[Identification of synthetic cannabinoid N-(adamantan-1-yl)-2-[1-(4- fluorobenzyl)-1H-indole-3-yl]acetamide]. / Identifikatsiya sinteticheskogo kannabinoida N-(adamantan-1-il)-2-[1-(4-ftorbenzil)-1H-indol-3-il]atsetamid.

The aim of this study is to identify the N-(adamantan-1-yl)-2-[1-(4-fluorobenzyl)-1H-indole-3-yl]acetamide in extracted criminal sample using modern high-relable physico-chemical methods for the determination of organic matter (GC-MS, 1H and 13C NMR, IR spectroscopy). It is possible to be used in expert practice, chemicotoxicological and forensic chemical analysis, and can improve knowledge about substances, belonging to synthetic cannabinoids. As a result of research, the test substance was identified and its mass spectral data, that absented in available sources during the investigation, were obtained. According to its chemical structure, N-(adamantan-1-yl)-2-[1-(4-fluorobenzyl)-1H-indole-3-yl]acetamide is homolog of the synthetic cannabinoid N-(adamantan-1-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide (ACBM-BZ-F). Therefore, the further substance study is of interest in order to find out its psychoactive features.

A simplified sample preparation for hair and skin proteins towards the application of archaeological fur and leather.

Conventional protocols for proteomics analysis usually start by extracting or solubilizing the proteins from their substrates. This step can be challenging for archaeological proteins, when they are heavily contaminated or decayed. The remains of animal fur/leather objects from an early medieval burial in Trossingen (580 CE) from Southwest Germany were submitted to proteomics analysis for species identification. One leather sample (TS3) yielded enough proteins to be identified as cow using a urea-based extraction (method "U"), confirming the microscopic identification. But two other samples (TS1 and TS2), compacted in a greyish brittle matrix with embedded hair visible only under microscope, could not be characterized with that method. A series of tests was performed using reduction/alkylation with tris(2-carboxyethyl)phosphine/chloroacetamide at 95 °C directly on the matrix (method "95C"), with or without the use of paramagnetic beads as cleaning procedure (from the single-pot solid-phase-enhanced sample preparation or SP3). Hair keratins were best recovered in the fur samples when digestion was performed directly on the insoluble fraction after reduction/alkylation. For both samples TS1 and TS2, an ovicaprine species was identified, with TS1 firmly identified as sheep due to the exceptional preservation of keratins and keratin-associated proteins. The simplified protocol also showed improvements on the identification of collagen in the leather sample TS3. SIGNIFICANCE: North European burials had a strong tradition of bodies wrapped or covered in animal skins; textiles, furs, items of leather and other organic materials were essential parts of grave furnishings (as part of the deceased's clothing as well as grave goods) but are mostly only preserved as residues, uncharacterized layers or stains. Even well preserved finds like the waterlogged organic remains from Trossingen show strong limitations for visual identification. Because the traditional protocol was unable to extract proteins efficiently from the soil matrix in which the samples were embedded, a new method was devised that enabled the determination of the sampled fur remains as sheep and the leather fragments as cow leather. Analyses showed that the key step for accessing the proteins in the soiled archaeological samples was heating for 10 min at 95 °C with a solution of tris(2-carboxyethyl)phosphine/chloroacetamide (TCEP/CAA). The protocol proposed in this study offers to work on minute samples (1 mg of sample or less) and overcame the challenge of separating the proteins from their archaeological matrix. It offers interesting perspectives for archaeological sites or objects where clothing are suspected but hardly detectable, such as burial sites.

Development of an efficient stability-indicating LC-MS/MS method for the analysis of selexipag and characterization of its degradation products.

