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Understanding the current situation and risk of environmental contamination by anti-influenza drugs in aquatic environments is key to prevent the unexpected emergence and spread of drug-resistant viruses. However, few reports have been focused on newer drugs that have recently been introduced in clinical settings. In this study, the behaviour of the prodrug baloxavir marboxil (BALM)-the active ingredient of Xofluza, an increasingly popular anti-influenza drug-and its pharmacologically active metabolite baloxavir (BAL) in the aquatic environment was evaluated. Additionally, their presence in urban rivers and a wastewater treatment plant (WWTP) in the Yodo River basin was investigated and compared with those of the major anti-influenza drugs used to date (favipiravir (FAV), peramivir (PER), laninamivir (LAN), and its active metabolite, laninamivir octanoate (LANO), oseltamivir (OSE), and its active metabolite, oseltamivir carboxylate (OSEC), and zanamivir (ZAN)) to comprehensively assess their environmental fate in the aquatic environment. The results clearly showed that BALM, FAV, and BAL were rapidly degraded through photolysis (2-h, 0.6-h, and 0.4-h half-lives, respectively), followed by LAN, which was gradually biodegraded (7-h half-life). In addition, BALM and BAL decreased by up to 47 % after 4 days and 34 % after 2 days of biodegradation in river water. However, the remaining conventional drugs, except for LANO (<1 % after 10 days), were persistent, being transported from the upstream to downstream sites. The LogK d values for the rates of sorption of BALM (0.5-1.6) and BAL (1.8-3.1) on river sediment were higher than those of conventional drugs (-0.5 to 1.7). Notably, all anti-influenza drugs were effectively removed by ozonation (>90-99.9 % removal) after biological treatment at a WWTP. Thus, these findings suggest the importance of introducing ozonation to reduce pollution loads in rivers and the environmental risks associated with drug-resistant viruses in aquatic environments, thereby promoting safe river environments., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The photodegradations of three selected neonicotinoid insecticides nitenpyram, thiacloprid, and acetamiprid were investigated in both water and soil samples under natural sunlight, UVA light, and UVB light. The results indicate that these insecticides undergo significant degradations when subjected to sunlight, whether they are in deionized (DI) water, tap water, and DI water containing 100 mg/L humic acids or in soil. The degradation half-lives of nitenpyram, thiacloprid, and acetamiprid in tap water under sunlight were found to be 3.7, 4.7, and 8.9 h, respectively, in DI water 5.4, 6.3, 9.1 h, respectively, in DI water containing 100 mg/L humic acids 3.6, 3.3, 6.5 h, respectively, and in soil 7.5, 7.9, and 15.9 h, respectively. The degradation due to hydrolysis was found insignificant as compared to photodegradation. The examination of the effects of light source revealed that the UVB in the sunlight plays a major role in the photodegradation of these three neonicotinoids, and the effects of UVA and visible light are negligible. The analysis on the degradation products indicated that the nitroguanidine group in these insecticides is unstable and prone to break up under sunlight. A total of nine degradation products were detected, of which the health effects and the fate and transport in the environment need to be further studied., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the current study, a new magnetic sorbent (Fe 3 O 4 @2,6-diamino-4-(3,4-dihydroxyphenyl) pyridine-3,5-dicarbonitrile) was prepared as a new and efficient sorbent to be used in the magnetic solid-phase extraction method to extract tebuconazole and propiconazole as model compounds. In this regard, effective parameters such as pH of the sample solution, desorption volume, ionic strength, extraction time, desorption time, and amount of the magnetic sorbent were optimized using experimental design. In the optimal condition, the linear dynamic ranges for tebuconazole and propiconazole were between 0.5 and 200.0 µg/L. Also, the limits of detection, limits of quantification, and relative standard deviations were 0.21-0.14 µg/L, 0.49-0.45 µg/L, and 1.3%-4.6%, respectively. The estimated enrichment factors for tebuconazole and propiconazole were 22 and 28, respectively. The absolute recovery (AR%) values for tebuconazole and propiconazole were also 67% and 84%, respectively. Finally, the proposed method was used for determination of tebuconazole and propiconazole in cucumber, tomato, orange, and lemon fruits. The obtained result confirmed that the presented method is capable for the analysis of the selected analytes in complicated matrices. In addition, the ARs% were in the range of 67%-84%. The result proved that the presented method can be an alternative to the extraction process of various pesticides., (© 2024 Wiley‐VCH GmbH.)

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050-10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022., (© 2024. The Author(s).)

Supervised field trial was conducted to study the dissipation pattern of fluopyram in rice plant after application of fluopyram 400 g/L SC(Velum Prime) as soil drenching at the time of sowing in nursery bed at X (500 g a.i. ha -1 ) and 1.25X (625.2 g a.i. ha -1 ) doses. Samples of rice plant were collected on 0, 1, 3, 7, 10, 15, and 20 days after transplanting. QuEChERS-based extraction method was validated and adopted to determine the residues of fluopyram in rice seedlings, whole rice grains (with husk), polished rice grain, husk, straw, and soil using LC-MS/MS (liquid chromatography-tandem mass spectrometry).The initial deposit of fluopyram in rice plant recorded were 0.27 and 0.41 mg kg -1 in X and 1.25X doses, respectively. Fluopyram residues dissipated following first-order kinetics with half-life of 2.53 and 2.57 days at X and 1.25X doses, respectively. Residues were detected in seedlings up to 15 days after transplanting and were at below LOQ in whole rice grains (with husk), polished rice grain, husk, straw, and soil collected at harvest. Monitoring study revealed that application of novel nematicide fluopyram for the management of nematodes in rice does not pose any risks to consumers., (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Edoxaban is a direct oral anticoagulant available in Europe but not in France. Given the high tourist traffic in France, understanding the pharmacology of edoxaban and the availability of its laboratory testing seemed crucial in emergency situations. The aim of this work was to describe the methodology for measuring the anti-Xa activity of edoxaban, highlighting pre-analytical and analytical aspects, along with essential clinico-biological data for therapeutic guidance. The analysis was performed using the chromogenic method on the STAR-Max analyzer, with the STA®-Liquid ANTI-Xa kit (Diagnostica Stago®). Anti-Xa Edoxaban level measurement has a detection limit of 15 ng/mL, a quantification limit of 20 ng/mL and a linearity limit of 400 ng/mL. Repeatability, intermediate precision, accuracy, and measurement uncertainty studies were conducted to assess method performance, meeting quality requirements. The comparison between two STAR-Max® analyzers showed excellent results with linear regression and a low bias with good precision and no loss of dispersion regardless of edoxaban levels. In conclusion, although the measurement of edoxaban level may be rarely necessary in clinical practice, its implementation is straightforward. The availability of edoxaban in neighboring countries, underscores the importance of having its measurement available in hospital laboratories.

