On extremal solutions to stochastic control problems,II

The set of attainable laws of the joint state-control process of a controlled diffusion is analyzed from a convex analytic viewpoint. Various equivalence relations depending on one-dimensional marginals thereof are defined on this set and the corresponding equivalence classes are studied.     

On infinitesimal σ-fields generated by random processes

It is proved that the infinitesimal look-ahead and look-back σ-fields of a random process disagree at atmost countably many time instants.     

Characterization of forced degradation products of ketorolac tromethamine using LC/ESI/Q/TOF/MS/MS and in silico toxicity prediction

Ketorolac, a nonsteroidal anti‐inflammatory drug, was subjected to forced degradation studies as per International Conference on Harmonization guidelines. A simple, rapid, precise, and accurate high‐performance liquid chromatography combined with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry (LC/ESI/Q/TOF/MS/MS) method has been developed for the identification and structural characterization of stressed degradation products of ketorolac. The drug was found to degrade in hydrolytic (acidic, basic, and neutral), photolytic (acidic, basic, and neutral solution), and thermal conditions, whereas the solid form of the drug was found to be stable under photolytic conditions. The method has shown adequate separation of ketorolac tromethamine and its degradation products on a Grace Smart C‐18 (250 mm × 4.6 mm i.d., 5 µm) column using 20 mM ammonium formate (pH = 3.2): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 1.0 ml/min. A total of nine degradation products were identified and characterized by LC/ESI/MS/MS. The most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the [M + H]⁺ ions of ketorolac and its degradation products. In silico toxicity of the drug and degradation products was investigated by using topkat and derek softwares. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization guidelines. Copyright © 2014 John Wiley & Sons, Ltd.     

In vivo metabolic investigation of silodosin using UHPLC–QTOF–MS/MS and in silico toxicological screening of its metabolites

Silodosin (SLD) is a novel α1‐adrenoceptor antagonist which has shown promising clinical efficacy and safety in patients with benign prostatic hyperplasia (BPH). However, lack of information about metabolism of SLD prompted us to investigate metabolic fate of SLD in rats. To identify in vivo metabolites of SLD, urine, feces and plasma were collected from Sprague–Dawley rats after its oral administration. The samples were prepared using an optimized sample preparation approach involving protein precipitation followed by solid‐phase extraction and then subjected to LC/HR‐MS/MS analysis. A total of 13 phase I and six phase II metabolites of SLD have been identified in rat urine which includes hydroxylated, N‐dealkylated, dehydrogenated, oxidative, glucosylated, glucuronide and N‐sulphated metabolites, which are also observed in feces. In plasma, only dehydrogenated, N‐dealkylated and unchanged SLD are observed. The structure elucidation of metabolites was done by fragmentation in MS/MS in combination with HRMS data. The potential toxicity profile of SLD and its metabolites were predicted using TOPKAT software and most of the metabolites were proposed to show a certain degree of skin sensitization and occular irritancy. Copyright © 2016 John Wiley & Sons, Ltd.     

Unexpectedly similar charge transfer rates through benzo-annulated bicyclo[2.2.2]octanes

A 4-(pyrrolidin-1-yl)phenyl electron donor and 10-cyanoanthracen-9-yl electron acceptor are attached via alkyne linkages to the bridgehead carbon atoms of bicyclo[2.2.2]octane and all three benzo-annulated bicyclo[2.2.2]octanes. The sigma-system of bicyclo[2.2.2]octane provides a scaffold having nearly constant bridge geometry on which to append multiple, weakly interacting benzo pi-bridges, so that the effect of incrementally increasing numbers of pi-bridges on electron transfer rates can be studied. Surprisingly, photoinduced charge transfer rates measured by transient absorption spectroscopy in toluene show no benefit from increasing the number of bridge pi-systems, suggesting dominant transport through the sigma-system. Even more surprisingly, the significant changes in hybridization undergone by the sigma-system as a result of benzo-annulation also appear to have no effect on the charge transfer rates. Natural Bond Orbital analysis is applied to both sigma- and pi-communication pathways. The transient absorption spectra obtained in 2-methyltetrahydrofuran (MTHF) show small differences between the benzo-annulated molecules that are attributed to changes in solvation. All charge transfer rates increase significantly upon cooling the MTHF solutions to their glassy state. This behavior is rationalized using combined molecular dynamics/electronic structure trajectories.     

Cell adhesion on nanofibrous polytetrafluoroethylene (nPTFE)

Here, we described the in vitro biocompatibility of a novel nanostructured surface composed of PTFE as a potential polymer for the prevention of adverse host reactions to implanted devices. The foreign body response is characterized at the tissue-material interface by several layers of macrophages and large multinucleated cells known as foreign body giant cells (FBGC), and a fibrous capsule. The nanofibers of nanofibrous PTFE (nPTFE) range in size from 20 to 30 nm in width and 3-4 mm in length. Glass surfaces coated with nPTFE (produced by jet-blowing of PTFE 601A) were tested under in vitro conditions to characterize the amount of protein adsorption, cell adhesion, and cell viability. We have shown that nPTFE adsorbs 495 +/- 100 ng of bovine serum albumin (BSA) per cm2. This level was considerably higher than planar PTFE, most likely due to the increase in hydrophobicity and available surface area, both a result of the nanoarchitecture. Endothelial cells and macrophages were used to determine the degree of cell adsorption on the surface of the nanostructured polymer. Both cell types were significantly more round and occupied less area on nPTFE as compared to tissue culture polystyrene (TCPS). Furthermore, a larger majority of the cells on the nPTFE were dead compared to TCPS, at dead-to-live ratios of 778 +/- 271 to 1 and 23 +/- 5.6 to 1, respectively. Since there was a high amount of cell death (due to either apoptosis or necrosis), and the foreign body response is a form of chronic inflammation, an 18 cytokine Luminex panel was performed on the supernatant from macrophages adherent on nPTFE and TCPS. As a positive control for inflammation, lipopolysaccharide (LPS) was added to macrophages on TCPS to estimate the maximum inflammation response of the macrophages. From the data presented with respect to IL-1, TNF-alpha, IFN-gamma, and IL-5, we concluded that nPTFE is nonimmunogenic and should not yield a huge inflammatory response in vivo, and cell death observed on the surface of nPTFE was likely due to apoptosis resulting from the inability of cells to spread on these surface. On the basis of the production of IL-1, IL-6, IL-4, and GM-CSF, we concluded that FBGC formation on nPTFE may be decreased as compared to materials known to elicit FBGC formation in vivo.     