A new RP-HPLC method with a quick, sensitive and stable indication for the quantitative measurement of selexipag and its associated substances was developed and validated in the present study. In this new method, using the impurity-spiked solution, the chromatographic approach was optimized. Similarly, using the X-bridge phenyl column with isocratic elution of mobile phase containing acetonitrile and formic acid, selexipag and its impurities were separated. Recovery experiments obtained were satisfactory, and also the calibration graphs plotted for selexipag and its five impurities were found to be linear. The system validation parameters such as specificity, linearity, precision, accuracy and robustness were determined successfully. The obtained results indicated that the developed method was found to be useful for analyzing selexipag from its impurities. Further, using stress tests against acid, alkali, peroxide, reduction, thermal, hydrolysis and UV conditions, the present established method of HPLC was assessed and validated as per ICH Q2(R1) guidelines.

Prognostic Value of the 13 C-Methacetin Breath Test in Adults with Acute Liver Failure and Non-acetaminophen Acute Liver Injury.

BACKGROUND AND AIMS: The 13 C-methacetin breath test (MBT) is a noninvasive, quantitative hepatic metabolic function test. The aim of this prospective, multicenter study was to determine the utility of initial and serial 13 C-MBT in predicting 21-day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI). APPROACH AND RESULTS: The 13 C-MBT BreathID device (Exalenz Biosciences, Ltd.) provided the percent dose recovery (PDR) for a duration of 60 minutes after administration of 13 C-methacetin solution as the change in exhaled 13 CO2 /12 CO2 compared with pre-ingestion ratio on study days 1, 2, 3, 5, and 7. Results were correlated with 21-day transplant-free survival and other prognostic indices. A total of 280 subjects were screened for enrollment between May 2016 and August 2019. Median age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian, 76% had ALF with the remaining 24% having ALI. The mean PDR peak on day 1 or day 2 was significantly lower in nonsurvivors compared with transplant-free survivors (2.3%/hour vs. 9.1%/hour; P < 0.0001). In addition, serial PDR peaks were consistently lower in nonsurvivors versus survivors (P < 0.0001). The area under the receiver operating characteristic curve (AUROC) of the 13 C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King's College (AUROC = 0.70) and Model for End-Stage Liver Disease scores (AUROC = 0.83). The 13 C-MBT was well tolerated with only two gastrointestinal adverse events reported. CONCLUSIONS: The 13 C-MBT is a promising tool to estimate the likelihood of hepatic recovery in patients with ALF and ALI. Use of the PDR peak data from the 13 C-MBT point-of-care test may assist with medical decision making and help avoid unnecessary transplantation in critically ill patients with ALF and ALI.

Dual-Modal Immunosensor with Functionalized Gold Nanoparticles for Ultrasensitive Detection of Chloroacetamide Herbicides.

Convenient and ultrasensitive detection of pesticides is demanded for healthcare and environmental monitoring, which can be realized with a dual-modal strategy. In this paper, based on a biotin-labeled IgG-modified gold nanoparticle (AuNP@IgG-bio) probe, a dual-modal immunosensor was proposed for detecting chloroacetamide herbicides. This platform is relied on the dephosphorylation of ascorbic acid 2-phosphate (AA2P) by alkaline phosphatase (ALP). In addition to this process, ascorbic acid (AA)-triggered deposition of silver on gold nanostars (AuNSs) and the fluorogenic reaction of dehydrogenated AA and o-phenylenediamine (OPD) occur sequentially. Thus, the dual readout of the color change of red-green-blue (RGB) and fluorescence generation in situ induced by crystal growth can be used. The limits of detection (LODs) were as low as 1.20 ng/mL of acetochlor (ATC), 0.89 ng/mL of metolachlor, 1.22 ng/mL of propisochlor, and 0.99 ng/mL of their mixture by a smartphone and 0.44 ng/mL of ATC, 1.59 ng/mL of metolachlor, 2.80 ng/mL of propisochlor, and 0.72 ng/mL of their mixture by a spectrofluorometer. The recoveries from corn were 91.4-105.1% of the colorimetric mode and 92.4-106.2% of the fluorescent mode. Due to its simple observation mode and good performance, this dual-modal immunosensor possesses considerable application prospects.