Hydroxyl compounds are widely present in plants and play essential roles in plant growth and development. High-coverage detection of hydroxyl compounds is crucial for understanding the physiological processes of plants. Despite the prevalence of chemical derivatization-assisted liquid chromatography-high resolution mass spectrometry (CD-LC-HRMS) in high-coverage detection of compounds with diverse functional groups, the confident identification of these compounds after derivatization remains a significant challenge. Herein, a novel method was developed for the identification of pyridine (PY)-derivatized hydroxyl compounds by comparing the MS/MS similarity of derivatized and corresponding underivatized compounds. Fragmentation rules of standards were summarized, and theoretical calculations have demonstrated the MS/MS similarity of PY-derivatized hydroxyl compounds with their underivatized counterparts. The effectiveness of the developed method was demonstrated by identifying PY-derivatized authentic standards. A total of 90 hydroxyl compounds were putatively identified in maize using the proposed method. This method can significantly enhance ionization efficiency with minimal impact on the quality of the MS/MS spectra, enabling the effective utilization of mass spectra databases for the identification of hydroxyl compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Estimation of drug ingestion time (event time) and distinguishing between drug ingestion and external contamination are important for interpreting hair analysis results in forensics practice. Here, we present a matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) method for in situ analysis of intact hair. We applied a longitudinal cutting method for a single hair to analysis authentic hair samples from a victim of a drug-facilitated sexual assault (DFSA) case and zolpidem-soaked hair. MALDI-MSI showed that zolpidem-positive segments distributed at 4-6 mm or 6-8 mm from the root in three single hairs of a DFSA victim collected 25 days after the event, at concentrations ranging from 0.1 to 5.7 pg mm -1 , in agreement with the results from segmental analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS). The estimation of drug intake time was about 20-30 days before sampling, which was consistent with the known time of drug intake. This MALDI-MS method allows imaging analysis of trace substances in a single hair and can realize the intuitive reflection of drug taking time. In addition, zolpidem applied by soaking was mainly distributed on both sides of the longitudinal hair shaft, whereas ingested zolpidem was found only in the middle of the hair shaft of the DFSA victim. The MALDI-MS images of unwashed and washed hair suggested that the amount of externally applied drug was decreased by washing, it was still present on surface layer (cuticle) sides although. Visualization using MALDI-MSI could therefore distinguish between drug ingestion and contamination by reflecting the distribution and deposition site of the drug in hair., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of a fluorescent probe for pyriproxyfen (PPF) is crucial due to its potential threat to human health. However, the chemical inertness and low solubility of PPF present significant challenges for the detection of PPF in aqueous solutions using fluorescent probes. Herein, we have originally proposed a complex based on 2-(4-(dimethylamino)phenyl)-3-hydroxy-6,7-dimethoxy-4 H-chromen-4-one (HOF) and serum albumin (SA) as a dual-mode fluorescent probe, HOF@SA. This probe utilizes an indicator displacement assay (IDA) to release the dye HOF from the probe at low PPF concentrations (< 10 µM) and embeds the free dye HOF into the micelle of PPF at high concentrations (> 10 µM). This results in dual-mode fluorescent response characteristics for PPF: a turn-off response at low concentrations and a ratiometric response at high concentrations. An investigation of sensing behavior of HOF@SA for PPF detection exhibits rapid response (< 60 s), high sensitivity (LOD ∼4.7 ppb), high selectivity, and excellent visual detection capability (from cyan to yellow). Moreover, with the aid of a portable device, this method enables to analyze PPF in environmental and food samples. These results promote the advancement of a fluorescent probe approach for PPF analysis in environment and food., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale: Phosphodiesterase 4 (PDE4) inhibitors are a newer class of drugs that induce bronchodilation and have anti-inflammatory effects, making them susceptible to misuse as performance enhancers in competitive sports., Methods: This study explores the metabolic conversion of PDE4 inhibitor ibudilast in thoroughbred horses after oral administration and in vitro using equine liver microsomes and Cunninghamella elegans. A liquid chromatography-high resolution mass spectrometry method was used to postulate the plausible structures of the detected metabolites., Results: A total of 20 in vivo metabolites were identified under experimental conditions, including 12 Phase I and 8 Phase II conjugated metabolites. Phase I metabolites were predominantly formed through hydroxylation (mono-, di-, and tri-hydroxylation). Demethylated metabolites were also identified during this investigation. Additionally, the research detected Phase II metabolites conjugated with glucuronic and sulfonic acids., Conclusions: The data presented here can assist in detecting the PDE4 inhibitor ibudilast and uncover its illicit use in competitive sports., (© 2024 John Wiley & Sons Ltd.)

Palbociclib (Ibrance; Pfizer) was approved for the management of metastatic breast cancer characterized by hormone receptor-positive/human epidermal growth factor receptor 2 negative status. The objective of this study was to create a fast, precise, environmentally friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry approach for quantifying palbociclib (PAB) in human liver microsomes with the application for assessing metabolic stability. The validation features were performed in agreement with the bioanalytical method validation standards outlined by the US Food and Drug Administration. The StarDrop software (WhichP450 and DEREK modules) was used in screening the metabolic lability and structural alerts of PAB. The separation of PAB and encorafenib (as an internal standard) was achieved on a C8 column, employing an isocratic mobile phase. The inter-day and intra-day accuracy and precision ranged from -6.00% to 4.64% and from -2.33% to 3.13%, respectively. The constructed calibration curve displayed a linearity in the range of 1-3000 ng/mL. The sensitivity of the established approach was proven by the lower limit of quantification of 0.73 ng/mL. The Analytical GREEness calculator results revealed the high level of greenness of the developed method. The PAB's metabolic stability (t 1/2 of 18.5 min and a moderate clearance (Cl int ) of 44.8 mL/min/kg) suggests a high extraction ratio medication that matched the WhichP450 software results., (© 2024 Wiley‐VCH GmbH.)

Grapes are among the most popular fruits globally, and insecticides are commonly used on grape farms. Sulfoxaflor, a novel sulfoximine insecticide that works against various insect pests, is extensively used in Egypt. Our field trials assessed the dynamics and final residues of sulfoxaflor in grapes and grape leaves grown in Egyptian environments with different application rates, including worst-case scenarios. A QuEChERS-based method with LC-MS/MS was used to analyze residues of sulfoxaflor in grapes and grape leaves. The limit of quantification (LOQ) was validated at 0.01 mg‧kg -1 . Sulfoxaflor residues are degraded in grapes and grape leaves according to a first-order kinetic model, with an estimated half-life (t 1/2 ) of 7.04 and 7.7 days, respectively, and considerable degradation (74.68 and 72.16%, respectively) after 14 days. The final residues in grapes and grape leaves were below the Codex or EU maximum residue limit (MRL) (2 mg‧kg -1 ) after 3 days of the recommended and high application rates. The findings showed that grapes and leaves treated with sulfoxaflor at the recommended rate are safe for humans 3 days after two or three consecutive treatments with intervals of 14 days. The current study should pave the way for implementing safe and appropriate sulfoxaflor use in grapes and grape leaves in Egypt., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breath analysis with secondary electrospray ionization (SESI) coupled to mass spectrometry (MS) is a sensitive method for breath metabolomics. To enable quantitative assessments using SESI-MS, a system was developed to introduce controlled amounts of gases into breath samples and carry out standard addition experiments. The system combines gas standard generation through controlled evaporation, humidification, breath dilution, and standard injection with the help of mass-flow controllers. The system can also dilute breath, which affects the signal of the detected components. This response can be used to filter out contaminating compounds in an untargeted metabolomics workflow. The system's quantitative capabilities have been shown through standard addition of pyridine and butyric acid into breath in real time. This system can improve the quality and robustness of breath data.

