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Alzheimer’s disease (AD) is a worldwide problem, and there are currently no treatments that can stop this disease. To investigate the binding affinity of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) with acetylcholinesterase (AChE), to verify the effects of FSP in an AD model in mice and to evaluate the toxicological potential of this compound in mice. The binding affinity of FSP with AChE was investigated by molecular docking analyses. The AD model was induced by streptozotocin (STZ) in Swiss mice after FSP treatment (1 mg/kg, intragastrically (i.g.)), 1st-10th day of the experimental protocol. Anxiety was evaluated in an elevated plus maze test, and memory impairment was evaluated in the Y-maze, object recognition and step-down inhibitory avoidance tasks. The cholinergic system was investigated based on by looking at expression and activity of AChE and expression of choline acetyltransferase (ChAT). We evaluated expression and activity of Na+/K+-ATPase. For toxicological analysis, animals received FSP (300 mg/kg, i.g.) and aspartate aminotransferase, alanine aminotransferase activities were determined in plasma and δ-aminolevulinate dehydratase activity in brain and liver. FSP interacts with residues of the AChE active site. FSP mitigated the induction of anxiety and memory impairment caused by STZ. FSP protected cholinergic system dysfunction and reduction of activity and expression of Na+/K+-ATPase. FSP did not modify toxicological parameters evaluated and did not cause the death of mice. FSP protected against anxiety, learning and memory impairment with involvement of the cholinergic system and Na+/K+-ATPase in these actions.

Elemental copper can be utilized to generate C–C bonds in order to synthesize nanographenes in a mechanochemical environment. Utilizing the solvent-free environment of a ball mill, we present a fac...

The present study evaluated the anti-amnesic activity of 1-(7-chloroquinolin-4-yl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (QTCA-1) against scopolamine (SCO)-induced amnesia in mice. It was evaluated cholinergic dysfunction, oxidative stress and Na+/K+-ATPase activity in cerebral cortex and hippocampus of mice. Male Swiss mice were treated with QTCA-1 (10 mg/kg, intragastrically (i.g.), daily) for nine days. Thirty minutes after the treatment with compound, the animals received a injection of SCO (0.4 mg/kg, intraperitoneally (i.p.)). Mice were submitted to the behavioral tasks 30 min after injection of SCO (Barnes maze, open-field, object recognition and location, and step-down inhibitory avoidance tasks) during nine days. In day 9, cerebral cortex and hippocampus of mice were removed to determine the thiobarbituric acid reactive species (TBARS) levels, and catalase (CAT), Na+/K+-ATPase and acetylcholinesterase (AChE) activities. SCO caused amnesia in mice for changing in step-down inhibitory avoidance, Barnes maze, and object recognition and object location tasks. QTCA-1 treatment attenuated the behavioral changes caused by SCO. Moreover, SCO increased AChE and CAT activities, decreased Na+/K+-ATPase activity and increased TBARS levels in the cerebral structures of mice. QTCA-1 protected against these brain changes. In conclusion, QTCA-1 had anti-amnesic action in the experimental model used in the present study, through the anticholinesterase effect, modulation of Na+/K+-ATPase activity and antioxidant action.

Angewandte Chemie / International edition International edition 58(52), 18942 - 18947 (2019). doi:10.1002/anie.201911356, The milling ball is the catalyst. We introducea palladium-catalyzed reaction inside a ball mill, whichmakes catalyst powders, ligands, and solvents obsolete. Wepresent a facile and highly sustainable synthesis concept forpalladium-catalyzed C@C coupling reactions, exemplarilyshowcased for the Suzuki polymerization of 4-bromo or 4-iodophenylboronic acid giving poly(para-phenylene). Surprisingly,we observe one of the highest degrees of polymerization(199) reported so far., Published by Wiley-VCH, Weinheim

Wound healing can be a painful and time-consuming process in patients with diabetes mellitus. In light of this, the use of wound healing devices could help to accelerate this process. Here, cellulose-based films loaded with vitamin C (VitC) and/or propolis (Prop), two natural compounds with attractive properties were engineered. The starting materials and the cellulose-based films were characterized in detail. As assessed, vitamin C can be released from the Cel-PVA/VitC and Cel-PVA/VitC/Prop films in a controlled manner. In vitro antibacterial activity studies showed a reduction of bacteria counts (Escherichia coli and Staphylococcus aureus) after Cel-PVA/VitC, Cel-PVA/Prop, and Cel-PVA/VitC/Prop treatments. Moreover, we examined the antibacterial and wound healing properties of the cellulose-based films in a streptozotocin (STZ)-induced diabetic animal model. Diabetic mice exhibited impaired wound healing while the Cel-PVA/VitC/Prop treatment increased the wound closure. A marked reduction in bacterial counts present in the wound environment of diabetic mice was observed after Cel-PVA/VitC, Cel-PVA/Prop and Cel-PVA/VitC/Prop treatment. Histological analysis demonstrated that the non-treated diabetic mice group did not exhibit adequate wound healing while the treated group with Cel-PVA/VitC and Cel-PVA/VitC/Prop films presented good cicatricial response. Furthermore, these novel eco-friendly films may represent a new therapeutic approach to accelerate diabetic wound healing.