Zero-Background Surface-Enhanced Raman Scattering Detection of Cymoxanil Based on the Change of the Cyano Group after Ultraviolet Irradiation.

A zero-background method based on surface-enhanced Raman scattering (SERS) was developed for the rapid determination of cymoxanil residue in food. Because of the influence of complex matrices, conventional Raman spectroscopy has multiple peaks that overlap with those of target molecules, which makes qualitative and quantitative detection difficult. However, the cyano group (C≡N) of cymoxanil after ultraviolet irradiation has a special characteristic peak in the Raman-silent region (1800-2800 cm-1), which eliminates the possible background interference. The intensity of the characteristic peak at 2130 cm-1 exhibited a good linear relationship (R2 = 0.9907) with the concentration of cymoxanil in the range of 1.0-50.0 mg/L, whose limit of detection was 0.5 mg/L. The novel method was also applied to the detection of cymoxanil residue in real samples such as cucumber and grape, and the results were in good agreement with those from high-performance liquid chromatography analysis. This revealed that the SERS method has great potential in the detection of cymoxanil in fruits and vegetables. Moreover, ultraperformance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-QTOF/MS) was adopted to identify the photoproducts of cymoxanil. The photolysis mechanism was explored by SERS and the UPLC-QTOF/MS technique, which provided basic information on photodegradation of cymoxanil.

Sensitive Determination of Acetochlor, Alachlor, Metolachlor and Fenthion Utilizing Mechanical Shaking Assisted Dispersive Liquid-Liquid Microextraction Prior to Gas Chromatography-Mass Spectrometry.

A green, sensitive and accurate dispersive liquid-liquid microextraction (DLLME) method was used to preconcentrate four selected pesticides in dam lake water samples for determination by gas chromatography-mass spectrometry (GC-MS). Conditions of the DLLME method were comprehensively investigated and optimized according to type/volume of extraction solvent, type/volume of dispersive solvent, and type/period of mixing. The developed method was validated according to the limits of detection and quantitation, accuracy, precision and linearity. Under the optimum conditions, limit of detection values calculated for alachlor, acetochlor, metolachlor and fenthion were 1.7, 1.7, 0.2 and 7.8 µg/kg (mass based), respectively. The method recorded 202, 104, 275 and 165 folds improvement in detection power values for acetochlor, alachlor, metolachlor and fenthion, respectively, when compared with direct GC-MS measurements. In order to evaluate the accuracy of the developed method, real sample application with spiking experiments was performed on dam lake water samples, and satisfactory percent recovery results in the range of 81%-120% were obtained.

Examination of degradation and ecotoxicology of pethoxamid and metazachlor after chlorine dioxide treatment.

Chlorine dioxide has been reported as very efficiently removing pesticides and other organic compounds from water matrixes. Due to pesticide toxicity and potential toxicity of their degradation products, it is important to monitor these compounds as environmental pollutants in ground and surface waters. Evaluating the effects of chlorine dioxide treatment is necessary, and toxicity studies are used to ascertain the severity of effects of intermediates due to incomplete degradation of the parent compounds. In this paper, for the first time, chlorine dioxide is applied and evaluated for the removal of chloroacetamide herbicides (pethoxamid and metazachlor) from waters (deionized water and Sava River water). The degradation degree of herbicides was measured by high-performance liquid chromatography, the main degradation products were identified using gas chromatography with a triple quadrupole mass detector, and the degree of mineralization was monitored by total organic carbon analysis. Four and two degradation products were identified after pethoxamid and metazachlor degradation, respectively. Total organic carbon analysis showed mineralization occurred, but it was incomplete. The mineralization and the characteristics of the degradation products obtained were tested using Daphnia magna and showed lower toxicity than the parent herbicides. The advantage of the applied treatment was a very high degradation percentage for pethoxamid removal from deionized water and Sava River water (100% and 97%, respectively), with higher mineralization efficiency (65%) than metazachlor. Slightly lower degradation efficiency in the Sava River water was due to chlorine dioxide oxidizing the herbicides and dissolved organic matter simultaneously.

