Enhanced Recovery of Natural Antioxidants from Grape Waste Using Natural Eutectic Solvents-Based Microwave-Assisted Extraction.

The evaluation of sustainable solvents as alternatives to more harmful conventional solvents combined with intensification techniques to recover phenolic compounds from agri-food waste is in the spotlight. The wine industry generates large amounts of waste as a consequence of grape processing operations, which can be revalued by solvent extraction of valuable antioxidants for food and fine chemical applications. Therefore, the present study focuses on the use of natural eutectic solvents (NAESs) with benign environmental, health, and safety profiles, for valorization of grape waste in the context of a circular economy. Herein, up to 15 NAESs consisting of combinations of three hydrogen bond acceptors (choline chloride, L-proline, and betaine) and four hydrogen bond donors (1,2-propanediol, glycerol, and 1,2- and 1,3-butanediol) were evaluated for antioxidant recovery. After an initial screening of the performance of NAESs by conventional extraction, the process was intensified by microwave-assisted extraction (MAE). The extracts were analyzed by UV/VIS spectrophotometric and HPLC methods. Promising results were obtained with the solvent betaine, 1,2-butanediol [1:4], using MAE at 100 °C for 3 min. Overall, the proposed NAESs-based MAE method was successfully applied to recover target compounds from grape waste, with great prospects for the antioxidants market and sustainable development for the winery sector.

Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial.

BACKGROUND: Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. METHODS: CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 µg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. FINDINGS: Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. INTERPRETATION: CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. FUNDING: AbbVie.

Presence of diclofenac, estradiol, and ethinylestradiol in Manzanares River (Spain) and their toxicity to zebrafish embryo development.

Diclofenac (DCF), 17-ß-estradiol (E2), and 17-α-ethinylestradiol (EE2) are emerging pollutants included in the first watch list agreed by European countries and set in the EU Water Directive. The objective of the present study was the analytical monitoring of DCF, E2, and EE2 in surface water and sediment of the Manzanares River in a stretch that crosses the city of Madrid, Spain, and to assess whether such environmental levels could affect the development of aquatic vertebrates through a zebrafish embryo-larval assay. Samples taken during two campaigns in the spring of 2015 were analyzed for DCF, E2, and EE2 by LC-MS or GC-MS. The levels of E2 and EE2 measured in surface water and sediments of the Manzanares were within the ranges reported in other Spanish and European studies; however, DCF levels were higher in the present study. The zebrafish embryos exposed to the Manzanares River water (0-144h) showed lethal effects and sublethal effects (developmental delay, bradycardia, and reduced locomotion). Nevertheless, these effects were not primarily associated with the levels of DCF, E2, and EE2 present in the Manzanares River, because representative mixtures of the field study prepared in the laboratory did not exhibit such toxicity to the zebrafish embryos.

Pharmacokinetics and pharmacodynamics of a single bolus of propofol 2% in healthy volunteers.

This study was undertaken to assess the bioequivalence between a new formulation of propofol 2% and the commercially available product Diprivan. Secondary objectives were to compare the times to onset of and emergence from hypnosis, the hemodynamic effects, and the safety profiles. Twelve healthy male volunteers were included in a randomized crossover study. Subjects were administered a 2-mg/kg single bolus injection of each formulation separated by a 7- to 10-day washout period. Plasma propofol was determined by reversed-phase liquid chromatography with fluorescence detection. Eleven subjects completed the study, and both formulations were considered bioequivalent. There were no serious or severe adverse events. The concentration-time profiles of all the subjects could adequately be described using a three-compartment model. The mean times to cessation of counting out loud (17 vs. 18 s) and to eye opening (245 vs. 244 s) were not statistically different between treatment groups. Moreover, they seem to show some degree of pharmacodynamic bioequivalence, although a higher number of subjects are necessary to unequivocally demonstrate it.

Metal-catalyzed oxidation and epoxidation of alpha-hydroxy vinyl and dienyl sulfoxides.

Treatment of acyclic alpha-hydroxyalkyl alpha,beta-unsaturated sulfoxides with t-BuOOH/VO(acac)2 results in rapid oxidation to the unsaturated sulfones followed by an unusual regio- and stereoselective epoxidation at the unsaturated sulfones; this methodology has been applied to the preparation of carbohydrate-like fragments.

Nucleophilic epoxidation of alpha'-hydroxy vinyl sulfoxides.

The nucleophilic epoxidation of a variety of alpha'-(1-hydroxyalkyl) vinyl sulfones and sulfoxides has been studied. The sulfones give rise to anti oxiranes with modest (E) or excellent (Z) selectivities and in good yields. The (E)-sulfoxides display low reactivity within a reinforcing/nonreinforcing scenario. The use of t-BuOOLi in Et(2)O allows for a highly syn-selective epoxidation-oxidation. The (Z)-sulfoxides display a remarkably high reactivity under these conditions. The reinforcing (S,S(S)) diastereomers (3e-g) yield hydroxy sulfinyl oxiranes with high yields and selectivities. In contrast, the (R,S(S)) diastereomers (4e-g) show diminished reactivities and a very substrate-dependent stereochemical outcome. The structure of these oxiranes has been secured by chemical correlations and an X-ray crystal structure.