Pheromone regulate and the behavior, physiology and development of insects. Since Butenandt and colleagues identified the Bombyx mori sex attractant pheromone bombykol in 1959, considerable research has focused on the identification of pheromones across the insects, and how these molecules are synthesized by one sex and detected by the other. Advances in research have often been driven by advances in technology. The previous edition of this book appeared shortly after the first successfully sequencing of an insect genome, that of the fly Drosophila melanogaster; this, and the subsequently increased availability of insect genomic sequences, allowed for rapid identification of chemosensory relevant genes and gene products and the resulting characterizations using traditional and novel techniques. This chapter provides an introduction to the book’s chapters, which were written by experts working at the frontiers of pheromone physiology, biochemistry and molecular biology.

Pheromone and other odor molecules are detected by chemosensory neurons housed within olfactory and taste/contact sensilla. Proteins involved in this detection process include Odor Receptors, Odorant Binding Proteins, Odor Degrading Enzymes and membrane proteins called SNMPs. In this chapter we discuss the origins, evolution and uniqueness of the Lepidoptera specific OBPs Pheromone Binding Proteins (PBPs) and General Odorant Binding Proteins (GOBPs) whose genes are largely organized into a single gene cluster. We then comment on the diversity of Odor and Pheromone Degrading Enzymes and enzymatic activities, their roles in signal termination, and their potential as targets in insect control. Finally, we present studies examining the spatial-and co-expression of SNMP1 and SNMP2 in Drosophila, and the behavioral effects of deleting their genes: SNMP1 and SNMP2 frequently co-express in the same sensilla, both olfactory and taste, but often differentially with one expressing in neurons and the other in support cells; SNMP1 gene knockouts affect fitness and both male-female and male-male courtship, while SNMP2 knockouts affect fitness and male-male courtship but not male-female courtship. We encourage consideration of additional roles for all these proteins, and for evaluating these proteins in an ethological context.

Objectives A microemulsion-based delivery system was designed to improve vitamin E (VE) properties, and its antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice were evaluated. Methods Male Swiss mice received, by intragastric route, canola oil (20 ml/kg), blank microemulsion (B-ME) (20 ml/kg), VE free (VE-F) (200 mg/kg) or VE microemulsion (VE-ME) (200 mg/kg). In acute treatment, a single dose of treatments was administrated and 30 min after behavioural tests were performed. In the subchronic treatment, mice received such treatments, once a day, for 8 days. On the eighth day, behavioural tests were performed. Key findings In the subchronic treatment, VE-ME increased entries and spent time in the open arms in the elevated plus-maze test and decreased the immobility time in the tail suspension test, but no change was found after acute treatment. Acute and subchronic treatments with VE-ME increased response latency to thermal stimulus in the hot-plate test. VE-ME decreased the thiobarbituric acid reactive species levels in the acute and subchronic protocols. Additionally, in subchronic treatment, VE-ME increased renal catalase activity, but VE-F reduced its activity. Conclusions Vitamin E-microemulsions showed antioxidant, antinociceptive, antidepressant- and anxiolytic-like actions; thus, ME-based delivery improved pharmacological properties of VE.

The present study evaluated the in vitro acetylcholinesterase (AChE) inhibitor activity of two new selanyl amide derivatives in cerebral structures of mice. Our results demonstrated that N-(2-(3-(phenylselanyl)propoxy)phenyl)furan-2-carboxamide (1) and N-(2-(3-(phenylselanyl)propoxy)phenyl)thiophene-2-carboxamide (2) inhibited the in vitro AChE activity in mice. Another objective was to assess the effect of the best AChE inhibitor in an amnesic model induced by scopolamine (SCO) in male Swiss mice. The involvement of AChE activity and lipid peroxidation in the cerebral structures was investigated. Our results showed that compound 1 (10 mg/kg, intragastrically) attenuated the latency to find the escape box and the number of holes visited in the Barnes maze task, without altering the locomotor and exploratory activities in an open-field test. Compound 1 protected against increasing in lipid peroxidation levels and AChE activity caused by SCO in the cerebral cortex and hippocampus of mice. In conclusion, the present study evidenced the in vitro anticholinesterase effect of two new selanyl amide derivatives in the cerebral structures of mice. Moreover, compound 1, a selanyl amide derivative containing a furan ring, demonstrated antiamnesic action due to its antioxidant and anticholinesterase activities in cerebral structures.

The present study was designed to examine the antinociceptive and anti-inflammatory effects of 7-chloro-4-phenylsulfonyl quinoline (PSOQ). Mice were orally (p.o) pretreated with PSOQ (0.01–10 mg/kg), meloxicam (10 mg/kg), 30 min prior to the acetic acid, hot-plate and open field tests. PSOQ reduced abdominal writhing induced by acetic acid, while meloxicam presented no effect. The latency time in the hot-plate test and locomotor/exploratory activities in the open field test were not altered by treatments. In order to evaluate the gastric tolerability after oral administration of PSOQ or meloxicam (10 mg/kg), mice were fasted for 18 h prior to drug exposure. Four hours later, the development of lesions was assessed. PSOQ and meloxicam did not induce ulcer at the dose and time evaluated. Indeed, anti-inflammatory and anti-edematogenic properties of PSOQ were investigated. For this, animals were pretreated with PSOQ (0.01–50 mg/kg; p.o.), meloxicam (50 mg/kg; p.o.), 30 min prior to croton oil application. PSOQ and meloxicam (50 mg/kg) diminished the edema formation and myeloperoxidase activity induced by croton oil in the ear tissue. Taken together these data demonstrated that PSOQ exerts acute anti-inflammatory and antinociceptive actions, suggesting that it may represent an alternative in the development of future new therapeutic strategies.