Determination of 10 Haloacetamides in drinking water by gas chromatography with automated solid phase extraction.

Drinking water disinfection may result in the formation of different classes of toxic disinfection by-products (DBPs). Haloacetamides (HAcAms) are an emerging class of nitrogenous DBPs (N-DBPs), which are generally more prevalent at lower concentrations in disinfected water than carbonaceous DBPs. Herein a fast, convenient, and effective method of analyzing 10 HAcAms in drinking water samples was demonstrated. This method was developed using gas chromatography /electron capture detection (GC/ECD) supplemented with automated solid phase extraction (auto-SPE). The variables for automated SPE procedures were further optimized, including the selection of SPE sorbents, types and volumes of extraction solvents, SPE washing solvents and wash times. Under optimized conditions, the instrumental linearity range was 0.5-150 µg L-1 with correlation coefficients>0.9975. The limits of detection and quantification of this method were 0.002-0.003 µg L-1 and 0.005-0.010 µg L-1, respectively. The recovery values ranged from 72.4% to 108.5%, and the relative standard deviations ranged from 3.3% to 9.1%. Therefore, the auto-SPE-GC-ECD method showed acceptable linearity and repeatability and was subsequently validated and applied to analyze 10 HAcAms in drinking water.

Residue analysis of fungicides fenpicoxamid, isofetamid, and mandestrobin in cereals using zirconium oxide disposable pipette extraction clean-up and ultrahigh-performance liquid chromatography-tandem mass spectrometry.

In the present study, a fast multiresidue method determining three novel fungicides fenpicoxamid, isofetamid, and mandestrobin in cereals was developed and validated for the first time using ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). Samples were extracted by QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) methodology, and cleaned up using the disposable pipette extraction (DPX) tips containing primary secondary amine (PSA) and silica gel modified with zirconium oxide (Z-Sep) in less than 1 min. Linearity (r > 0.99) of three fungicides in the calibration range of 0.001-0.1 µg mL-1 was satisfactory. Mean recoveries (n = 15) from all matrices were between 84.8% and 100.3% as the corresponding intra-day and inter-day relative standard deviations (RSDs) were less than 10.6%. Limits of quantitation (LOQs) of all analytes in different matrices were defined at 0.01 mg kg-1. The results indicate this method can serve as a sensitive and rapid approach to monitoring contents of fenpicoxamid, isofetamid, and mandestrobin in cereals.

Improved analysis of propamocarb and cymoxanil for the investigation of residue behavior in two vegetables with different cultivation conditions.

BACKGROUND: A modified quick, easy, cheap, effective, rugged and safe (QuEChERS) method was developed for the simultaneous determination of highly water-soluble propamocarb and hydrophobic cymoxanil in potato tuber and tomato fruit. Residue behaviors of the fungicides in open field or greenhouse were investigated for the safety evaluation of these two pesticides, and the effects of cultivation conditions, fungicide exposure and fruit size of tomato on residue level are discussed. RESULTS: Vegetable samples were extracted with ammonia-acetonitrile, further purified with multiwall carbon nanotubes and analyzed using high-performance liquid chromatography tandem mass spectrometry. The method was validated with fortified samples at different concentration levels (0.05-2.0 mg kg-1 ). Average recoveries ranged from 84 to 111% with relative standard deviations between 0.3 and 5.5%. Limits of quantification (LOQs) were set at the lowest spiking level of 0.05 mg kg-1 . In tomato and cherry tomato, initial residue level of cymoxanil was below LOQ at recommended good agricultural practices. Propamocarb residues were affected by the cultivation conditions, with highest levels of 0.52 and 0.72 mg kg-1 in open field and greenhouse, respectively. In addition, residues of propamocarb in cherry tomatoes were found to be present at 1.25 mg kg-1 . CONCLUSIONS: The field trial results showed that propamocarb and cymoxanil residues in potato tubers were below LOQ due to the tubers not being exposed to sprayed pesticides. The unexpected high residue levels in cherry tomato seem to indicate that cherry tomato with small size presents certain accumulative effects of propamocarb. © 2020 Society of Chemical Industry.

