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Three carbonyl-functional novel hypercrosslinked polymers (HCP-TPS, HCP-TPA, and HCP-TPP) were successfully fabricated through an one-step Friedel–Crafts acylation reaction by copolymerizing paraphthaloyl chloride with triphenylsilane, triphenylamine, and triphenylphosphine, respectively. The resultant HCPs contained plenty of carbonyl-functional groups. Among the series of such HCPs, HCP-TPS displayed the best adsorption capability to chlorophenols (CPs), and thus it was employed as solid-phase extraction (SPE) adsorbent for enrichment of chlorophenols from water, honey, and white peach beverage prior to determination by high-performance liquid chromatography. Under the optimal conditions, the detection limits of the method (S/N = 3) were 0.15–0.3 ng mL −1 for tap water and leak water, 2.5–6.0 ng g −1 for honey sample and 0.4–0.6 ng mL −1 for white peach beverage sample. The recoveries of CPs in the spiked water, honey samples, and white peach beverage were in the range of 89.0–108.4%, 81.4–118.2%, and 85.0–113.5%, respectively. This work provides a new strategy for constructing functionalized HCPs as efficient SPE adsorbents. Graphical abstract In this work, three novel hypercrosslinked polymers (HCPs) were synthesized by the Friedel–Crafts alkylation reaction (paraphthaloyl chloride as the alkylating agent, triphenylsilane, triphenylamine, and triphenylphosphine as the aromatic units). Then, HCP-TPS was applied to soild-phase extraction sorbent for enrichment CPs from water, honey, and white peach beverage samples.

Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections 1 . Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family 2 . Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter 2 . Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics—the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin—that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins—essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection. The glycopeptide antibiotic-related compounds complestatin and corbomycin function by binding to peptidoglycan and blocking the action of autolysins—peptidoglycan hydrolase enzymes that remodel the cell wall during growth.

Cenobamate is one of the latest antiseizure medications (ASMs) developed for the treatment of focal onset seizures in adult patients. The recommended starting dose is 12.5 mg/day, titrated gradually to the target daily dose of 200 mg, which may be increased to a maximum of 400 mg/day based on clinical response. Although the high rate of seizure freedom observed in randomized, placebo-controlled clinical trials has resulted in exciting expectations, further clinical studies are needed to better define its clinical profile. Cenobamate is characterized by a peculiar pharmacology regarding both pharmacodynamics and pharmacokinetics. The mechanism of action has only partly been described, with the drug acting on voltage-gated sodium channels through a pronounced action on persistent rather than transient currents. Cenobamate also acts as a positive allosteric modulator of GABA A receptors independently from the benzodiazepine binding site. The bioavailability of cenobamate is not influenced by other drugs, except phenytoin; it can inhibit cytochrome P450 (CYP) 2C19 and induce CYP3A4 and 2B6, and hence can potentially interact with many drugs (e.g. dose adjustments may be required for lamotrigine, carbamazepine and clobazam). The pharmacokinetics of cenobamate are not linear and dosage increases imply a disproportional increase in plasma levels, particularly at doses higher than 300 mg. The most common and dose-related adverse effects associated with cenobamate include central nervous system-related symptoms, mainly somnolence, dizziness, diplopia, and disturbances in gait and coordination. A somewhat higher incidence of adverse events has been observed in patients concomitantly treated with sodium channel blockers. The most relevant safety issues are currently represented by the risk of severe skin reactions (apparently avoidable by a slow titration) and QT shortening (the drug is contraindicated in patients with familial short QT syndrome or taking QT-shortening drugs). Overall, cenobamate is a promising ASM with an intriguing and not fully understood mechanism of action; pharmacokinetic issues need to be considered in clinical practice.