Vinyl sulfides (a–c), a new class of organosulfur compounds, were screened for antioxidant and antinociceptive activities. In view of this, in vitro antioxidant effect was investigated through the determination of the thiobarbituric acid reactive substances and protein carbonyl levels in rat brain homogenate. Considering the results obtained in vitro, antinociceptive activity of vinyl sulfides (a–c) (5–50 mg/kg, intragastrically) was investigated in a model of nociception induced by glutamate (20 μmol/paw, 20 μl, intraplantar) in mice. A close inspection of the results revealed that unsymmetrical substituted vinyl sulfides (compounds a–c) presented weak antioxidant activity against lipid peroxidation and protein carbonilation in vitro. In vivo experiments showed that compounds a, b, and c, at all doses (5–50 mg/kg), caused an inhibition of the licking and edema induced by glutamate in mice. However, antinociceptive action of sulfides was not dose-dependent, as well as the antioxidant effect was not concentration-dependent. Thus, chemical structure of vinyl sulfides is not related with pharmacological effects. The results demonstrated that vinyl sulfides presented weak antioxidant effect and potent antinociceptive and antiedematogenic effect.

The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A2A receptor antagonist, on striatal toxicity induced by 3-nitropropionic acid (3-NP) in rats. The experimental protocol consisted of 10 administrations (once a day) of SCH58261 (0.01 or 0.05 mg/kg/day, intraperitoneal, i.p.). From 7th to 10th day, 3-NP (20 mg/kg/day, i.p.) was injected 1 h after SCH58261 administration. Twenty-four hours after the last 3-NP injection, the body weight gain, locomotor activity (open-field test), motor coordination (rotarod test), striatal succinate dehydrogenase (SDH) activity and parameters linked to striatal oxidative status were evaluated in rats. The marked body weight loss resulting from 3-NP injections in rats was partially protected by SCH 58261 at both doses. SCH 58261 at the highest dose was effective against impairments on motor coordination and locomotor activity induced by 3-NP. SCH 58261 was unable to restore the inhibition of SDH activity caused by 3-NP. In addition, the increase in striatal reactive species (RS) levels, depletion of reduced glutathione (GSH) content and stimulation of glutathione reductase (GR) activity provoked by 3-NP injections were alleviated by both doses of SCH 58261. The highest dose of SCH 58261 was also effective in attenuating the increase of protein carbonyl levels as well as the inhibition of glutathione peroxidase (GPx) activity in rats exposed to 3-NP. Our results revealed that reduction of oxidative stress in rat striatum by adenosine A2A receptor antagonism contributes for alleviating 3-NP-induced toxicity.

Climate change projections are subject to uncertainty arising from climate model deficiencies, unknown initial conditions and scenario assumptions. In the IPCC reports and many other publications climate changes and uncertainty ranges are usually displayed in terms of multi-model ensemble means and confidence intervals, respectively. In this study, we present a more quantitative assessment and statistical testing of climate change signals in the light of uncertainty. The approach is based on a two-way analysis of variance, referring to 24 climate models from the CMIP3 multi-model ensemble, and extents over the 21st century. The method also distinguishes between different climate variables, time scales and emission scenarios and is combined with a simple bias correction algorithm. The Mediterranean region has been chosen as a case study because it represents an assumed hot spot of future climate change, where temperature is projected to rise substantially and precipitation may decrease dramatically by the end of the 21st century. It is found that future temperature variations are mainly determined by radiative forcing, accounting for up to 60% of total variability, especially in the western Mediterranean Basin. In contrast, future precipitation variability is almost completely attributable to model uncertainty and model internal variability, both being important in more or less equal shares. This general finding is slightly depending on the prescribed emission scenario and strictly sensitive to the considered time scale. In contrast to precipitation, the temperature signal can be enhanced noticeably when bias-correcting the models' climatology during the 20th century: the greenhouse signal then accounts for up to 75% of total temperature variability in the regional mean.

This study determined whether meloxicam in nanocapsules modifies stomach and liver damage caused by free meloxicam in mice. Male Swiss mice were treated with blank nanocapsules or meloxicam in nanocapsules or free meloxicam (10 mg/kg, intragastrically, daily for five days). On the seventh day, blood was collected to determine biochemical markers (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, total bilirubin, unconjugated bilirubin, albumin and alkaline phosphatase). Stomachs and livers were removed for histological analysis. There was no significant difference in the biochemical markers in the plasma of mice. Meloxicam in nanocapsules did not have an ulcerogenic potential in the stomach or cause lipid peroxidation in the stomach and liver. Free meloxicam increased the ulcerogenic potential in the stomach and lipid peroxidation in the stomach and liver. Meloxicam in nanocapsules caused less histological changes than free meloxicam. In conclusion, polymeric nanocapsules can represent a technological alternative to reduce the toxicity caused by meloxicam.

