Controlled ex‐vivo plasma hydrolysis of valaciclovir to acyclovir demonstration using tandem mass spectrometry

Plasma estimation of valaciclovir, an antiviral drug, is challenging due to both in‐vivo and ex‐vivo hydrolysis to active metabolite acyclovir. A simultaneous method is described involving the solid‐phase ion‐exchange extraction procedure requiring 100 μL of plasma volume, a reverse‐phase Lichrosphere RP Select B (125 × 6 mm, 5 μm) column and isocratic mobile phase to achieve the desired chromatographic separation. ESI‐MS/MS multiple reaction monitoring in positive polarity, detected mass pairs for valaciclovir (m/z 325.5 → 152.2), acyclovir (m/z 226.3 → 152.2) and respective internal standards valganciclovir (m/z 307.1 → 220.3) and acyclovir‐d4 (m/z 230.2 → 152.0). Fully fledged method validation was evaluated as per current regulatory requirements and results were deemed acceptable. The plasma samples showed extensive hydrolysis of valaciclovir when collected or processed at room temperature, without buffer stabilization prior to storage at −15°C. Our results showed that using prechilled K₃EDTA vacutainers immersed in an iced‐water bath during blood sample collection, and addition of 50% orthophosphoric acid solution to plasma samples prior to storage at −50°C for at least 120 days controlled the hydrolysis of valaciclovir to acyclovir. While monitoring drug absorption into systematic circulation, the valaciclovir to acyclovir formation ratio was improved to 1:20 in healthy volunteers for the first time. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of (+)-isofagomine

The synthesis of (+)-isofagomine 1 using 4-pentenol 3 as a chiral precursor is described herein.     

Crystallization and dissolution of flow-induced precursors

We make use of a specially synthesized linear high density polyethylene with a bimodal molecular weight distribution (MWD) to demonstrate that it is possible to produce a suspension of extended-chain (shish) crystals only. Such a suspension can be generated at high temperatures, above but close to the equilibrium melting temperature of the unconstrained extended-chain crystals (T(m)(0)=141.2 degrees C) and requires stretch of the longest chains of the MWD. After the application of a shear flow of 120 s(-1) for 1 s at 142 degrees C, x-ray scattering suggests the presence of a large number of metastable needlelike precursors with limited or no crystallinity. Precursors that are too small dissolve on a timescale that correlates perfectly with the reptation time of the longest polymer molecules. Whereas, precursors that exceed a critical size crystallize forming extended-chain shishes.     

Common fixed points for weakly compatible maps

The purpose of this paper is to prove a common fixed point theorem, from the class of compatible continuous maps to a larger class of maps having weakly compatible maps without appeal to continuity, which generalizes the results of Jungck [3], Fisher [1], Kang and Kim [8], Jachymski [2], and Rhoades [9].     

Ethylene Polymerization with Combinations of Early- and Late-Transition Metal Catalysts Immobilized on MgCl2 Supports

Immobilization of combinations of early- and late-transition metal catalysts on MgCl₂ supports has led to significant increases in catalyst activity when a nickel diimine is incorporated into a Fe-, Cr- or Ti-based catalyst system, and to the formation of intimately mixed, bimodal blends of high- and low-molecular weight polyethylene via coimmobilization of Cr and Fe catalysts.     

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV^pro) and NS5 RNA dependent RNA polymerase (ZIKV^RdRp) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (−7.9 to −11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV^pro (B:His⁵¹, B:Asp⁷⁵, and B:Ser¹³⁵) and ZIKV^RdRp (Asp⁵⁴⁰, Ile⁷⁹⁹, and Asp⁶⁶⁵) by comparison to the reference compounds, O7N inhibitor (ZIKV^pro) and Sofosbuvir inhibitor (ZIKV^RdRp). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV^pro and ZIKV^RdRp against ZIKV for further experimental assessment.     

