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The antiepileptic drug carbamazepine (CBZ) has been widely detected in freshwater, yet its toxic actions in fish at multiple endpoints and the subsequent recovery patterns of the impacted are less discussed. This study investigated the bioaccumulation, physiological and behavioral changes of crucian carp (Carassius carassius) following CBZ exposure (G1 = 6.15 μg/L, G2 = 61.5 μg/L, G3 = 615 μg/L, G4 = 6150 μg/L) and subsequent recovery. Our results showed that CBZ was more likely to accumulate in the liver and brain than in the gills. A concentration-dependent phenomenon was observed; however, the residual CBZ decreased to similar levels after recovery. The behavioral indicators (i.e. feeding, social and spontaneous swimming) were significantly inhibited after 7-days of CBZ exposure, and only recovered at low concentration treatment (G1) after 7-days recovery in CBZ-free water. The acetylcholinesterase (AChE) activity in the brain and superoxide dismutase (SOD) activity in the liver and gills were induced after CBZ exposure and returned to normal levels after 7-days of recovery. In contrast, the inhibition of catalase (CAT) activity caused by CBZ exposure persisted in the high concentration treatment (G4) after recovery. Furthermore, correlation analysis indicated that changes in feeding behavior were closely related to the variation of CBZ concentrations in tissues, and the persistence of abnormal swimming and social behavior was closely related to gill CAT activity. These findings contribute to explore the toxic mechanisms of CBZ and highlight the recovery process and connections between various endpoints., 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 risk assessment of an expanding array of emerging contaminants in aquatic ecosystems and the establishment of water quality criteria rely on species sensitivity distribution (SSD), necessitating ample multi-trophic toxicity data. Computational methods, such as quantitative structure-activity relationship (QSAR), enable the prediction of specific toxicity data, thus mitigating the need for costly experimental testing and exposure risk assessment. In this study, robust QSAR models for four aquatic species (Rana pipiens, Crassostrea virginica, Asellus aquaticus, and Lepomis macrochirus) were developed using leave-one-out (LOO) screening variables and the partial least squares algorithm to predict toxicity data for paraquat, bisphenol A, and carbamazepine. These predicted data can be integrated with experimental data to construct SSD models and derive hazardous concentration for 5 % of species (HC 5 ) for the criterion maximum concentration. The chronic water quality criterion for paraquat, bisphenol A, and carbamazepine were determined at 6.7, 11.1, and 3.5 μg/L, respectively. The QSAR-SSD approach presents a viable and cost-effective method for deriving water quality criteria for other emerging contaminants., 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.)

Carbamazepine is an anticonvulsant medication commonly used to treat epilepsy and other neurological disorders. The purpose of this study was to assess the impact of carbamazepine on prenatal development, including maternal-fetal, external, visceral, and skeletal toxicity. Additionally, the study aimed to investigate the effects of orally administered Carbamazepine at a lower dose range in Wistar rats. Pregnant female rats were randomly distributed into control (G1) group administered with distilled water orally (n=8), low dose (G2) group administered at 25 mg/kg, intermediate dose (G3) group at 50 mg/kg, and high dose (G4) group at 100 mg/kg through oral gavage from gestation day (GD) 5-19. Pregnant female rats were scheduled to necropsy on gestation day (GD) 20. During the evaluation, the uterus was observed for number of live or viable fetuses, dead fetuses, early resorptions, late resorptions, number of corpora lutea and the sex ratio (m/f) per litter. Further, fetuses were subjected to materno-fetal examination which included observation for placenta, amniotic fluid, and umbilical cord followed by external evaluation. Additionally, half of the fetuses were subjected to visceral, craniofacial evaluation and other half of the fetuses were subjected to skeletal evaluation by double staining method using Alcian Blue for cartilages and Alizarin Red S for bones. It was observed that there was a significant decrease in the rate of pregnancy in the intermediate dose (G3) group and in high dose (G4) group when compared with the control group. Moreover, treatment with the Carbamazepine caused significant increase in fetal malformations such as dilation of lateral and third ventricle in brain, in intermediate dose (G3) group and high dose (G4) group when compared with the control (G1) group, dilation of ureters in high dose (G4) group. Fetal skeletal malformations like bent and nodulated ribs were also observed in intermediate dose (G3) group. Existing research substantially supports the claim that carbamazepine can cause teratogenic effects and prenatal development toxicity even at a lower dose range., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Subham Kumar Panda reports financial support was provided by Vipragen Biosciences Private Limited. Subham Kumar Panda reports a relationship with Vipragen Biosciences Private Limited that includes: employment. 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 Inc. All rights reserved.)