The present study evaluated the anti-amnesic activity of 1-(7-chloroquinolin-4-yl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (QTCA-1) against scopolamine (SCO)-induced amnesia in mice. It was evaluated cholinergic dysfunction, oxidative stress and Na

The present study evaluated the antioxidant, antinociceptive and anti-edematogenic effects of Se-[(2,2-dimethyl-l,3-dioxolan-4-yl) methyl] 4-chlorobenzoselenolate (Se-DMC). In vitro experiments were carried out to evaluate Se-DMC antioxidant action. Thiobarbituric acid reactive species levels, 2,2’-diphenyl-l-picrylhydrazyl and 2,2’-azino-bis(3-thylbenzthiazoline-6-sulfonic acid) radicals scavenging and glutathione S-transferase-like activity were determined. Male Swiss mice were orally pretreated with Se-DMC (1,10 and 50 mg/kg), meloxicam (50 mg/kg) or vehicle 30 min prior to acetic acid or glutamate test. To extend our knowledge of the pharmacological properties of this compound, it was tested in an inflammatory model through ear edema induced by croton oil. The contribution of glutamatergic and serotonergic systems was also investigated. In vitro experiments revealed that Se-DMC exerts antioxidant activity. Nociception induced by glutamate or acetic acid was reduced by Se-DMC or meloxicam. Se-DMC diminished the paw edema formation induced by glutamate, while meloxicam did not show any effect. Se-DMC and meloxicam decreased the ear edema formation and protected against the increase in myeloperoxidase activity in mice ear induced by croton oil. The pretreatment of animals with MK-801 did not alter antinociception caused by Se-DMC in the glutamate test. The antinociceptive effect exerted by Se-DMC in the acetic acid test was reverted by the pretreatment of mice with different serotonergic antagonists (WAY100635, ketanserin and pindolol). Data presented here showed that the modulation of serotonergic and glutamatergic systems and the anti-inflammatory and antioxidant actions could contribute to the antinociceptive and anti-edematogenic effects of Se-DMC and it supported the therapeutic potential of this compound.

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) to restore the cognitive impairment caused by aging in male Wistar rats. Moreover, modulation of neuroplasticity markers, acetylcholinesterase (AChE) activity, and cholesterol levels was performed. Aged rats were intragastrically treated with 4-PSQ (5 mg/kg) for 7 days. Animals were tested in behavioral tasks, and then plasma (to determine cholesterol levels), hippocampus, and cerebral cortex (to determine neural cell adhesion molecule (NCAM) and polysialyltransferase (PST) levels, and AChE activity) were removed. Our findings demonstrated that treatment of aged rats with 4-PSQ restored short-term and long-term memories in the object recognition tests. 4-PSQ treatment did not restore exploratory activity (rearings) but partially restored locomotor activity (crossings) reduced by aging in the open-field test. Moreover, the compound restored the reduction in the NCAM and PST levels, and AChE activity in cerebral structures, as well as the increase in the plasma cholesterol levels, caused by aging in rats. In conclusion, 4-PSQ restored cognitive impairment caused by aging in rats by modulating synaptic plasticity, cholinergic system, and cholesterol levels.

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) at a dose of 1 mg/kg in memory impairment and anxiety in an Alzheimer's disease (AD) model induced by amyloid β-peptide (Aβ) (fragment 25-35) in mice. The involvement of acetylcholinesterase (AChE) activity and lipid peroxidation in hippocampus and cerebral cortex was evaluated. Male Swiss mice were pretreated with 4-PSQ (1 mg/kg, intragastrically (i.g.), daily) for fourteen days. Thirty minutes after the first treatment with 4-PSQ, the animals received a single injection of Aβ (3 nmol/3 μl/per site, intracerebroventricular (i.c.v.)). Mice were submitted to the behavioral tasks (open-field, elevated plus maze, Barnes maze, object recognition and location, and step-down inhibitory avoidance tests) from the fifth day onwards. On the fifteenth day, blood was removed for analysis of biochemical markers (glucose, triglycerides, urea, aspartate (AST) and alanine (ALT) aminotrasferases), and cerebral cortex and hippocampus for determination of AChE activity and thiobarbituric acid reactive species (TBARS) levels. Aβ caused memory impairment, anxiogenic behavior, increased AChE activity in the cerebral structures and TBARS levels in the cerebral cortex. 4-PSQ was effective to protect against behavioral changes, AChE activity and TBARS levels. In conclusion, 4-PSQ protected against learning and memory impairment and anxiety in a mouse model of AD induced by Aβ, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound.

The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A

Dry powder inhalation aerosols of antibiotic drugs (a first-line aminoglycoside, tobramycin, and a first-line macrolide, azithromycin) and a sugar alcohol mucolytic agent (mannitol) as co-spray dried (co-SD) particles at various molar ratios of drug:mannitol were successfully produced by organic solution advanced co-spray drying from dilute solute concentration. These microparticulate/nanoparticulate aerosols consisting of various antibiotic drug:mannitol molar ratios were rationally designed with a narrow and unimodal primary particle size distribution, spherical particle shape, relatively smooth particle surface, and very low residual water content to minimize the interparticulate interactions and enhance in vitro aerosolization. These microparticulate/nanoparticulate inhalation powders were high-performing aerosols as reflected in the aerosol dispersion performance parameters of emitted dose, fine particle fraction (FPF), respirable fraction (RF), and mass median aerodynamic diameter (MMAD). The glass transition temperature (Tg) values were significantly above room temperature, which indicated that the co-SD powders were all in the amorphous glassy state. The Tg values for co-SD tobramycin:mannitol powders were significantly lower than those for co-SD azithromycin:mannitol powders. The interplay between aerosol dispersion performance parameters and Tg was modeled where higher Tg values (i.e., more ordered glass) were correlated with higher values in FPF and RF and lower values in MMAD. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2937–2949, 2014