Compound-Specific Chlorine Isotope Analysis of the Herbicides Atrazine, Acetochlor, and Metolachlor.

A gas chromatography-single quadrupole mass spectrometry method was developed and validated for compound-specific chlorine isotope analysis (Cl-CSIA) of three chlorinated herbicides, atrazine, acetochlor, and metolachlor, which are widespread contaminants in the environment. For each compound, the two most abundant ions containing chlorine (202/200 for atrazine, 225/223 for acetochlor, and 240/238 for metolachlor) and a dwell time of 30 ms were determined as optimized MS parameters. A limit of precise isotope analysis for ethyl acetate solutions of 10 mg/L atrazine, 10 mg/L acetochlor, and 5 mg/L metolachlor could be reached with an associated uncertainty between 0.5 and 1‰. To this end, samples were measured 10-fold and bracketed with two calibration standards that covered a wide range of δ37Cl values and for which amplitudes matched those of the samples within 20% tolerance. The method was applied to investigate chlorine isotope fractionation during alkaline hydrolysis of metolachlor, which showed a shift in δ37Cl of +46‰ after 98% degradation, demonstrating that chlorine isotope fractionation could be a sensitive indicator of transformation processes even when limited degradation occurs. This method, combined with large-volume solid-phase extraction (SPE), allowed application of Cl-CSIA to environmentally relevant concentrations of widespread herbicides (i.e., 0.5-5 µg/L in water before extraction). Therefore, the combination of large-volume SPE and Cl-CSIA is a promising tool for assessing the transformation processes of these pollutants in the environment.

Presence of Acetamide in Milk and Beef from Cattle Consuming AFEX-Treated Crop Residues.

AFEX treatment of crop residues can greatly increase their nutrient availability for ruminants. This study investigated the concentration of acetamide, an ammoniation byproduct, in AFEX-treated crop residues and in milk and meat from ruminants fed these residues. Acetamide concentrations in four AFEX-treated cereal crop residues were comparable and reproducible (4-7 mg/g dry matter). A transient acetamide peak in milk was detected following introduction of AFEX-treated residues to the diet, but an alternative regimen showed the peak can be effectively mitigated. Milk acetamide concentration following this transition was 6 and 10 ppm for cattle and buffalo, respectively, but also decreased over time for cattle while tending to decrease (p = 0.08) for buffalo. There was no difference in acetamide concentration in the meat of cattle consuming AFEX-treated residues for 160 days compared to controls. Further investigation is necessary to determine the metabolism of acetamide in ruminants and a maximum acceptable daily intake for humans.

NO2 and natural organic matter affect both soot aggregation behavior and sorption of S-metolachlor.

Soot is an important carbonaceous nanoparticle (CNP) frequently found in natural environments. Its entry into surface waters can occur directly via surface runoff or infiltration, as well as via atmospheric deposition. Pristine soot is likely to rapidly undergo aggregation and subsequent sedimentation in aquatic environments. Further, soot can sorb a variety of organic contaminants, such as S-metolachlor (log KD = 3.25 ± 0.12). During atmospheric transport, soot can be chemically transformed by reactive oxygen species including NO2. The presence of natural organic matter (NOM) in surface waters can further affect the aquatic fate of soot. To better understand the processes driving the fate of soot and its interactions with contaminants, pristine and NO2-transformed model soot suspensions were investigated in the presence and absence of NOM. NO2-oxidized soot showed a smaller particle size, a higher number of particles remaining in suspension, and a decreased sorption of S-metolachlor (log KD = 2.47 ± 0.40). In agreement with findings for other CNPs, soot stability against aggregation was increased for both pristine and NO2 transformed soot in the presence of NOM.