Background: Carbamazepine (CBX) is widely used for various medical conditions, but its associated toxicity poses significant clinical concerns. This study aims to provide insights into the clinical presentations, management strategies, and outcomes of CBX toxicity cases in an emergency department (ED) setting., Methodology: This was a 10-year retrospective cohort chart review study, including all patients with elevated CBX levels. Data on clinical features, CBX levels, laboratory findings, electrocardiograms (ECGs), patient management, and outcomes were analyzed. Cases were categorized as acute or chronic toxicity., Results: Out of the 1,965 medical charts reviewed, we included 70 patients with CBX levels above the therapeutic range (prevalence: 3.6%). Chronic CBX toxicity cases (55.7%) were predominant, with gastrointestinal (GI) symptoms being the most common. Most patients presented with isolated CBX overdoses (88.6%), while mixed overdoses (11.4%) were less frequent. Patients were categorized based on CBX levels: 44 had mild toxicity (>51 μmol/L), and 26 had moderate toxicity (>85 μmol/L). Within the mild group, 15 patients experienced acute toxicity, compared to 16 patients in the moderate group. Four patients who had mixed overdoses and low sensorium required intubation and mechanical ventilation. Three patients received activated charcoal (AC), and another 3 patients received multiple doses of AC to reduce drug absorption. The majority of patients (65.7%) required hospital admission, underscoring the seriousness of CBX toxicity. There were no fatalities among these 70 patients., Conclusion: This study emphasizes the importance of a systematic approach to assessing and managing CBX toxicity, considering its diverse clinical presentations and variations in serum CBX levels., How to Cite This Article: Hazra D, Ellouze NF, Abri SA. Prevalence and Outcomes of Carbamazepine Toxicity in the Emergency Department: A Single-center Retrospective Study. Indian J Crit Care Med 2024;28(9):866-870., Competing Interests: Source of support: Nil Conflict of interest: NoneConflict of interest: None, (Copyright © 2024; The Author(s).)

Carbamazepine is utilized for various indications. Due to its pharmacokinetic profile and drug properties, toxicity can be delayed and persistent despite supportive care. We report a severe case of intentional carbamazepine toxicity in a carbamazepine naive individual mimicking brain death that was not diagnosed until three days after consumption of carbamazepine when the patient was comatose. Symptoms of overdose persisted for several days despite attempted treatment with activated charcoal and whole bowel irrigation, hemodialysis, and plasmapheresis. Symptoms only began to improve with bowel evacuation as a result of administration of neostigmine intravenously plus hemodialysis and plasmapheresis additionally. Despite previous literature that reported success with hemodialysis and/or plasmapheresis we did not find either to be overly effective in our case possibly due to lack of ability to perform multidose activated charcoal and whole bowel irrigation. To our knowledge this is one of the few cases of carbamazepine overdose utilizing both hemodialysis and plasmapheresis but without activated charcoal and the only case report in which neostigmine was administered as an attempt to remove drug via the gastrointestinal tract with success. [ABSTRACT FROM AUTHOR]