For energy-efficient design of district heating networks and their components, knowledge about load profiles and the peak simultaneity are of crucial importance. Heating load profiles are needed in high temporal and spatial resolution as well as information about their composition. Due to high computational and temporal effort for transient calculations of a whole district heating network a less complex method is needed. For this reason different areas of use of non-residential buildings are analyzed separately to identify their characteristical variations and main influences on their individual load profiles to finally superpose their load profile in one overall building/district heat load profile. In a first step similar use areas in four buildings are calculated transiently and the deviation of the results were analyzed. Additionally, the building age and the associated structural-physical parameters are varied to get results for different building age classes. In a second step the profiles are superposed up to the district scale by using the area as scale factor. The gained district heat load profile is compared to time series of the observed consumption in order to assess the reliability of the method. The first results show promising conformity of modelled and measured energy demand. So the method will be applied to several buildings with varying structural-physical parameters and geometries.

Fiducial markers are necessary for the accurate overlay of images obtained by different methods from small areas of a sample. Thus far, fiducial markers have been used for biological sample analysis by mass spectrometry imaging. In this work, spatial distributions of excipient and active drug substance at the surfaces of drug tablets produced under different pressures are observed by multimodal desorption electrospray ionization–mass spectrometry (DESI-MS) imaging with two novel fiducial marker systems being used to achieve accurate overlay of ion and optical images. DESI-MS ion images in the negative and positive ion modes as well as ion and optical images obtained from circa 3 mm2 areas have been precisely superimposed, allowing observing the particulate composition of the tablet's ingredients, a feature that is remarkably conserved in spite of the pressure used to produce the tablet. This approach can be applied broadly for product development, quality control, and counterfeit detection. [Supplementary...

Two polymorphic forms of ethyl 3-{3-[((2R)-3-{[2-(2,3-dihydro-1H-inden-2-yl)-1,1-dimethylethyl]amino}-2-hydroxypropyl)oxy]-4,5-difluorophenyl} propanoate hydrochloride, an investigational pharmaceutical compound, are characterized using spectroscopic and diffractometric techniques. These polymorphic forms exhibit very similar spectra and diffraction patterns and present challenges for analytical and physical characterization techniques. Capillary powder X-ray diffraction (PXRD) patterns for the two forms show minor but distinct differences. A single crystal X-ray diffraction structure for one of the forms was obtained. The unit cell of the other form was obtained by PXRD indexing. Detailed solid-state nuclear magnetic resonance (SSNMR) studies observing the 1H, 13C, 15N, 19F, and 35Cl nuclei are performed to characterize the subtle structural differences between the two forms. Molecular spectroscopic methods including infrared, Raman, UV–visible, and fluorescence spectroscopy are also applied. The combine...

Chemical imaging using confocal Raman microscopy is a useful analytical tool in drug development because of its ability to spatially image active ingredients and excipients in dosage forms and relate their distribution to product performance. While Raman spectra are highly specific for individual components of a formulation, most Raman microscopic mapping experiments require extensive experimental time. Laser wavelengths in the near-infrared range are used to suppress fluorescence but reduce sensitivity because of the inverse quadratic dependence of Raman scattering on laser wavelength. Compact, simple ultraviolet (UV) laser designs now allow for confocal UV Raman microscopy to be performed using a versatile instrument also capable of conventional Raman microscopy and epifluorescence imaging analyses. This study presents the results of UV Raman microscopy analyses using 266 nm laser irradiation of four pharmaceutical compositions of interest, including two types of tablets containing low doses of active ingredients (in the 0.2% w/w range), an amorphous dispersion containing 1% w/w of a small molecule drug, and an enteric coated layered peptide formulation. Resonance Raman enhancements are observed for four of the active ingredients studied in these formulations. The spectroscopic properties of the materials used in this study are also assessed by diffuse reflectance UV-visible spectroscopy, fluorescence spectroscopy, and conventional bulk Fourier transform Raman spectroscopy using 1064 nm laser irradiation. Confocal UV Raman microscopy was found to offer good sensitivity and allowed for rapid microscopic mapping of drugs and excipients at low concentrations in pharmaceutical formulations.

This study investigates whether a regional climate model (RCM) driven by a global general circulation model (GCM) in a nesting approach with observed atmospheric CO2 concentrations shows predictability for temperature and precipitation trends during 1961–1990 in the Mediterranean area, a region strongly influenced by large-scale circulation. Resulting discrepancies between model and observations raise the question whether the model predictability increases after removing impacts of mid-latitude circulation variability. For temperature and precipitation trends we use the RCM REMO and the observational dataset E-OBS, and for atmospheric circulation the driving coupled GCM ECHAM5/MPI-OM and NCEP/NCAR reanalyses. Cross-validated multiple regression analyses between large-scale circulation and regional temperature and precipitation are performed for observed and simulated data. The impact of circulation is removed from the original temperature and precipitation data, and the trends of circulation-related and circulation-unrelated parts are compared. The circulation-related trends of models and observations show discrepancies owing to differing observed and simulated mid-latitude circulation dynamics, i.e. different temporal evolutions of North Atlantic Oscillation and East Atlantic pattern in winter and East Atlantic Jet and a blocking pattern in summer. Such differences can be related to unknown initial conditions of GCM simulations. In fact, we find strong impacts of initial conditions on mid-latitude circulation dynamics of ECHAM5/MPI-OM ensemble members over 30-year periods. The agreement between simulated and observed circulation-unrelated trends is generally higher than for original trends indicating that the predictability of this nesting approach increases by removing impacts of mid-latitude circulation variability. We conclude that initial conditions affect climate variability up to the multi-decadal timescale, at least in parts of the globe which are governed by extratropical circulation modes, and hence, hinder the comparability of simulated and observed climate trends over time periods shorter than the timescale dominated by radiative forcing. In the Mediterranean Basin the latter is definitely beyond 30 years.

