6, 28.5, 33.5 and 35.5 min, respectively. The proposed method is simple, selective and could be applicable for routine analysis of HMG-CoA reductase inhibitors in pharmaceutical preparations as well as in vitro metabolism studies.     

Nonlinear Elasticity in a Deforming Ambient Space

In this paper, we formulate a nonlinear elasticity theory in which the ambient space is evolving. For a continuum moving in an evolving ambient space, we model time dependency of the metric by a time-dependent embedding of the ambient space in a larger manifold with a fixed background metric. We derive both the tangential and the normal governing equations. We then reduce the standard energy balance written in the larger ambient space to that in the evolving ambient space. We consider quasi-static deformations of the ambient space and show that a quasi-static deformation of the ambient space results in stresses, in general. We linearize the nonlinear theory about a reference motion and show that variation of the spatial metric corresponds to an effective field of body forces.     

Selective Structural Derivatization of Flavonoid Acetamides Significantly Impacts Their Bioavailability and Antioxidant Properties

Flavonoids show abundant favorable physicochemical and drug related properties, leading to substantial biological applications which are limited by undesirable properties such as poor solubility, high polarity, low bioavailability, and enzymatic degradations. Chemical modification with bioisosteres can be used to address some of these challenges. We report the synthesis and characterization of partial flavonoid acetamide derivatives from quercetin, apigenin and luteolin and the evaluation of their structure-activity relationships based on antioxidant, bioavailability, drug likeness, and toxicity properties. The sequential synthesis was achieved with 76.67–87.23% yield; the structures of the compounds were confirmed using ¹H & ¹³C NMR characterizations. The purity of each compound was determined by HPLC while the molecular weights were determined by mass spectrometry. The % bioavailability was determined using the dialysis tubing procedure and the values were in the range 15.97–38.12%. The antioxidant activity was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and expressed as the IC₅₀ values which were in the range 31.52–198.41 µM. The drug likeness and the toxicity properties of compounds 4, 5, 7, 11 and 15 were predicted using computational tools and showed satisfactory results. A structure-activity relationship evaluation reveals that hydroxyl and methylene groups attached on the 2-phenylchromen-4-one structure of the flavonoid play a colossal role in the overall antioxidant and bioavailability properties. The improved bioavailability and excellent drug relevance and toxicity properties present flavonoid acetamide derivatives as prospective drug candidates for further evaluations.     

The behavior of lipid debris left on cell surfaces from microbubble based ultrasound molecular imaging

Lipid monolayer coated microbubbles are currently being developed to identify vascular regions that express certain surface proteins as part of the new technique of ultrasound molecular imaging. The microbubbles are functionalized with targeting ligands which bind to the desired cells holding the microbubbles in place as the remaining unbound microbubbles are eliminated from circulation. Subsequent scanning with ultrasound can detect the highly reflectant microbubbles that are left behind. The ultrasound scanning and detection process results in the destruction of the microbubble, creating lipid fragments from the monolayer. Here we demonstrate that microbubbles targeted to 4T1 murine breast cancer cells and human umbilical cord endothelial cells leave behind adhered fragments of the lipid monolayer after exposure to ultrasound with peak negative pressures of 0.18 and 0.8 MPa. Most of the observed fragments were large enough to be resistant to receptor mediated endocytosis. The fragments were not observed to incorporate into the lipid membrane of the cell over a period of 96 min. They were not observed to break into smaller pieces or significantly change shape but they were observed to undergo translation and rotation across the cell surface as the cells migrated over the substrate. These large fragments will apparently remain on the surface of the targeted cells for significant periods of time and need to be considered for their potential effects on blood flow through the microcapillaries and potential for immune system recognition.     

Pressure assisted chelating extraction: a novel technique for digesting metals in solid matrices

This work describes a novel technique for the digestion of metals in solid matrices. The technique is called pressure assisted chelating extraction (PACE). In a typical procedure, a solid sample is placed in a stainless steel cell and is mixed with appropriate chelating agents. Using a programmed sequence of temperature, static time, pressure and thermal equilibration available in ASE 200, the metal is removed under moderate temperature (up to 200 degrees C) and pressure (up to 3000 psi). PACE achieves metal recovery that is equivalent to that of wet digestion techniques and also provides for a clean and safe operation by substituting the strong acids commonly used during wet digestion with chelating agents. It uses less solvents and significantly less time (minutes vs. hours) for metal digestion. PACE has been validated using certified standard reference materials (SRMs) including industrial sludge, buffalo river sediments and coal fly ash. The total time required to remove metals was approximately 20 min. Results show that the PACE system provides an ideal platform for efficient, rapid, and safe metal digestion. Good agreement between measured and reference values for Pb, Mn, and Cu were found with recoveries averaging between 80 and 101% and a relative standard deviation of less than 5%. This approach may provide an alternative digestion technique for environmental samples, alloys, biological materials and samples of geological importance. The potential advantage offered lies in non-destruction of the sample, automation and the exclusion of concentrated mineral acids during the digestion procedure.     