After regulation of pesticides, determination of their persistence in the environment is an important indicator of effectiveness of these measures. We quantified concentrations of two types of systemic insecticides, neonicotinoids (imidacloprid, acetamiprid, clothianidin, thiacloprid, and thiamethoxam) and butenolides (flupyradifurone), in off-crop nontarget media of hummingbird cloacal fluid, honey bee (Apis mellifera) nectar and honey, and wildflowers before and after regulation of imidacloprid on highbush blueberries in Canada in April 2021. We found that mean total pesticide load increased in hummingbird cloacal fluid, nectar, and flower samples following imidacloprid regulation. On average, we did not find evidence of a decrease in imidacloprid concentrations after regulation. However, there were some decreases, some increases, and other cases with no changes in imidacloprid levels depending on the specific media, time point of sampling, and site type. At the same time, we found an overall increase in flupyradifurone, acetamiprid, thiamethoxam, and thiacloprid but no change in clothianidin concentrations. In particular, flupyradifurone concentrations observed in biota sampled near agricultural areas increased twofold in honey bee nectar, sevenfold in hummingbird cloacal fluid, and eightfold in flowers after the 2021 imidacloprid regulation. The highest residue detected was flupyradifurone at 665 ng/mL (parts per billion [ppb]) in honey bee nectar. Mean total pesticide loads were highest in honey samples (84 ± 10 ppb), followed by nectar (56 ± 7 ppb), then hummingbird cloacal fluid (1.8 ± 0.5 ppb), and least, flowers (0.51 ± 0.06 ppb). Our results highlight that limited regulation of imidacloprid does not immediately reduce residue concentrations, while other systemic insecticides, possibly replacement compounds, concurrently increase in wildlife. Environ Toxicol Chem 2024;43:1497-1508. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sharon A. Riddler reports a relationship with Gilead Sciences Inc that includes: funding grants. Sharon A. Riddler reports a relationship with Merck & Co Inc that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tegafur, gimeracil, and oteracil potassium are widely used pharmaceuticals to treat lung cancers of the gastrointestinal tract, such as those of the oral cavity, esophagus, colon and rectum, and pancreas, as well as non-small cell lung cancers. The literature review revealed that no study has yet offered a completely stability-demonstrating, validated liquid chromatography-mass spectrometric approach for the concurrent estimation of tegafur, gimeracil, and oteracil potassium, along with all known degradation products. The simultaneous detection of tegafur, gimeracil, and oteracil potassium and their forced degradation product characterization necessitated the invention of a simpler, faster, and less expensive method. Therefore, this study aimed to follow the ICH method validation standards to develop and validate a fast, easy, and rugged liquid chromatography-mass spectrometry (LC-MS) technique for the concurrent estimation of tegafur, gimeracil, and oteracil potassium in the drug substance and the finished dosage form. Tegafur, gimeracil, and oteracil potassium were examined on the Waters HPLC Alliance system, coupled to the SCIEX QTRAP 5500 mass spectrometer, and endowed with an interface capable of carrying electrospray ionization. The tegafur, gimeracil, and oteracil peaks eluted at retention times of 2.338 min, 3.756 min, and 5.338 min, respectively. The limit of detection values of tegafur, gimeracil, and oteracil were detected to be 0.6, 0.174, and 0.474 μg/mL, respectively. The results for the quantification limit were calculated at 2.0, 0.58, and 1.58 µg/mL concentrations, respectively. Tegafur, gimeracil, and oteracil had linear ranges of 50-300 µg/ml, 14.5-87 µg/ml, and 39.5-237 µg/ml, with regression coefficients of 0.99956, 0.99986, and 0.999479, respectively. The accuracy values of tegafur, gimeracil, and oteracil in the ranges of 50%, 100%, and 150% were determined at 99.9%, 99.9%, and 99.4%, respectively. The RSD for the six replicates was less than 2% for precision. According to the ICH Q2 guidelines, this approach was effectively evaluated with LC-MS to validate the chemical structures of the freshly created tegafur, gimeracil, and oteracil degradation products. An accurate and sensitive LC-MS technique was developed and validated for the concurrent quantification of tegafur, gimeracil, and oteracil potassium in the drug material and the medicinal dosage form., Competing Interests: The authors state that they do not have any known conflicting financial interests or personal connections that may seem to have influenced the work disclosed in this study.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which is a label-free imaging technique, determines the spatial distribution and relative abundance of versatile endogenous metabolites in tissues. Meanwhile, matrix selection is generally regarded as a pivotal step in MALDI tissue imaging. This study presents the first report of a novel MALDI matrix, 2-hydroxy-5-nitro-3-(trifluoromethyl)pyridine (HNTP), for the in situ detection and imaging of endogenous metabolites in rat liver and brain tissues by MALDI-MS in positive-ion mode. The HNTP matrix exhibits excellent characteristics, including strong ultraviolet absorption, μm-scale matrix crystals, high chemical stability, low background ion interference, and high metabolite ionization efficiency. Notably, the HNTP matrix also shows superior detection capabilities, successfully showing 185 detectable metabolites in rat liver tissue sections. This outperforms the commonly used matrices of 2,5-dihydroxybenzoic acid and 2-mercaptobenzothiazole, which detect 145 and 120 metabolites from the rat liver, respectively. Furthermore, a total of 152 metabolites are effectively detected and imaged in rat brain tissue using the HNTP matrix, and the spatial distribution of these compounds clearly shows the heterogeneity of the rat brain. The results demonstrate that HNTP is a new and powerful positive-ion mode matrix to enhance the analysis of metabolites in biological tissues by MALDI-MSI.

Pyridine derivatives are the most common and significant heterocyclic compounds, which play an important role in various fields ranging from medicinal to chemosensing applications. Pyridine derivatives possess different biological activities such as antifungal, antibacterial, antioxidant, antiglycation, analgesic, antiparkinsonian, anticonvulsant, anti-inflammatory, ulcerogenic, antiviral, and anticancer activity. Furthermore, these derivatives have a high affinity for various ions and neutral species and can be used as a highly effective chemosensor for the determination of different species. In this review article, generally used synthetic routes of pyridine, structural characterization, medicinal applications, and potential of pyridine derivatives in analytical chemistry as chemosensors have been discussed. We hope this study will support the new thoughts to design biological active compounds and highly selective and effective chemosensors for the detection of various species (anions, cations, and neutral species) in various samples (environmental, agricultural, and biological). [Figure: see text].

Pyridine and its derivatives are widely used in many applications and inevitably cause extreme scenarios of serious soil contamination, which pose a threat to soil organisms. Still, the eco-toxicological effects and underlying mechanisms of pyridine-caused toxicity toward soil fauna have not been well established. Thus, earthworms (Eisenia fetida), coelomocytes, and oxidative stress-related proteins were selected as targeted receptors to probe the ecotoxicity mechanism of extreme pyridine soil exposure targeted to earthworms by using a combination of in vivo animal experiments, cell-based in vitro tests, in vitro functional and conformational analyses, and in silico analyses. The results showed that pyridine caused severe toxicity to E. fetida at extreme environmental concentrations. Exposure of pyridine induced excessive ROS formation in earthworms, causing oxidative stress and various deleterious effects, including lipid damage, DNA injury, histopathological change, and decreased defense capacity. Also, pyridine destroyed the cell membrane of earthworm coelomic cells and triggered a significant cytotoxicity. Importantly, the intracellular ROS (e.g., O 2 - , H 2 O 2 , and OH· - ) was release-activated, which eventually inducing oxidative stress effects (lipid peroxidation, inhibited defense capacity, and genotoxicity) through the ROS-mediated mitochondrial pathway. Moreover, the antioxidant defence mechanisms in coelomocytes responded quickly to reduce ROS-mediated oxidative injury. It was conformed that the abnormal expression of targeted genes associated with oxidative stress in coelomic cells was activated after pyridine exposure. Particularly, we found that the normal conformation (particle sizes, intrinsic fluorescence, and polypeptide backbone structure) of CAT/SOD was destroyed by the direct binding of pyridine. Furthermore, pyridine bound easily to the active center of CAT, but preferentially to the junction cavity of two subunits of SOD, which is considered to be a reason for impaired protein function in cells and in vitro. Based on these evidences, the ecotoxicity mechanisms of pyridine toward soil fauna are elucidated based on multi-level evaluation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abnormal changes occurring in the mitochondrial microenvironment are important markers indicating mitochondrial and cell dysfunction. Herein, we designed and synthesized a multifunctional fluorescent probe DPB that responds to polarity, viscosity, and peroxynitrite (ONOO - ). DPB is composed of an electron donor (diethylamine group) and electron acceptor (coumarin, pyridine cations, and phenylboronic acid esters), in which the pyridine group with a positive charge is responsible for targeting to mitochondria. D-π- A structure with strong intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) properties give rise to respond to polarity and viscosity. The introduction of cyanogroup and phenylboronic acid esters increases the electrophilicity of the probe, which is prone to oxidation triggered by ONOO - . The integrated architecture satisfies the multiple response requirements. As the polarity increases, the fluorescence intensity of probe DPB at 470 nm is quenched by 97%. At 658 nm, the fluorescence intensity of DPB increases with viscosity and decreases with the concentration of ONOO - . Furthermore, the probe is not only successfully used to monitor mitochondrial polarity, viscosity, and endogenous/exogenous ONOO - level fluctuations but also to distinguish cancer cells from normal cells by multiple parameters. Therefore, as-prepared probe provides a reliable tool for better understanding of the mitochondrial microenvironment and also a potential approach for the diagnosis of disease.