Respirable microparticles/nanoparticles of the antibiotics vancomycin (VCM) and clarithromycin (CLM) were successfully designed and developed by novel organic solution advanced spray drying from methanol solution. Formulation optimization was achieved through statistical experimental design of pump feeding rates of 25% (Low P), 50% (Medium P) and 75% (High P). Systematic and comprehensive physicochemical characterization and imaging were carried out using scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Karl Fischer titration (KFT), laser size diffraction (LSD), gravimetric vapor sorption (GVS), confocal Raman microscopy (CRM) and spectroscopy for chemical imaging mapping. These novel spray-dried (SD) microparticulate/nanoparticulate dry powders displayed excellent aerosol dispersion performance as dry powder inhalers (DPIs) with high values in emitted dose (ED), respirable fraction (RF), and fine particle fraction (FPF). VCM DPIs displayed better aerosol dispersion performance compared to CLM DPIs which was related to differences in the physicochemical and particle properties of VCM and CLM. In addition, organic solution advanced co-spray drying particle engineering design was employed to successfully produce co-spray-dried (co-SD) multifunctional microparticulate/nanoparticulate aerosol powder formulations of VCM and CLM with the essential lung surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPC), for controlled release pulmonary nanomedicine delivery as inhalable dry powder aerosols. Formulation optimization was achieved through statistical experimental design of molar ratios of co-SD VCM:DPPC and co-SD CLM:DPPC. XRPD and DSC confirmed that the phospholipid bilayer structure in the solid-state was preserved following spray drying. Co-SD VCM:DPPC and co-SD CLM:DPPC dry powder aerosols demonstrated controlled release of antibiotic drug that was fitted to various controlled release mathematical fitting models. The Korsmeyer-Peppas model described the best data fit for all powders suggesting super case-II transport mechanism of controlled release. Excellent aerosol dispersion performance for all co-SD microparticulate/nanoparticulate DPIs was higher than the SD antibiotic drugs suggesting that DPPC acts as an aerosol performance enhancer for these antibiotic aerosol dry powders. Co-SD VCM:DPPC DPIs had higher aerosol dispersion parameters compared to co-SD CLM:DPPC which was related to differences in the physicochemical properties of VCM and CLM.

A novel crystalline form of the boron-containing antibacterial drug (S)-3-(aminomethyl)-7-(3-hydroxypropoxy)benzo[c] [1,2]oxaborol-1(3H)-ol hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) and single-crystal X-ray diffraction techniques. After determination of the crystal structure by X-ray diffraction, SSNMR spectroscopy of this form is performed to obtain structural information using experimental approaches based on dipolar correlation, chemical shift analysis, and quadrupolar interaction analysis. 1H SSNMR experiments at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling, 2D SSNMR experiments based on (1)H–(13)C and (1)H–(11)B dipolar heteronuclear correlation, and density functional theory (DFT) calculations are combined in a novel approach to obtain a nearly complete assignment of the (1)H spectrum of this crystalline phase. (11)B and (35)Cl chemical shift and quadrupolar parameters are obtained using the analysis of MAS spectra and are found to be accurately reproduced using DFT calculations. NMR chemical shielding and electric field gradient parameters obtained using these methods are related to hydrogen-bonding trends in the crystal structure. The results illustrate the increasing capability of SSNMR techniques involving (1)H, (11)B, and (35)Cl SSNMR in the analysis of the crystal structure of a pharmaceutical compound containing covalently bonded boron.

The aim of this study was to investigate the effects of petroselinic acid, found in coriander oil, on the ability of rainbow trout hepatocytes to increase the production of eicosapentaenoic acid (20:5n-3; EPA) and docosahexaenoic acid (22:6n-3; DHA) from [1- 14 C] α-linolenic acid (18:3n-3; ALA) and to reduce the production of arachidonic acid (20:4n-6; ARA) from [1- 14 C] 18:2n-6. Addition of coriander oil increased the production of 22:6n-3, from [1- 14 C] 18:3n-3, at the 0.5 and 1.0% inclusion levels and reduced the conversion of [1- 14 C] 18:2n-6 to 20:4n-6. β -Oxidation was significantly increased at the 1.5% inclusion level for [1- 14 C] 18:2n-6, however β -oxidation for [1- 14 C] 18:3n-3 only showed an increasing trend. Acetate, a main breakdown product of fatty acids (FA) via peroxisomal β -oxidation, decreased three-fold for [1- 14 C] 18:2n-6 and nearly doubled for [1- 14 C] 18:3n-3 when coriander was added at a 1.5% inclusion level. Acyl coenzyme A oxidase (ACO) enzyme activity showed no significant differences between treatments. Relative gene expression of ∆6 desaturase decreased with addition of coriander oil compared to the control. The addition of petroselinic acid via coriander oil to vegetable oil (VO) based diets containing no fishmeal (FM) or fish oil (FO), significantly increased the production of anti-inflammatory precursor 22:6n-3 ( P = 0.011) and decreased pro-inflammatory precursor 20:4n-6 ( P = 0.023) in radiolabelled hepatocytes of rainbow trout.