An Orthogonal Approach for Determination of Acetamide Content in Pharmaceutical Drug Substance and Base-Contaminated Acetonitrile by GC and GC-MS External Method.

Acetamide is a potential genotoxic impurity; it should control in drug substance based on daily dosage level. It forms from base-contaminated acetonitrile and by-product of some drug substances. The available methods for acetamide in drug substance and water samples were determined by GC-MS using internal standard with critical procedures. These developed and validated methods can assist in evaluating the reaction between acetonitrile and different bases and also determine trace level acetamide in drug substances. The method development was initiated with DB-624, 30 m, 0.32 width and 1.0-µm column. The column was used to validate at the 600 ppm TTC value. Similarly, the CP-SIL 5CB, 60 m, 0.32 width, the 5-µm column was used for the remaining TTC values. The validation study was performed for all TTC limits. The % RSD for precision at 600, 60, 20, 10 and 2.5 ppm was <15%. The % recovery at all TTC level was in between the 70 and 130%. Solution stability study was performed up to the 24 h. At 2.5 ppm, the results were <15% variation from the initial value. The linearities from the 50 to 150% concerning TTC values were more than limit of 0.98 correlation coefficient. The limit of detection and limit of quantitation values were 0.4 to the 1.3 ppm, respectively, for 2.5 ppm TTC limit method.

Dissipation of mecoprop-P, isoproturon, bentazon and S-metolachlor in heavy metal contaminated acidic and calcareous soil before and after EDTA-based remediation.

The ability of contaminated farmland soils reclaimed by remediation to dissipate pesticides and thus to mitigate their unwanted environmental effects, i.e., leaching and run-off, was studied. Novel EDTA-based soil washing technology (EDTA and process waters recycling; no toxic emissions) removed 79 and 73% of Pb from acidic and calcareous soil with 740 and 2179 mg kg-1 Pb, respectively. The dissipation kinetics of four herbicides: mecoprop-P, isoproturon, bentazon and S-metolachlor was investigated under field conditions in beds with maize (Zea mays) and barley (Hordeum vulgare). The biphasic First-Order Multi-Compartment (FOMC) model was used to fit experimental data and calculate the herbicides' half-life (DT50) in soil. Remediation significantly (up to 64%) decreased dehydrogenase activity assessed as a marker of soil microbial activity and prolonged the DT50 of herbicides in acidic soils from 16% (isoproturon) to 111% (S-metachlor). Remediation had a less significant effect on herbicide dissipation in calcareous soils; i.e., mecoprop-P DT50 increased by 3%, while isoproturon and S-metachlor DT50 decreased by 29%. Overall, the dissipation from remediated soils was faster than the average DT50 of tested herbicides published in the Pesticides Properties DataBase. Results demonstrate that EDTA-based remediation of the studied soils does not pose any threat of extended herbicide persistence.

Hydrological tracers, the herbicide metazachlor and its transformation products in a retention pond during transient flow conditions.

Since decades, surface water bodies have been exposed to pesticides from agriculture. In many places, retention systems are regarded as an important mitigation strategy to lower pesticide pollution. Hence, the processes governing the transport of pesticides in and through a retention system have to be understood to achieve sufficient pesticide attenuation. In this study, the temporal dynamics of metazachlor and its transformation products metazachlor-oxalic acid (OA) and -sulphonic acid (ESA) were observed in an agricultural retention pond and hydrologic tracers helped to understand system-inherent processes. Pesticide measurements were carried out for 80 days after their application during transient flow conditions. During a short-term (3 days) experiment, the tracers bromide, uranine and sulphorhodamine B were used to determine hydraulic conditions, residence times and sorption potential. A long-term experiment with sodium naphthionate (2 months) and isotopes (12 months) provided information about inputs via interflow and surface-groundwater interactions. During transient conditions, high concentration pulses of up to 35 µg L-1 metazachlor, 14.7 µg L-1 OA and 22.5 µg L-1 ESA were quantified that enduringly raised solute concentrations in the pond. Mean residence time in the system accounted for approximately 4 h showing first tracer breakthrough after 5 min and last tracer concentrations 72 h after injection. While input via interflow was confirmed, no evidence for surface-groundwater interaction was found. Different tracers illustrated potentials for sorption and photolytic degradation inside the system. This study shows that high-resolution sampling is essential to obtain robust results about retention efficiency and that hydrological tracers may be used to determine the governing processes.