A sensitive, accurate and precise liquid chromatography (LC) method for the simultaneous determination of ceftazidime and pyridine in human plasma has been developed and validated. Acetonitrile (ACN) was employed to precipitate the proteins in the plasma samples. Chromatographic separation was performed with a Kinetex® C18 (150 mm × 3 mm, 2.6 µm) column with gradient elution. Ammonium formate 20 mM and ACN were mixed in a ratio of 98:2 (v/v) for mobile phase A and 85:15 (v/v) for mobile phase B. Both were adjusted to pH 4.5 with formic acid. The flow rate was 0.4 mL/min. UV detection was performed at 254 nm. Calibration curves were linear in the range from 0.3 to 225 μg/mL for ceftazidime and from 0.2 to 10 μg/mL for pyridine with correlation coefficients ≥ 0.999. Within- and between-run precision and accuracy were satisfactory with coefficients of variation (CV) ≤ 8.0% and deviations ≤ 7.0%, respectively. The method fulfilled all validation criteria prescribed by the European Medicines Agency guidelines. Next, it has been used successfully to analyze plasma samples of patients who received ceftazidime under intermittent and continuous administration. With intermittent administration, the concentration of the antibiotics reached a peak and then dropped quickly, which may be below the minimal inhibitory concentration (MIC). With continuous administration, the concentration of the antibiotics remained stable over 24 h, certainly above the MIC. Although the same tendency in ceftazidime concentration changes over time was observed, a difference in concentration amongst the patients was noticeable. The concentration of pyridine in plasma was negligible., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Context: Tucatinib (CYP2C8 substrate) and quercetin (CYP2C8 inhibitor) are two common drugs for the treatment of cancer. However, the effect of quercetin on the metabolism of tucatinib remains unknown., Objective: We validated a sensitive method to quantify tucatinib levels in rat plasma based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which was successfully employed to explore the effect of quercetin on tucatinib pharmacokinetics in rats., Materials and Methods: An Acquity UPLC BEH C18 column was applied to achieve the separation of tucatinib and internal standard (IS) talazoparib after protein precipitation with acetonitrile. Then, we used this assay to investigate the effect of different doses of quercetin (25, 50 and 100 mg/kg) on the exposure of orally administered tucatinib (30 mg/kg) in 24 Sprague-Dawley (SD) rats, which were randomly divided into three quercetin pre-treated groups and one control group ( n  = 6)., Results: Our developed assay was verified in all aspects of bioanalytical method validation, involving lower limit of quantification (LLOQ), selectivity, accuracy and precision, calibration curve, extraction recovery, matrix effect and stability. After pre-treatment with 100 mg/kg quercetin, AUC 0→ t , AUC 0→∞ and C max of tucatinib were remarkably increased by 75.4%, 75.8% and 59.1% ( p  < 0.05), respectively, while CLz/F was decreased significantly by 47.3% ( p  < 0.05) when compared with oral administration of 30 mg/kg tucatinib alone. This change is dose-dependent., Conclusions: This study will help better understand the pharmacokinetic properties of tucatinib with concurrent use with quercetin, and more clinical verifications were inspired to confirm whether this interaction has clinical significance in humans.

Extensive presence of aromatic organic compounds (AOCs) is a major course for the non-biodegradability of coking wastewater (COW). In-depth understanding of bio-degradation of AOCs is crucial for optimizing the design and operation of COW biological treatment systems in practical applications. Herein, the behavior and fate of AOCs were explored in a lab-scale step-feed three-stage integrated A/O biofilter (SFTIAOB) treating synthetic COW. Long-term operation demonstrated that COD, phenol, indole, quinoline and pyridine could be simultaneously removed. Phenol and indole were chiefly removed by anoxic zones, while quinoline and pyridine removal occurred in both anoxic and aerobic zones. Ultraviolet-visible spectrum observed that initial carboxylation and subsequent ring cracking and mineralization. Infrared spectroscopy also confirmed that key functional groups were cracked and produced during AOCs bio-degradation. Three-dimensional fluorescence spectrum indicated that significant transformation and elimination of tryptophan and humic acid with high molecular weight. Ring cleavage, distinct degradation and even complete mineralization of complex AOCs were further verified by gas chromatography-mass spectrometry. Moreover, functional degrading bacteria and aromatic ring-cleavage enzymes was successfully identified. Finally, AOCs biodegradation mechanisms by alternating anoxic and aerobic treatment was unraveled. This research provides thorough insights on AOCs biodegradation using a step-feed multi-stage alternating anoxic/oxic COW treatment process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Broccoli was selected as the research object in this paper to reveal the dissipation, distribution, and degradation pathway of sulfoxaflor under greenhouse and open-field cultivation conditions for the ecological risk assessment of sulfoxaflor. Results showed that the dissipation of sulfoxaflor in broccoli leaves, flowers, stems, roots, and the whole broccoli was in accordance with the first-order kinetic equation. The sulfoxaflor concentration in broccoli roots reached the maximum value after 1 day of application and then gradually decreased. The degradation half-lives of sulfoxaflor in the roots, leaves, flowers, stems, and whole broccoli were between 2.3 and 19.8 days. The longest degradation half-life of sulfoxaflor was in Heilongjiang under greenhouse cultivation. The terminal residue of sulfoxaflor in broccoli was in the range of 0.005-0.029 mg/kg, and the proportion of sulfoxaflor residue in broccoli leaves was the largest. Thirteen transformation products were separated and identified by ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and their kinetic evolution was studied. The cleavage of the N = S bond, C-S bond, C-O bond, and cyanide, as well as glucosylation, hydroxylation, SO extrusion, elimination, sulfhydrylation, ketonization, defluorination, and rearrangement, was inferred as the mechanism. Overall, these results can provide guidance for the supervision of the safe application of sulfoxaflor., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of the study was to analyze the process of roasting coffee beans in a convection-conduction roaster (CC) without a heat exchanger and a convection-conduction-radiation roaster (CCR) with a heat exchanger for determination of the aroma profile. The aroma profile was analyzed using the SPME/GC-MS technique, and an Agrinose electronic nose was used to determine the aroma profile intensity. Arabica coffee beans from five regions of the world, namely, Peru, Costa Rica, Ethiopia, Guatemala, and Brazil, were the research material. The chemometric analyses revealed the dominance of azines, alcohols, aldehydes, hydrazides, and acids in the coffee aroma profile. Their share distinguished the aroma profiles depending on the country of origin of the coffee beans. The high content of pyridine from the azine group was characteristic for the coffee roasting process in the convection-conduction roaster without a heat exchanger, which was shown by the PCA analysis. The increased content of pyridine resulted from the appearance of coal tar, especially in the CC roaster. Pyridine has an unpleasant and bitter plant-like odor, and its excess is detrimental to the human organism. The dominant and elevated content of pyridine is a defect of the coffee roasting process in the CC roaster compared to the process carried out in the CCR machine. The results obtained with the Agrinose showed that the CC roasting method had a significant effect on the sensor responses. The effect of coal tar on the coffee beans resulted in an undesirable aroma profile characterized by increased amounts of aromatic volatile compounds and higher responses of Agrinose sensors.