(17)O solid-state NMR (SSNMR) can provide insight into hydrogen bonding interactions in pharmaceutical polymorphs, cocrystals, and amorphous dispersions. When combined with straightforward (17)O synthetic labeling, the use of (17)O SSNMR allows for direct study of key interactions such as hydrogen bonding in these systems. In this work, novel applications of (17)O SSNMR are demonstrated in the analysis of a polymorph of diflunisal, a cocrystal of diflunisal with pyrazinamide, and amorphous dispersions of diflunisal in two polymers. The observation of the (17)O nucleus is shown to be a highly specific and useful alternative to more conventional studies of the (1)H, (13)C, and (19)F nuclei in these systems and offers unique insight into hydrogen bonding interactions. Quantum chemical calculations are used to assess the (17)O SSNMR measurements for the polymorph of diflunisal for which a crystal structure has been previously determined. Empirical hydrogen bonding trends are then examined in the cocrystal and amorphous solid forms using (17)O NMR parameters. A novel application of (1)H-(17)O cross-polarization heteronuclear correlation (CP-HETCOR) experiments is also demonstrated for the cocrystal and two dispersions. This experiment offers specific information about proton environments in proximity to the labeled oxygen sites. The use of (17)O SSNMR techniques extends the utility of SSNMR in applications to cocrystals and amorphous dispersions.

Projected changes of extreme precipitation in the Mediterranean area up until the end of the 21st century are analysed by means of statistical downscaling. Generalized linear models are used as downscaling technique to assess different percentile-based indices of extreme precipitation on a fine-scale spatial resolution. In the region under consideration extreme precipitation is related to anomalies of the large-scale circulation as well as to convective conditions. To account for this, predictor selection encompasses variables describing the large-scale circulation (geopotential heights of the 700 hPa and 500 hPa levels, u- and v-wind components of the 850 hPa level) as well as thermo-dynamic parameters (specific humidity of the 850 hPa and 700 hPa levels, Showalter-Index, convective inhibition). In the scope of the statistical downscaling approach a specific statistical ensemble technique is applied in order to allow for non-stationarities in the predictors–predictand relationships. Consequently, the statistical ensembles include a range of possible future evolutions of extreme precipitation. Two different emission scenarios (A1B and B1), multiple runs for each scenario, and output of two different general circulation models (ECHAM5 and HadCM3) are applied to assess extreme precipitation under enhanced greenhouse warming conditions. The results yield mainly decreases over many parts of the Mediterranean area in spring. In summer increases are assessed around the Tyrrhenian Sea, the Ionian Sea, and the Aegean Sea, whereas decreases are projected for most of the western and northern Mediterranean regions. In autumn reductions of heavy rainfall occur over many parts of the western and central areas. In winter distinct increases are widespread in the Mediterranean area. Beyond the assessments using all predictors it is shown in the present contribution that different predictor variables can lead to varying statistical downscaling results. It points to distinct impacts of the change of specific atmospheric conditions on local extreme precipitation.

In the present study, we hypothesised whetherin vitrodigestion of salmon oil would release different amounts of PUFA depending on the origin of the lipolytic enzymes used. For this purpose,in vitrodigestion of salmon oil (SO) was performed using human duodenal juice (HDJ) or a commercial enzyme preparation consisting of porcine pancreatin and bile (PB). The lipolytic effect was determined by measuring the release of fatty acids (FA) using solid-phase extraction and GC–flame ionisation detection, withdrawing samples every 20 min during digestion. The amount of FA released indicated that a plateau was reached after 80 min with approximately similar amounts of FA detected using both HDJ and PB (379 (sd18) and 352 (sd23) mg/g SO, respectively). However, the release of 18 : 2, EPA (20 : 5) and DHA (22 : 6) was significantly different duringin vitrodigestion. At 80 min, HDJ and PB released 43 and 33 % of 18 : 2, 14 and 9 % of EPA and 11 and 9 % of DHA, respectively. Both enzyme preparations released approximately the same amounts of the other FA analysed. The effect of the addition of bile salts (BS) was significantly different in the two enzyme systems, where porcine pancreatin highly responded to the increase in BS concentration, in contrast to HDJ.

Cocrystals and amorphous solid dispersions have generated interest in the pharmaceutical industry as an alternative to more established solid delivery forms. The identification of intermolecular hydrogen bonding interactions in a nicotinamide palmitic acid cocrystal and a 50% w/w acetaminophen-polyvinylpyrrolidone solid dispersion are reported using advanced solid-state magic-angle spinning (MAS) NMR methods. The application of a novel (14)N-(1)H HMQC experiment, where coherence transfer is achieved via through-space couplings, is shown to identify specific hydrogen bonding motifs. Additionally, (1)H isotropic chemical shifts and (14)N electric field gradient (EFG) parameters, both accessible from (14)N-(1)H HMQC experiments, are shown to be sensitive to changes in hydrogen bonding geometry. Numerous indicators of molecular association are accessible from this experiment, including NH cross-peaks occurring from intermolecular hydrogen bonds and changes in proton chemical shifts or electric field gradient parameters. First-principles calculations using the GIPAW approach that yield accurate estimates of isotropic chemical shifts, and EFG parameters were used to assist in assignment. It is envisaged that (14)N-(1)H HMQC solid state NMR experiments could become a valuable screening technique of solid delivery forms in the pharmaceutical industry.