Chlorophenol compounds and their derivatives are ubiquitous contaminants in the environment. These compounds are used as intermediates in manufacturing agricultural chemicals, pharmaceuticals, biocides, and dyes. Chlorophenols gets into the environment from a variety of sources such as industrial waste, pesticides, and insecticides, or by degradation of complex chlorinated hydrocarbons. Thermal and chemical degradation of chlorophenols leads to the formation of harmful substances which constitute public health problems. These compounds may cause histopathological alterations, genotoxicity, mutagenicity, and carcinogenicity amongst other abnormalities in humans and animals. Furthermore, the recalcitrant nature of chlorophenolic compounds to degradation constitutes an environmental nuisance, and a good understanding of the fate and transport of these compounds and their derivatives is needed for a clearer view of the associated risks and mechanisms of pathogenicity to humans and animals. This review looks at chlorophenols and their derivatives, explores current research on their effects on public health, and proffers measures for mitigation.

Nanocomposites (NCs) of crosslinked polyaniline (CPA)-coated oxidized carbon nanomaterials (OXCNMs) were fabricated as a very sensitive and simple electrochemical sensor to be utilized in 2,4-dichlorophenol (2,4-DCPH) detection. CPA/OXCNMs NCs were prepared by chemical copolymerization of polyaniline with triphenylamine and p-phenylenediamine in the presence of OXCNMs. The CPA/GO-OXSWCNTNCs exhibited a higher affinity for the oxidation of chlorophenols compared to the glassy carbon electrode (GCE), CPA/GCE, and other NCs. Cyclic voltammetry was performed to investigate and assess the electrocatalytic oxidation of 2,4-DCPH on the modified GCE. The compound yielded a well-defined voltammetric response in a Britton-Robinson buffer (pH 5) at 0.54 V (vs. silver chloride electrode). Quantitative determination of 2,4-DCPH was performed by differential pulse voltammetry under optimal conditions in the concentration range of 0.05 to 1.2 nmol L-1, and a linear calibration graph was obtained. The detection limit (S/N = 3) was found to be 4.2 nmol L-1. In addition, the results demonstrated that the CPA/GO-OXSWCNTs/GCE sensor exhibited a strong anti-interference ability, reproducibility, and stability. The prepared CPA/GO-OXSWCNTs/GCE sensor was used to rapidly detect 2,4-DCPH with a high degree of sensitivity in fish farm water with proven levels of satisfactory recoveries.

Background Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs. Methods We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs. Results 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged. Conclusions CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.

Aryl chlorides are among the most versatile synthetic precursors, and yet inexpensive and benign chlorination techniques to produce them are underdeveloped. We propose a process to generate aryl chlorides by chloro-group transfer from chlorophenol pollutants to arenes during their mineralization, catalyzed by Cu(NO₃)₂/NaNO₃ under aerobic conditions. A wide range of arene substrates have been chlorinated using this process. Mechanistic studies show that the Cu catalyst acts in cooperation with NOₓ species generated from the decomposition of NaNO₃ to regulate the formation of chlorine radicals that mediate the chlorination of arenes together with the mineralization of chlorophenol. The selective formation of aryl chlorides with the concomitant degradation of toxic chlorophenol pollutants represents a new approach in environmental pollutant detoxication. A reduction in the use of traditional chlorination reagents provides another (indirect) benefit of this procedure.

Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Furthermore, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder, and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30 new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover, therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall, the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