According to EU guidance SANCO/7525/VI/95 Rev. 10.3, residue data extrapolation from a surrogate major crop to a minor crop can be used for setting maximum residue levels (MRLs) with a reduced number of residue trials and representative selected pesticides. In this work, a QuEChERS method (citrate-buffered version and PSA with MgSO 4 clean-up) and LC-ESI-MS/MS for the determination of boscalid, pyraclostrobin, fludioxonil, fluopyram and tebuconazole in persimmon was developed and validated according to EU Commission guidelines and afterwards used for the determination of residues in four field trials. Residue levels at harvest for each pesticide ranged between 0.347 and 0.028 mg/kg. After comparing EFSA residue data on apples, as the surrogate major crop, and conducting a consumer risk assessment, a proposal of residue data extrapolation to set MRLs in persimmons was performed. The results showed that pesticide residues in persimmons at harvest were consistently lower than residues in apples when substances were applied according to the same critical GAP. MRLs were set at 0.5 mg/kg for fludioxonil, 0.6 mg/kg for boscalid, 0.3 mg/kg for tebuconazole, 0.4 mg/kg for fluopyran and 0.3 mg/kg for pyraclostrobin. The ratio of the MRLs for apple/persimmon varied between 2.5 for boscalid and 1.25 for fluopyram, suggesting that residue extrapolation can be feasible, promoting the process of pesticide registration for minor crops and the settlement of MRL.

Biomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [ 11 C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [ 11 C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague-Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [ 11 C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [ 11 C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [ 11 C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [ 11 C]UCB-J does not appear to have sufficient sensitivity for this application., (© 2021. The Author(s).)

We report [ 18 F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson's disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies. Because the small size of mice brain poses challenges for PET imaging, improved methods for radiosynthesis of [ 18 F]nifene and simplified PET/CT procedures in mice were developed by comparing intravenous (IV) and intraperitoneal (IP) administered [ 18 F]nifene. An optimal PET/CT imaging time of 30-60 min post injection of [ 18 F]nifene was established to provide thalamus to cerebellum ratio of 2.5 (with IV) and 2 (with IP). Transgenic Hualpha-Syn(A53T) mice brain slices exhibited 20-35% decrease while in vivo a 20-30% decrease of [ 18 F]nifene was observed. Lewy bodies and α-synuclein aggregates were confirmed in human PD brain sections which lowered the [ 18 F]nifene binding by more than 50% in anterior cingulate. Thus [ 18 F]nifene offers a valuable tool for PET imaging studies of PD.

Soybean is an important oilseed crop, but weed can have a significant effect on soybean yield. Clomazone, fomesafen, and haloxyfop-methyl are high-efficacy herbicides, and the combination of these herbicides shows an ideal effect on weed control. However, the residues of these herbicides and their impacts on human health are still largely unknown. In the current study, a rapid, sensitive, and selective method using modified QuECHERS procedure combined with HPLC-MS/MS was established to detect these herbicides in soybean matrices. The limits of quantification were 0.01, 0.01 and 0.025 mg/kg for haloxyfop-methyl, haloxyfop and fomesafen, and 0.005, 0.005 and 0.0125 mg/kg for clomazone in green soybean, soybean grain, and straw, with the average recoveries ranging from 80% to 107%. The terminal residues of the target compounds were all below the corresponding limits of quantification. The dietary risk assessment showed that the risk quotient values were far below the acceptable human consumption levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The frequency of arboviral disease epidemics is increasing and vector control remains the primary mechanism to limit arboviral transmission. Container inhabiting mosquitoes such as Aedes albopictus and Aedes aegypti are the primary vectors of dengue, chikungunya, and Zika viruses. Current vector control methods for these species are often ineffective, suggesting the need for novel control approaches. A proposed novel approach is autodissemination of insect growth regulators (IGRs). The advantage of autodissemination approaches is small amounts of active ingredients compared to traditional insecticide applications are used to impact mosquito populations. While the direct targeting of cryptic locations via autodissemination seems like a significant advantage over large scale applications of insecticides, this approach could actually affect nontarget organisms by delivering these highly potent long lasting growth inhibitors such as pyriproxyfen (PPF) to the exact locations that other beneficial insects visit, such as a nectar source. Here we tested the hypothesis that PPF treated male Ae. albopictus will contaminate nectar sources, which results in the indirect transfer of PPF to European honey bees (Apis mellifera). We performed bioassays, fluorescent imaging, and mass spectrometry on insect and artificial nectar source materials to examine for intra- and interspecific transfer of PPF. Data suggests there is direct transfer of PPF from Ae. albopictus PPF treated males and indirect transfer of PPF to A. mellifera from artificial nectar sources. In addition, we show a reduction in fecundity in Ae. albopictus and Drosophila melanogaster when exposed to sublethal doses of PPF. The observed transfer of PPF to A. mellifera suggests the need for further investigation of autodissemination approaches in a more field like setting to examine for risks to insect pollinators., Competing Interests: The authors have declared that no competing interests exist.

Residue distribution of fluopyram and tebuconazole was assessed in pomegranate whole fruit, aril, outer peel (pericarp), inner peel (mesocarp) and leaves. The method LOQ of fluopyram and tebuconazole were 0.01 and 0.02 mg kg -1 , respectively. Both fungicides remained in fruit peel and residues in edible aril were < LOQ. In fruit peel major portion of the fungicides remained on pericarp with minimal movement to mesocarp. In mesocarp fluopyram was 5.7-14.2%; tebuconazole, 7.5-14.4% of the residues in pericarp. Terminal residues of fluopyram and tebuconazole in pomegranate whole fruit were 0.037-0.094 and 0.036-0.096 mg kg -1 . Half-life of fluopyram in pomegranate fruit and leaves were 7.3-9.1 and 15 days; tebuconazole, 8-10.3 and 11.2-12.6 days, respectively. Pre-harvest intervals for treatment of combination formulation of fluopyram and tebuconazole, were 47-59 days in fruits, 158-173 in leaves. Dietary risk assessment demonstrated that consumption of peel and leaves may pose risk to human health, whereas fruit consumption was considered safe., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In recent years, heated tobacco products (HTPs), which are widely used in Japan, have been sold by various brands using additives such as flavors. It has been reported that the components of mainstream smoke are different from those of conventional cigarettes. In this study, we established an analytical method for furans and pyridines in the mainstream smoke, which are characteristic of HTPs and particularly harmful among the generated components, and investigated the amount of component to which the smokers are exposed., Methods: We established a simple analytical method for simultaneous analysis of gaseous and particulate compounds in the mainstream smoke of HTPs (IQOS, glo, ploom S) in Japan by combining a sorbent cartridge and glass fiber filter (Cambridge filter pad (CFP)). Both the sorbent cartridge and CFP were extracted using 2-propanol and analyzed via GC-MS/MS to determine the concentration of furans and pyridines generated from each HTP., Results: The results showed that the levels of target furans such as furfural, 2-furanmethanol, 2(5H)-furanone, and 5-methylfurfural tended to be higher in the mainstream smoke of glo than in standard cigarettes (3R4F). Pyridine, which is generated at a high level in 3R4F as a combustion component, and 4-ethenylpyridine (EP), which is a known marker of environmental tobacco smoke, were detected. Among these components, 2-furanmethanol and pyridine are classified as Group 2B (possibly carcinogenic to humans) by the International Agency for Research on Cancer (IARC). Therefore, it is possible that they will contribute to the health effects caused by use of HTPs., Conclusions: Using the new collection and analytical method for furans and pyridines in the mainstream smoke of HTPs, the level of each compound to which smokers are exposed could be clarified. By comprehensively combining information on the amount of ingredients and toxicity, it will be possible to perform a more detailed calculation of the health risks of using HTPs. In addition, the components detected in this study may be the causative substances of indoor pollution through exhaled smoke and sidestream smoke; therefore, environmental research on the chemicals generated from HTPs would be warranted in future studies., (© 2021. The Author(s).)

Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity.

Sotorasib is a KRAS inhibitor with promising anticancer activity in phase I clinical studies. This compound is currently under further clinical evaluation as monotherapy and combination therapy against solid tumors. In this study, a liquid chromatography-tandem mass spectrometric method to quantify sotorasib in mouse plasma and eight tissue-related matrices (brain, liver, spleen, kidney, small intestine, small intestine content, lung, and testis homogenates) was developed and validated. Protein precipitation using acetonitrile was utilized in 96-well format to extract sotorasib and erlotinib (internal standard) from mouse plasma and tissue homogenates. Separation of the analytes was performed on an Acquity UPLC® BEH C18 column by gradient elution of methanol and 0.1% formic acid in water at a flow rate of 0.6 ml/min. Sotorasib was detected by a triple quadrupole mass spectrometer with positive electrospray ionization in selected reaction monitoring mode. A linear calibration range of 2-2,000 ng/ml of sotorasib was achieved during the validation. Accuracy values were in the range of 90.7-111.4%, and precision values (intra- and interday) were between 1.7% and 9.2% for all tested levels in all investigated matrices. The method was successfully applied to investigate the plasma pharmacokinetics and tissue accumulation of sotorasib in female wild-type mice., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

A gas chromatography-electron ionization-tandem mass spectrometric (GC-EI-MS/MS) method was developed and validated for determination of the major metabolites of zolpidem, zolpidem phenyl-4-carboxylic acid (ZPCA) and zolpidem 6-carboxylic acid (ZCA) in human hair. The sample preparation procedure involves decontamination, mechanical pulverization, incubation, extraction and purification prior to instrumental analysis. The extracts were derivatized using hexafluoroisopropanol and heptafluorobutyric anhydride and analyzed by GC-EI-MS/MS. The linear ranges were 8-100 pg/mg for ZPCA and 16-200 pg/mg for ZCA, with the correlation coefficients >0.997. The limits of detection were 1.8 pg/mg for ZPCA and 1.7 pg/mg for ZCA. The recoveries ranged from 77.6 to 111.7%. The intra- and inter-day precisions were within 16.9 and 11.7%, while intra- and inter-day accuracies were -7.0-8.7 and -2.8-7.8%, respectively. The developed method was applied for the analysis of forensic hair samples obtained from suspected zolpidem abusers and the following concentration ranges were monitored: ZPCA 11.9-35.9 pg/mg and ZCA 16.6-21.8 pg/mg. The method proved to be suitable for picogram-level determination of ZPCA and ZCA in human hair., (© 2021 John Wiley & Sons, Ltd.)

Maize seed treatment with chemicals to control underground pests is a common agricultural practice, but inappropriate use of insecticides poses a considerable threat to plant development and soil nontarget organisms. In this study, the availability of tetraniliprole seed dressing to control the black cutworm Agrotis ipsilon (Lepidoptera: Noctuidae) in the maize seeding stage and its safety to earthworms (Eisenia fetida) were investigated. The selective toxicity (ST) of tetraniliprole between E. fetida and A. ipsilon was greater than 4000. No significant adverse effect of tetraniliprole seed treatment on the germination of maize seeds was observed at concentrations of 2.4-9.6 g a.i. /kg seed. Compared with the untreated control, seed treatment with tetraniliprole at 9.6 g a.i. /kg seed greatly reduced the percentage of damaged plants from 88.73% to 26.67%, and achieved the highest control effect of 69.91%. Tetraniliprole of 2.4 g a.i. /kg seed can effectively inhibit A. ipsilon until 14 days after seed germination, with the lowest mortality rate of 44.44%. During the entire exposure period, the maximum residual concentration of tetraniliprole detected in the soil (5.86 mg/kg) was considerably lower than the LC 50 value of tetraniliprole to E. fetida (>4000 mg/kg). According to the low-tier risk assessment, the highest risk quotient (RQ) of tetraniliprole seed treatment to earthworms at test concentrations was 2.8 × 10 -3 , which was evaluated as acceptable. This study provided data support for tetraniliprole seed treatment to control underground pests in maize fields., (Copyright © 2021. Published by Elsevier Inc.)

The main sample preparation method for analysis of pesticide residues in fruits is QuEChERS. In this study, a novel sample preparation method using molecular complex-based dispersive liquid-liquid microextraction is introduced with detection of forchlorfenuron by high-performance liquid chromatography coupled with diode array and mass spectrometric detection. Sample treatment involves initial extraction of a 5 g sample with 3 mL acetonitrile, and then the selective concentration of the analyte is performed using 150 µL tributyl phosphate by forming intermolecular hydrogen bonds with the analyte. The extraction mechanism was proved using ATR-FTIR. Under the optimised conditions, recovery rates varied between 88% and 107% for various sample matrices spiked at three levels in the range 0.01-0.1 mg kg -1 . Intra-day and inter-day repeatabilities were in the ranges of 2.2-8.0% and 1.6-9.5%, respectively. Detection limit and quantitation limit were 0.33 µg kg -1 and 1.09 µg kg -1 for diode-array detection; 0.01 µg kg -1 and 0.04 µg kg -1 for tandem mass spectrometry detection. This method was successfully applied for the analysis of 149 various fruits. The analyte was found in 4 of the 149 samples and the contents were not over the specific maximum residue limit established by domestic and international regulations.

A reliable, selective and sensitive stability-indicating RP-HPLC assay was established for the quantitation of bromazepam (BMZ) and one of the degradant and stated potential impurities; 2-(2-amino-5-bromobenzoyl) pyridine (ABP). The assay was accomplished on a C18 column (250 mm × 4.6 mm i.d., 5 μm particle size), and utilizing methanol-water (70: 30, v/v) as the mobile phase, at a flow rate of 1.0 ml min-1. HPLC detection of elute was obtained by a photodiode array detector (DAD) which was set at 230 nm. ICH guidelines were adhered for validation of proposed method regarding specificity, sensitivity, precision, linearity, accuracy, system suitability and robustness. Calibration curves of BMZ and ABP were created in the range of 1-16 μg mL-1 with mean recovery percentage of 100.02 ± 1.245 and 99.74 ± 1.124, and detection limit of 0.20 μg mL-1 and 0.24 μg mL-1 respectively. BMZ stability was inspected under various ICH forced degradation conditions and it was found to be easily degraded in acidic and alkaline conditions. The results revealed the suitability of the described methodology for the quantitation of the impurity (ABP) in a BMZ pure sample. The determination of BMZ in pharmaceutical dosage forms was conducted with the described method and showed mean percentage recovery of 99.39 ± 1.401 and 98.72 ± 1.795 (n = 6), respectively. When comparing the described procedure to a reference HPLC method statistically, no significant differences between the two methods in regard to both accuracy and precision were found., Competing Interests: The authors have declared that no competing interests exist.