The present study investigated the antioxidant effect of a new class of quinoline derivatives (a-d) on assays in vitro. Lipid peroxidation, thiol peroxidase-like and free radical scavenging activities were determined to evaluate antioxidant activity of compounds. Thiol oxidase-like and δ-aminolevulinate dehydratase activities were performed as a toxicological parameter. A second objective of this study was to evaluate the in vivo antinociceptive effect of the compound with better antioxidant effect and without toxic effects in a model of nociception induced by formalin in mice. In liver, at 100 µM, compound a reduced the lipid peroxidation to the control levels, while compounds c and d partially reduced it. In brain, only compound d partially reduced the lipid peroxidation at 50 and 100 µM. Compound b did not have an effect on the lipid peroxidation. Thiol peroxidase-like and free radical scavenging activities are not involved in the antioxidant mechanisms of these compounds. Compounds did not present thiol oxidase-like activity and effect on the δ-aminolevulinate dehydratase. In vivo experiments showed that compound a caused an inhibition of licking time in the first and second phases, and edema formation induced by formalin. In conclusion, quinoline derivative without selenium presented better in vitro antioxidant effect and in vivo antinociceptive activity.

The solubility of drug molecules can often be improved through preparation and delivery of cyclodextrin (CD) inclusion complexes. These drug-oligosaccharide complexes can be prepared in solution and converted to the solid state via methods such as lyophilization and spray-drying, or they can be prepared directly from solids by a variety of methods. The development of drug-CD complexes as solids allows for potential advantages in dosage form design, such as the preparation of layered formulations, and it also can yield improvements in chemical and physical stability. 2D solid-state NMR (SSNMR) methods provide a direct way to probe drug-CD interactions in solid complexes through dipolar interactions between nuclei within the drug and CD molecules. In this study, 2D heteronuclear and homonuclear correlation SSNMR experiments involving (1)H, (13)C, (19)F, and (31)P nuclei are used to demonstrate the inclusion of drug within the CD cavity in a variety of powder samples. To illustrate the general applicability of the SSNMR approach presented, examples are shown for the drugs diflunisal, adefovir dipivoxil, voriconazole, dexamethasone, and prednisolone in complexes with α-CD, β-CD, and sulfobutylether-substituted β-CD. The quantitative analysis of included and free drug fractions in a solid drug-CD complex using SSNMR is also demonstrated. On the basis of these results, general approaches to the characterization of these materials using SSNMR are proposed.

Cocrystals of tenoxicam, a non-steroidal anti-inflammatory drug, are screened, prepared, and characterized in this study. Nine tenoxicam cocrystals were identified using solvent-drop grinding (SDG) techniques. Structural characterization was performed using powder X-ray diffraction (PXRD), differential scanning calorimetry, and multinuclear solid-state NMR (SSNMR). Thermal analysis, PXRD, and 1D SSNMR are used to detect solvates and phase mixtures encountered in SDG cocrystal screening. 2D SSNMR methods are then used to confirm cocrystal formation and determine structural aspects for selected cocrystals formed with saccharin, salicylic acid, succinic acid, and glycolic acid in comparison to Forms I and III of tenoxicam. Molecular association is demonstrated using cross-polarization heteronuclear dipolar correlation (CP-HETCOR) methods involving 1 H and 13 C nuclei. Short-range 1 H– 13 C CP-HETCOR and 1 H– 1 H double-quantum interactions between atoms of interest, including those engaged in hydrogen bonding, are used to reveal local aspects of the cocrystal structure. 15 N SSNMR is used to assess ionization state and the potential for zwitterionization in the selected cocrystals. The tenoxicam saccharin cocrystal was found to be similar in structure to a previously-reported cocrystal of piroxicam and saccharin. The four selected cocrystals yielded intrinsic dissolution rates that were similar or reduced relative to tenoxicam Form III.

While the occurrence of desulfurization of phosphorothioate oligonucleotides in solution is well established, this study represents the first attempt to investigate the basis of the unexpected desulfurization via the net sulfur-by-oxygen (S-O) replacement during negative electrospray ionization (ESI). The current work, facilitated by quantitative mass deconvolution, demonstrates that considerable desulfurization can take place even under common negative ESI operating conditions. The extent of desulfurization is dependent on the molar phosphorothioate oligonucleotide-to-hydroxyl radical ratio, which is consistent with the corona discharge-induced origin of the hydroxyl radical leading to the S-O replacement. This hypothesis is supported by the fact that an increase of the high-performance liquid chromatography (HPLC) flow rate and the on-column concentration of a phosphorothioate oligonucleotide, as well as a decrease of the electrospray voltage reduce the degree of desulfurization. Comparative LC-tandem mass spectrometry (MS/MS) sequencing of a phosphorothioate oligonucleotide and its corresponding desulfurization product revealed evidence that the S-O replacement occurs at multiple phosphorothioate internucleotide linkage sites. In practice, the most convenient and effective strategy for minimizing this P = O artifact is to increase the LC flow rate and the on-column concentration of phosphorothioate oligonucleotides. Another approach to mitigate possible detrimental effects of the undesired desulfurization is to operate the ESI source at a very low electrospray voltage to diminish the corona discharge; however this will significantly compromise sensitivity when analyzing the low-level P = O impurities in phosphorothioate oligonucleotides. Copyright © 2012 John Wiley & Sons, Ltd.