New proton-ionizable macrocyclic compounds containing one and two triazole subcyclic units — synthesis and complexation properties

A series of new macrocyclic compounds containing one and two proton-ionizable triazole subcyclic units have been prepared and characterized. These triazolo-crowns containing benzo, tert-butylbenzo or cyclohexano lipophilic groups show varying solubilities in chloroform. The bistriazolo-crowns dissolved in chloroform are highly effective for extraction of lead, mercury, and gold from aqueous solutions.     

Synthesis of lariat ethers with pendent amine,amide, O‐benzylhydroxamate,and urethane groups

Synthetic routes to twenty‐six new crown ether compounds with pendent amine, amide, O‐benzylhydrox‐amate, and urethane groups are reported. The new lariat ether compounds are based on sym‐dibenzo‐16‐crown‐5, sym‐dicyclohexano‐16‐crown‐5, and 14‐crown‐4 scaffolds.     

Extremal Problems on Components and Loops in Graphs

The authors recently defined a new graph invariant denoted by Ω(G) only in terms of a given degree sequence which is also related to the Euler characteristic. It has many important combinatorial applications in graph theory and gives direct information compared to the better known Euler characteristic on the realizability, connectedness, cyclicness, components, chords, loops etc. Many similar classification problems can be solved by means of Ω. All graphs G so that Ω(G) ≤-4 are shown to be disconnected, and if Ω(G) ≥-2, then the graph is potentially connected. It is also shown that if the realization is a connected graph and Ω(G) =-2, then certainly the graph should be a tree.Similarly, it is shown that if the realization is a connected graph G and Ω(G) ≥ 0, then certainly the graph should be cyclic. Also, when Ω(G) ≤-4, the components of the disconnected graph could not all be cyclic and if all the components of G are cyclic, then Ω(G) ≥ 0. In this paper, we study an extremal problem regarding graphs. We find the maximum number of loops for three possible classes of graphs.We also state a result giving the maximum number of components amongst all possible realizations of a given degree sequence.     

Synthesis and characterization of lipid-polymer hybrid nanoparticles with pH-triggered poly(ethylene glycol) shedding

Novel lipid-polymer hybrid nanoparticles are designed with a poly(ethylene glycol) (PEG) coating that is shed in response to a low pH trigger. This allows the nanoparticles to be stable during systemic circulation and at neutral pH, but destabilize and fuse with lipid membranes in acidic environments. The hybrid nanoparticles consist of a poly(lactic-co-glycolic acid) core with a lipid and lipid-PEG monolayer shell. To make the hybrid nanoparticles pH sensitive, a lipid-(succinate)-mPEG conjugate is synthesized to provide a hydrolyzable PEG stealth layer that is shed off the particle surface at low pH. The pH-sensitivity of the nanoparticles is tunable using the molar concentration of the lipid-(succinate)-mPEG incorporated in the lipid shell of the particles. Possible uses of these pH-sensitive nanoparticles include aggregating in acidic tumor microenvironments, escaping acidified endosomes, or aggregating in deep lung tissue for improved inhalation administration.     

Validation of the S‐CLSVOF method with the density‐scaled balanced continuum surface force model in multiphase systems coupled with thermocapillary flows

Three numerical methods, namely, volume of fluid (VOF), simple coupled volume of fluid with level set (S‐CLSVOF), and S‐CLSVOF with the density‐scaled balanced continuum surface force (CSF) model, have been incorporated into OpenFOAM source code and were validated for their accuracy for three cases: (i) an isothermal static case, (ii) isothermal dynamic cases, and (iii) non‐isothermal dynamic cases with thermocapillary flow including dynamic interface deformation. Results have shown that the S‐CLSVOF method gives accurate results in the test cases with mild computation conditions, and the S‐CLSVOF technique with the density‐scaled balanced CSF model leads to accurate results in the cases of large interface deformations and large density and viscosity ratios. These show that these high accuracy methods would be appropriate to obtain accurate predictions in multiphase flow systems with thermocapillary flows. Copyright © 2016 John Wiley & Sons, Ltd.