A novel analytical method, based on high-performance liquid chromatography with a UV (HPLC-UV) detection system for the sensitive detection of a genotoxic impurity (GTI) 5-amino-2-chloropyridine (5A2Cl) in a model active pharmaceutical ingredient (API) tenoxicam (TNX), has been developed and validated. The HPLC-UV method was used for the determination of GTI 5A2Cl in API TNX. The compounds were separated using a mobile phase composed of water (pH 3 adjusted with orthophosphoric acid): MeOH, (50:50: v/v) on a C18 column (150 × 4.6 mm i.d., 2.7 μm) at a flow rate of 0.7 mL min-1. Detection was carried out in the 254 nm wavelength. Column temperature was maintained at 40°C during the analyses and 10 μL volume was injected into the HPLC-UV system. The method was validated in the range of 1-40 μg mL-1. The obtained calibration curves for the GTI compound was found linear with equation, y = 40766x - 1125,6 (R2 = 0.999). The developed analytical method toward the target compounds was accurate, and the achieved limit of detection and limit of quantification values for the target compound 5A2Cl were 0.015 and 0.048 μg mL-1, respectively. The recovery values were calculated and found to be between 98.80 and 100.03%. The developed RP-HPLC-UV analytical method in this research is accurate, precise, rapid, simple and appropriate for the sensitive analysis of target GTI 5A2Cl in model API TNX., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pesticide registration ensures the safety of agricultural products; however, the backlog of field samples often requires lengthy storage periods. Thus, the stability of pesticide residues in stored samples is required information for pesticide registration. We monitored the degradation rates of fluroxypyr and halosulfuron-methyl in maize straw, mature maize grain, and fresh corn matrices to evaluate their storage stability. Analytes were extracted and cleaned up with a modified Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method and then detected with liquid chromatography tandem-mass spectrometry. We optimized the workflow by testing different clean-up sorbents, LC columns, and chromatographic methods. The linearity correlation coefficients of fluroxypyr and halosulfuron-methyl in the three matrices were ≥0.994. At three fortification levels, the mean recoveries of fluroxypyr and halosulfuron-methyl were 84.2-114.8% and 83.8-105.5% with relative standard deviations of 2.4-9.4% and 2.7-10.2%, respectively. Degradation of the two herbicides in the three matrices was less than 30% over the 70-day storage period, indicating fluroxypyr and halosulfuron-methyl are stable in the tested maize matrices when stored at -20 °C for at least 70 days. This study provides a reference method for pesticide residue analysis and can be used as a guide to develop accurate and reasonable pesticide registration procedures.

An in-depth understanding of the mechanisms of cellular uptake and efflux would facilitate the design of metal complexes with not only better functionality and targeted theranostic efficiency, but also with controlled toxicity. Here we find, unexpectedly, that the DNA "light-switching" Ru(ii)-polypyridyl complex [Ru(phen) 2 (dppz)] 2+ already delivered to the nucleus via ion-pairing with chlorophenolate counter-anions can gradually efflux to the cytoplasm when the cells were washed and incubated with fresh culture-medium. Interestingly, [Ru(phen) 2 (dppz)] 2+ effluxed to the cytoplasm can be redirected back to the nucleus when the chlorophenolate counter-anions were added again. The efflux of nuclear [Ru(phen) 2 (dppz)] 2+ was found to be mediated mainly via ATP-binding cassette (ABC) transporter proteins. Analogous reversible, but enantio-selective nuclear uptake and efflux were observed with the two pure chiral forms of [Ru(phen) 2 (dppz)]Cl 2 . This represents the first report of reversible and controllable nuclear uptake and efflux of a DNA "light-switching" Ru(ii)-complex in living-cells via ion-pairing, which should provide novel insights for future research on using ion-pairing as an effective approach to control the cellular uptake and redistribution of other potential theranostic metal complexes.

The degradation of fluopyram (FLP) was investigated under ozone-microbubble treatment (OMBT). Kinetic models were established to study the influence of three treatments: ozonated water, microbubbles (MCB), and OMBT. FLP degraded completely in OMBT, and a clearance rate of 89.8-100% was achievable. Three direct transformation products [product 1 (F1), product 2 (F2), and product 3(F3)] were isolated and identified using a hybrid ion trap-orbitrap mass spectrometer. Moreover, a transformation theory of FLP degradation was developed according to targeted fragmentation, accurate mass measurements, and degradation profiles. These analyses showed that the products originated from a series of chemical reactions involving dechlorination, hydroxyl substitution, cleavage and oxidation, and were further confirmed based on molecular electrostatic potential and molecular orbital theory. In addition, the stability and toxicity of FLP and its transformation products were tested using the Toxicity Estimation Software Tool (T.E.S.T.) and the Ecological Structure Activity Relationships (ECOSAR) program. Products F1, F2 and F3 were found to be toxic substances, but their toxicity to aquatic organisms was lower than that of FLP. However, they were more toxic to rats than FLP, and their physicochemical properties were more stable. Overall, OMBT is a highly effective method for FLP removal during wastewater treatment., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pyridine and organics containing pyridine rings are widely used but persist in the environment and cause toxic pollution. Due to the attraction of the nitrogen atoms to the electrons in the pi bond, the pyridine ring is difficult to oxidize by oxidant. Here, we propose that ultraviolet (UV) irradiation activates the electrons in the pi bond and enables combination with the hydroxyl radical (OH) originating from hydrogen peroxide (H 2 O 2 ) to eliminate pyridine quickly and mineralize the byproducts. The removal rates of pyridine and total organic carbon (TOC) were compared in different treatments: UV irradiation, UV/H 2 O 2 treatment and Fenton oxidation with different initial pyridine concentrations, pH values and H 2 O 2 concentrations. The UV/H 2 O 2 treatment yielded a higher pyridine removal rate and greater mineralization than the other treatments. The removal rate of pyridine was highest in neutral aqueous solution and H 2 O 2 concentration of 10 mM. At an initial H 2 O 2 concentration of 10 mM, more than 90% of the pyridine was degraded in 10 min, and approximately 70% of the TOC was removed in 60 min. The absorption of UV light at 254 nm by the pi bond of pyridine can accelerate the damage to the stable pyridine structure, especially in the presence of OH. This study provides a promising alternative for the removal and mineralization of pyridine ring-containing materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: Haloxyfop is a pre/post-emergence herbicide with known organ toxicities and teratogenic effects in mammals. The European Union Commission on Food Safety has an established maximum residue limit of 10 μg/kg in all agricultural products including eggs. A sensitive highly specific method would be of value in determination of haloxyfop residues in foodstuffs such as eggs., Methods: The Michigan State University Veterinary Diagnostic Lab (MSU VDL) developed a method for the extraction of haloxyfop from eggs based on popular QuEChERS (quick, easy, cheap, effective, rugged, and safe) methodologies, essentially providing acetonitrile extracts following treatment with high ionic strength additives. Extracts derivatized with trimethylsilyl (TMS) groups were examined by gas chromatography/tandem mass spectrometry using developed multiple reaction monitoring (MRM) methodology., Results: The MSU VDL received eggs from chickens exposed to 760 μg/kg haloxyfop in flaxseed. Haloxyfop-TMS m/z 374→73 MRM setting enabled quantitation across the 1-50 ppb range in comparison with an ibuprofen MRM transition as internal standard., Conclusions: The determined limit of quantitation was 2.5 ng/g, and the method successfully identified haloxyfop residues in five of six batches of the chicken eggs, with nonzero values ranging from 2.7 to 14.5 ng/g. These values were consistent with flaxseed incorporation into the diet at 4-7% and known excretion into eggs at 2-3% of daily haloxyfop exposure, and establish the utility of the method in identifying regulatory noncompliance and adulteration of food sources., (© 2020 John Wiley & Sons, Ltd.)