In randomised controlled trials, adjunctive cenobamate (CNB) has been shown to reduce seizure frequency in patients with drug-resistant focal epilepsy. Studies conducted in real-world settings provide valuable complementary data to further characterise the drug's profile. To assess the efficacy, retention and tolerability of adjunctive cenobamate (CNB), and to identify factors that might predict these outcomes in the clinical treatment of focal epilepsies. This multicentre, retrospective cohort study included all patients who began CNB treatment between October 2020 and April 2023 at seven participating epilepsy centres. Baseline and follow-up data were collected from patients' medical records, covering clinical characteristics and outcome data such as seizure frequency, dosing of CNB, physician-assessed Clinical Global Impression of Change, treatment-emergent adverse events (TEAEs), CNB retention and reasons for discontinuation. A total of 234 patients [mean age 40.7 ± 14 years, median 40 years, range 11-82 years; five adolescents under 18 years; 99 (42.3%) males] were analysed. The mean epilepsy duration at study entry was 23.2 ± 14.5 years (median 21 years, range 0.75-63 years), with the average age of epilepsy onset being 17.5 ± 13.0 years (median 17 years, range 0.1-71 years). The patients were taking a mean of 2.6 ± 0.8 (median 3) anti-seizure medications (ASMs) before starting CNB, and had failed a mean of 6 ± 3.3 (median 6) of further ASMs in the past. CNB exposure ranged from 5 to 1162 days, amounting to a total exposure time of 264.7 years. The retention rate was 92.6% at 3 months, 87.2% at 6 months and 77.8% at 12 months. At 3 months, 52.6% achieved a 50% seizure reduction, with 14.5% reporting seizure freedom; by 12 months, 47.7% maintained a 50% response rate and 11.9% were seizure-free. No significant differences in responder rates were observed based on sex, aetiology, seizure localisation, number of ASMs or target dose. The mean maximum CNB dose was 236.7 ± 97.4 mg (median 200 mg, range 12.5-450 mg), with 28 patients (12.0%) titrated up to 400 mg or above. During CNB treatment, 43.6% of patients were able to discontinue, and a further 24.4% were able to reduce the dose of a concomitant ASM. During CNB treatment, 144 patients (61.5%) experienced TEAEs. The most common TEAEs were sedation (n = 84, 35.9%), dizziness (n = 58, 24.8%) and ataxia (n = 23, 9.8%). CNB showed a relatively high and clinically useful 50% responder rate of 47.7% and an overall retention of 77.8% at 1 year. We were unable to identify specific predictors for response and retention, indicating that CNB may be beneficial for patients with a history of multiple failed ASMs, a high number of concomitant ASMs and any localisation or aetiology of focal epilepsy.

A growing body of evidence supports the effectiveness of cenobamate (CNB). This study aimed to assess the clinical response to add-on CNB through a time-to-event approach and explore the potential contribution of the concomitant classes of antiseizure medications (ASMs) to improve CNB clinical use. This study is a subgroup analysis of a larger retrospective, multicenter study on adults with focal-onset seizures participating in the Italian Expanded Access Program at five pre-established centers. The primary endpoint was the time-to-baseline seizure count; secondary endpoints included the rates of seizure response, seizure freedom (defined as no seizures' occurrence since at least the previous follow-up visit), treatment discontinuation, and adverse events (AEs). Data on 92 participants were extracted, with a median age of 44 (first quartile (Q )-third quartile (Q ): 29.25-50.75) years. The number of seizures recorded during the 90-day baseline was reached by 59/92 (64.1%) subjects during the 12-month follow-up. A higher, but not statistically significant probability of reaching the baseline seizures count was shown in the subgroups of subjects taking CNB with sodium channel blockers (SCBs) (hazard ratio [HR] 2.75; 95% confidence interval [CI] 0.79-9.61, p = 0.112) and both SCBs and GABAergics (HR 1.48; 95% CI 0.43-5.09, p = 0.536) compared with subjects taking GABAergics without SCBs. At 12 months, the rates of seizure response, seizure-freedom, and treatment discontinuation were 42.0%, 13.6%, and 23.9%, respectively. A total of 47/92 (51.1%) subjects experienced AEs (mainly somnolence, dizziness, and balance disorders) at a median time of 61 (Q -Q : 30-101) days. There was a higher, but not statistically significant risk of AEs occurrence in subjects treated with both SCBs and GABAergics and in those taking SCBs without GABAergics (HR 2.24; 95% CI 0.51-9.82, p = 0.286 and HR 1.40; 95% CI 0.31-6.39, p = 0.661, respectively) compared with those taking GABAergics without SCBs. The main limitations are the retrospective design and the small sample size. This time-to-event analysis added new insights to the currently available evidence about the real-world effectiveness of add-on CNB. Explorative estimates suggested favorable trends for subjects treated with concomitant GABAergics and without SCBs, who seemed to reach baseline seizure count and experience AEs less frequently and later than subjects treated with other concomitant ASMs. Further studies are needed to identify the best combinations of CNB with other ASMs to maximize seizure control and tolerability.