Normal and anti Meyer–Neldel rule in conductivity of highly crystallized undoped microcrystalline silicon films

We have studied the electrical conductivity behavior of highly crystallized undoped hydrogenated microcrystalline silicon (μc-Si:H) films having different microstructures. The dark conductivity is seen to follow Meyer–Neldel rule (MNR) in some films and anti-MNR in others, which has been explained on the basis of variation in the film microstructure and the corresponding changes in the effective density of states distributions. A band tail transport and statistical shift of Fermi level are used to explain the origin of MNR as well as anti-MNR in our samples. The observation of MNR and anti-MNR in electrical transport behavior of μc-Si:H is discussed in terms of the basic underlying physics of their origin and the significance of these relationships.     

Ruthenium Catalyzed C−H Acylmethylation of N‐Arylphthalazine‐1,4‐diones with α‐Carbonyl Sulfoxonium Ylides: Highway to Diversely Functionalized Phthalazino‐fused Cinnolines

A direct ortho‐Csp²‐H acylmethylation of 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with α‐carbonyl sulfoxonium ylides is achieved through a Ru^II‐catalyzed C?H bond activation process. The protocol featured high functional group tolerance on the two substrates, including aryl‐, heteroaryl‐, and alkyl‐substituted α‐carbonyl sulfoxonium ylides. Thereafter, 2‐(ortho‐acylmethylaryl)‐2,3‐dihydrophthalazine‐1,4‐diones were used as potential starting materials for the expeditious synthesis of 6‐arylphthalazino[2,3‐a]cinnoline‐8,13‐diones and 5‐acyl‐5,6‐dihydrophthalazino[2,3‐a]cinnoline‐8,13‐diones under Lawesson's reagent and BF₃?OEt₂ mediated conditions, respectively. Of these, the BF₃?OEt₂‐mediated cyclization proceeded in DMSO as a solvent and a methylene source via dual C?C and C?N bond formations.     

Progress of Polymerization of D,L-Lactide Through Differential Scanning Calorimetry and Gel Permeation Chromatography

Melt polymerization conditions for D,L-lactide initiated with tetraphenyltin were studied with regard to polymer molecular weight. The present study was undertaken to investigate the progress of polymerization of D,L-lactide through differential scanning calorimetry (DSC), and also to explore the correlation between melt polymerization conditions and molecular weight. The physical characteristics, such as glass transition temperature (Tg) of the polymer and melting transition (Tm) of D,L-lactide are correlated with GPC data. DSC data shows that the Tm of D,L-lactide is 122.8 at 150°C polymerization time. ΔHf is 83.2 J g-1, and Tg of polymer is untraceable. At 180°C the Tm is 101.4°C, ΔHf is 34 J g-1, and Tg is around 29.5°C. The drop in Tm and ΔHf clearly shows the conversion of D,L-lactide to polymer. The maximum increment to molecular weight of polymer is achieved at 160°C and 8 h. After a short induction period, the slow polymerization of D,L-lactide resulted in maximal molecular weight followed by an almost constant value of molecular weight. This revised version was published online in July 2006 with corrections to the Cover Date.     

Vibrational assignments and electronic structure calculations for 3-acetylcoumarin

Laser Raman (3500-50 cm(-1)) and IR (4000-400 cm(-1)) spectral measurements have been made on the laboratory prepared solid 3-acetylcoumarin. Molecular electronic energy, equilibrium geometrical structure and harmonic vibrational spectra have been computed at the RHF/6-31G(d,p) and B3LYP/6-31G(d,p) levels of theory. A complete vibrational assignment aided by the theoretical harmonic frequency analysis has been proposed. The B3LYP/6-31G(d,p) geometrical parameters, and frequencies of the C=O in the pyrone and acetyl group are in good agreement with experiment. The difference in the frequencies due to the two carbonyl groups, 50 cm(-1), which is attributed to the conjugation effect, is accounted for by the B3LYP to be 56cm(-1).