Filgotinibis aselective Janus kinase 1 inhibitor drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn s disease. The aim of the present study was to develop an accurate, simple and sensitive LC-MS/MS method for the determination of filgotinib (FLG) in human liver microsomes (HLMs) and its application to a metabolic stability study. Chromatographic separation was carried on using of a reversed phase C18 column. The mobile phase was mixture of acetonitrile and ammonium formate (10 mM, pH 3.8) (30:70, v/v), under isocratic elution at a flow rate of 0.3 mL/min. Veliparib was used as internal standard. FLG was extracted from HLMs by precipitation. An electrospray ionization source was used to assay of FLG. The assay of FLG at m/z 426 → 358 and 426 → 291 for FLG and IS at 245 → 145 and 245 → 84 was attained through MRM. The linearity of the investigated method was observed from 5 to 500 ng/mL (correlation coefficient r 2  = 0.999). The LOD was 1.43 ng/mL, while the LOQ was 4.46 ng/mL. The investigated method exhibited good recovery (98.42-108.6%) and precision (ranged from 0.88% to 4.7%). The investigated method was successfully employed for a metabolic stability study of FLG in the HLMs matrix. The metabolic stability of FLG was evaluated by measuring two parameters, in vitro t 1/2 (48.47 min) and intrinsic clearance (14.29μL/min/mg). The results of the metabolic study confirm that FLG is execrated from the human body at a slower rate compared to related tyrosine kinase inhibitors. Therefore, drug plasma levels and kidney function should be monitored due to potential bioaccumulation., Competing Interests: Declaration of Competing Interest The authors declared there is no competing interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A method for simultaneous quantitation of rimsulfuron, quizalofop-P-ethyl and quizalofop-P in potato plant, soil and potato tuber samples was established. The mean recoveries of rimsulfuron, quizalofop-P-ethyl and quizalofop-P in different matrices spiked with them were 81.4%-101.1%, 76.1%-99.0% and 77.4%-106.4% with relative standard deviations (RSDs) of 2.7%-13.3%, 0.9%-5.5%, 1.7%-11.3%, respectively. The open-field trials in China were conducted in potato cultivation system of Changchun and Jinan. The results indicated that the half-lives of rimsulfuron and quizalofop-P-ethyl were 0.04-13.1 days. The residues of quizalofop-P during the harvest time in Jinan soil were < 0.01-0.044 mg kg -1 , while there was no residue of target herbicides detected in all other samples. The risk assessment results demonstrated that the risk quotients (RQs) of rimsulfuron and quizalofop-P-ethyl were 7.857 × 10 -5 and 8.730 × 10 -3 , respectively, which exhibited an acceptable dietary risk to Chinese consumers.

Community tobacco use can be monitored over time using wastewater-based epidemiological approaches by estimating the mass loads of nicotine and its metabolites, cotinine, or hydroxycotinine, in wastewater. However, due to the use of nicotine in smoking cessation products, other sources of nicotine contribute to cotinine and hydroxycotinine loads. The use of nicotine replacement therapies could vary in space and time and mask the true rates of tobacco consumption. Therefore, this work evaluated the content of tobacco specific markers, anatabine and anabasine, in cigarettes, in urine of smokers, and in wastewater. The results indicated that the anabasine content in both licit and illicit cigarettes in Australia is less variable than anatabine and is therefore considered a better measure of tobacco consumption. A study determining the excretion of tobacco-specific alkaloids of smoking and non-smoking volunteers gave an average urinary mass load of anabasine of 4.38 μg/L/person and a daily mass load of 1.13 μg/day/person. Finally, this was compared with the mass loads of anabasine from wastewater-based epidemiology data of 3 μg/day/person to estimate cigarette rates in a South Australian city: equivalent to 2.6 cigarettes/person/day. The rate of decline of cigarette use was greater when using anabasine as a measure of consumption compared with cotinine. This is the first study to estimate the rate of anabasine excretion, which can be used to estimate tobacco use independent of therapeutically prescribed nicotine., (© 2020 John Wiley & Sons, Ltd.)

The alkaloid enantiomers are well-known to have different physiological and pharmacological effects, and to play an important role in enantioselectivity metabolism with enzymes catalysis in tobacco plants. Here, we developed an improved method for simultaneous and high-precision determination of the individual enantiomers of nornicotine, anatabine and anabasine in four tobacco matrices, based on an achiral gas chromatography-nitrogen phosphorus detector (GCNPD) with commonly available Rtx-200 column using (1S)-(-)-camphanic chloride derivatization. The method development consists of the optimization of extraction and derivatization, screening of achiral column, analysis of the fragmentation mechanisms and evaluation of matrix effect (ME). Under the optimized experimental conditions, the current method exhibited excellent detection capability for the alkaloid enantiomers, with coefficients of determination (R 2 ) > 0.9989 and normality test of residuals P > 0.05 in linear regression parameters. The ME can be neglected for the camphanic derivatives. The limit of detection (LOD) and limit of quantitation (LOQ) ranged from 0.087 to 0.24 μg g  -   1 and 0.29 to 0.81 μg g  -   1 , respectively. The recoveries and within-laboratory relative standard deviations (RSD R ) were 94.3%~104.2% and 0.51%~3.89%, respectively. The developed method was successfully applied to determine the enantiomeric profiling of cultivars and curing processes. Tobacco cultivars had a significant impact on the nornicotine, anatabine, anabasine concentration and enantiomeric fraction (EF) of (R)-nornicotine, whereas the only significant change induced by the curing processes was an increase in the EF of (R)-anabasine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Ivosidenib, as an oral mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, was awarded approval in the USA for the targeted therapy of relapsed or refractory acute myeloid leukemia (AML) in adult patients, who also had a susceptible enzyme to mIDH1. The aim of our present study was to develop and validate an accurate and fast assay based on the ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique for the quantification of ivosidenib in plasma and to investigate the possible effects of different CYP3A4 inhibitors (voriconazole, itraconazole and fluconazole) on ivosidenib metabolism in rats. After the fast protein crash with acetonitrile, chromatographic separation of ivosidenib and erlotinib (used as the internal standard in this experiment, IS) was accomplished using an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column, and detection of the analyte was also performed using a Xevo TQ-S triple quadrupole tandem mass spectrometer in the positive ion electrospray ionization (ESI) interface. The assay showed enough linearity over a 0.5-6000 ng/mL calibration range. The application of the validated bioanalytical method based on the UHPLC-MS/MS technique was further successfully exhibited in an animal study of the drug-drug interaction between ivosidenib (50 mg/kg) and voriconazole (20 mg/kg)/itraconazole (20 mg/kg)/fluconazole (20 mg/kg) in rats. Voriconazole, itraconazole and fluconazole increased the exposure of ivosidenib in plasma by different degrees and also had a potential inhibitory effect on the metabolism of ivosidenib. Thus, a dose reduction or interruption of ivosidenib may be important to guide the practice of clinical medicine., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A simultaneous assay for the determination of lemborexant and three metabolites (M4, M9, and M10) in human plasma and phosphate buffered saline (PBS) was developed and validated using liquid chromatography with tandem mass spectrometry, in support of plasma protein binding (PPB) studies. The analytes were extracted from plasma and PBS by solid phase extraction and then chromatographed on a reversed phase C18 column to ensure peak separation of three metabolites with the same mass transition. The analytes and the corresponding deuterated substances used as an IS were detected in the positive ion mode by multiple reaction monitoring. Lemborexant and three metabolites were quantifiable from 4 and 300 pg/mL in PBS and plasma, respectively, without any carryover. Extraction recovery was almost complete without matrix effects. The accuracy and precision in the intra- and inter-assay reproducibility were within the criteria as well as in the dilution integrity. Stability of the four analytes was ensured to cover duration of equilibrium dialysis and storage of samples. The established method was applied to an ex vivo PPB study in humans., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)