Identification and characterization of in vitro and in vivo fidarestat metabolites: Toxicity and efficacy evaluation of metabolites

The progression of diabetic complications can be prevented by inhibition of aldose reductase and fidarestat considered to be highly potent. To date, metabolites of the fidarestat, toxicity, and efficacy are unknown. Therefore, the present study on characterization of hitherto unknown in vitro and in vivo metabolites of fidarestat using liquid chromatography–electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) is undertaken. In vitro and in vivo metabolites of fidarestat have been identified and characterized by using LC/ESI/MS/MS and accurate mass measurements. To identify in vivo metabolites, plasma, urine, and feces samples were collected after oral administration of fidarestat to Sprague–Dawley rats, whereas for in vitro metabolites, fidarestat was incubated in human S9 fraction, human liver microsomes, and rat liver microsomes. Furthermore, in silico toxicity and efficacy of the identified metabolites were evaluated. Eighteen metabolites have been identified. The main in vitro phase I metabolites of fidarestat are oxidative deamination, oxidative deamination and hydroxylation, reductive defluroniation, and trihydroxylation. Phase II metabolites are methylation, acetylation, glycosylation, cysteamination, and glucuronidation. Docking studies suggest that oxidative deaminated metabolite has better docking energy and conformation that keeps consensus with fidarestat whereas the rest of the metabolites do not give satisfactory results. Aldose reductase activity has been determined for oxidative deaminated metabolite (F‐1), and it shows an IC50 value of 0.44 μM. The major metabolite, oxidative deaminated, did not show any cytotoxicity in H9C2, HEK, HEPG2, and Panc1 cell lines. However, in silico toxicity, the predication result showed toxicity in skin irritation and ocular irritancy SEV/MOD versus MLD/NON (v5.1) model for fidarestat and its all metabolites. In drug discovery and development research, it is distinctly the case that the potential for pharmacologically active metabolites must be considered. Thus, the active metabolites of fidarestat may have an advantage as drug candidates as many drugs were initially observed as metabolites.     

Characterization of degradation products of Ivabradine by LC‐HR‐MS/MS: a typical case of exhibition of different degradation behaviour in HCl and H2SO4 acid hydrolysis

A validated stability‐indicating HPLC method was established, and comprehensive stress testing of ivabradine, a cardiotonic drug, was carried out as per ICH guidelines. Ivabradine was subjected to acidic, basic and neutral hydrolysis, oxidation, photolysis and thermal stress conditions, and the resulting degradation products were investigated by LC‐PDA and LC‐HR‐MS/MS. The drug was found to degrade in acid and base hydrolysis. An efficient and selective stability assay method was developed on Phenomenex Luna C18 (250 × 4.6 mm, 5.0 µm) column using ammonium formate (10 mM, pH 3.0) and acetonitrile as mobile phase at 30 °C in gradient elution mode. The flow rate was 0.7 ml/min and detection wavelength was 286 nm. A total of five degradation products (I‐1 to I‐5) were identified and characterized by LC‐HR‐MS/MS in combination with accurate mass measurements. The drug exhibited different degradation behaviour in HCl and H₂SO₄ hydrolysis conditions. It is a unique example where two of the five degradation products in HCl hydrolysis were absent in H₂SO₄ acid hydrolysis. The present study provides guidance to revise the stress test for the determination of inherent stability of drugs containing lactam moiety under hydrolytic conditions. Most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation pattern of the drug and its degradation products. In silico toxicity revealed that the degradation products ( I‐2 to I‐5 ) were found to be severe irritants in case of ocular irritancy. The analytical assay method was validated with respect to specificity, linearity, range, precision, accuracy and robustness. Copyright © 2015 John Wiley & Sons, Ltd.     

The stereoselective synthesis of cis-/trans-fused hexahydropyrano[4,3-b]chromenes via Prins cyclization trapping by a tethered nucleophile

A novel intramolecular Prins cyclization of (Z)-2-(5-hydroxypent-2-enyl)phenol with various aldehydes has been achieved using 10 mol% In(OTf)(3) and 30 mol% TsOH to produce the cis-fused hexahydropyrano[4,3-b]chromene derivatives in good yields, while the coupling of (E)-2-(5-hydroxypent-2-enyl)phenol with aldehydes under similar conditions affords the corresponding trans-fused hexahydropyrano[4,3-b]chromene derivatives.     

Stochastic approximation with long range dependent and heavy tailed noise

Stability and convergence properties of stochastic approximation algorithms are analyzed when the noise includes a long range dependent component (modeled by a fractional Brownian motion) and a heavy tailed component (modeled by a symmetric stable process), in addition to the usual ‘martingale noise’. This is motivated by the emergent applications in communications. The proofs are based on comparing suitably interpolated iterates with a limiting ordinary differential equation. Related issues such as asynchronous implementations, Markov noise, etc. are briefly discussed.