Different removal efficiency of disinfection-byproduct precursors between dichloroacetonitrile (DCAN) and dichloroacetamide (DCAcAm) by up-flow biological activated carbon (UBAC) process.

Up-flow biological activated carbon (UBAC) filter has been widely used in waterworks due to its less hydraulic loss, stronger biodegradation ability, and the prevention of excessive biomass growth relative to down-flow BAC treatment. In this study, the different removal efficiency (DRE) of disinfection byproduct precursors between dichloroacetonitrile (DCAN) and dichloroacetamide (DCAcAm) was evaluated when UBAC filter was used as advanced treatment process. Results showed that the UBAC filter with approximately 36 months of usage time had a poor performance in the removal of DCAcAm formation potential (FP) (i.e. 9.3-19.1%) compared to DCAN FP (i.e., 22.5-34.1%). After chlorination of UBAC effluent, the hydrolysis of DCAN to form DCAcAm only partly contributed to the DRE variations of both DCAN FP and DCAcAm FP. Using the high-throughput sequencing technology and the redundancy analysis (RDA), the second dominant genus Bacillus in UBAC filter, which may transform precursors of DCAN into inorganic matters, could be another reason that led to the DRE in DCAN and DCAcAm FP. The formation and leakage of soluble microbial products (SMPs) was identified by excitation-emission matrix (EEM) peak intensities as well as variation of biological index (BIX). The SMPs released into UBAC effluent, favoring the formation of DCAcAm, also contributed to the precursors of both DCAN and DCAcAm, causing a poor removal performance in DCAcAm FP by UBAC filter.

First-in-man study of ACT-709478, a novel selective triple T-type calcium channel blocker.

OBJECTIVE: Increased activity of T-type Ca2+ channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT-709478 is an orally available triple T-type Ca2+ channel blocker. The aim of this first-in-man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT-709478 in healthy subjects. METHODS: This double-blind, placebo-controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1-400 mg ACT-709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests. RESULTS: The maximum plasma concentration (Cmax ) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half-life (95% confidence interval) ranged from 36 (29-45) to 43 (22-86) hours. Multiple peaks were observed and Cmax and area under the plasma concentration-time curve (AUC)0-∞ increased in a less than dose-proportional manner. A 1.6-fold increase in Cmax and no change in AUC0-∞ was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo. SIGNIFICANCE: ACT-709478 exhibits good tolerability and safety after single-dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.

[Determination of Flufenacet and Its Metabolites in Agricultural Products by LC-MS/MS].

A simultaneous analytical method based on LC-MS/MS was developed for the determination of flufenacet and its metabolites, [(4-fluorophenyl)(1-methylethyl) amino]oxo-acetic acid and [N-(4-fluorophenyl)-N-(1-methylethyl) acetamide]-2-sulfinylacetic acid, in agricultural products. The compounds were extracted from samples with methanol. The crude extracts were purified using Bond Elut C18 and InertSep GC/PSA, then determined by LC-MS/MS. The average recoveries (n=5) from 4 kinds of agricultural products (wheat, soybean, potato and tomato) spiked at the level of the MRLs or the uniform limits (0.01 µg/g) were 70.6-97.0%, and the relative standard deviations were less than 5%. The lower limits of quantitation of flufenacet and its metabolites were 0.01 µg/g.