Bromate (BrO 3 - )-induced pharmaceutical and personal care products (PPCPs) oxidation is enhanced in freezing systems. Reduced forms of metals are widely present, often coexisting with various contaminants. However, their effects on the interaction of PPCPs with BrO 3 - in ice in cold regions may have been overlooked. Herein we investigated the effects of representative reducing metal Cr(III) on the interaction between the representative PPCP carbamazepine (CBZ) and BrO 3 - in the freezing system. Our findings demonstrated that the degradation rate constants of CBZ by BrO 3 - and Cr(III) were 29.4%-60.3% lower than those by BrO 3 - in ice, revealing the inhibition of Cr(III) on CBZ degradation by BrO 3 - in ice. In BrO 3 - /freezing/sunlight system, BrO 3 - contributed 62.8% to CBZ degradation. In BrO 3 - /Cr(III)/freezing/sunlight system, Cr(III) promoted the generation of hydroxyl radical (·OH), leading to 51.0% contribution of ·OH to CBZ degradation. Oxidants were consumed by Cr(III) to form Cr(VI) rather than reacting with CBZ, thereby decreasing CBZ degradation by BrO 3 - in ice. Due to sunlight-induced Cr(VI) reduction in ice, only 0.3% of Cr(III) was converted to Cr(VI) in BrO 3 - /Cr(III)/freezing/sunlight system. BrO 3 - -induced CBZ degradation rate in ice decreased in order of Fe(II), Cr(III), and Mn(II), which was due to the different reducing capabilities. An effective reduction in comprehensive toxicity of systems followed the freezing-sunlight process, even in the presence of Cr(III). This work sheds new light on the environmental behaviors and fate of PPCPs, brominated disinfection by-products, and reducing metals during seasonal freezing., 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 Inc. All rights reserved.)

Previous studies have highlighted the toxicity of pharmaceuticals and personal care products (PPCPs) in plants, yet understanding their spatial distribution within plant tissues and specific toxic effects remains limited. This study investigates the spatial-specific toxic effects of carbamazepine (CBZ), a prevalent PPCP, in plants. Utilizing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), CBZ and its transformation products were observed predominantly at the leaf edges, with 2.3-fold higher concentrations than inner regions, which was confirmed by LC-MS. Transcriptomic and metabolic analyses revealed significant differences in gene expression and metabolite levels between the inner and outer leaf regions, emphasizing the spatial location's role in CBZ response. Notably, photosynthesis-related genes were markedly downregulated, and photosynthetic efficiency was reduced at leaf edges. Additionally, elevated oxidative stress at leaf edges was indicated by higher antioxidant enzyme activity, cell membrane impairment, and increased free fatty acids. Given the increased oxidative stress at the leaf margins, the study suggests using in situ Raman spectroscopy for early detection of CBZ-induced damage by monitoring reactive oxygen species levels. These findings provide crucial insights into the spatial toxicological mechanisms of CBZ in plants, forming a basis for future spatial toxicology research of PPCPs.

Screening for sensitive toxicological indicators and understanding algal tolerance to pharmaceutical contaminants (PhCs) are essential for assessing PhCs risk and their removal by microalgae. Carbamazepine (CBZ) showed adverse effects on microalgae, but the specific toxicity mechanisms on the most sensitive algal photosynthetic system (PS) remain limited. This study delved into the impact of CBZ exposure on the growth, cell viability, pigment content, and PS of Chlorella vulgaris. The findings revealed a notable inhibition of C. vulgaris growth by CBZ, with an IC 50 value of 27.2 mg/L at 96 h. CBZ exposure induced algal membrane damage and cell viability. Intriguingly, CBZ drastically diminished intracellular pigment levels, notably showing "low promotion and high inhibition" of chlorophyll b (Chl b) by 72 h. Moreover, the study identified a decreased number of active reaction centers (RCs) within algal PSII alongside inhibited electron transport from Q A to Q B on the PSII receptor side, leading to PSII disruption. As an adaptive response to CBZ stress, C. vulgaris stimulated its Chl b synthesis, increased non-photochemical quenching (NPQ), and adapted its tolerance to bright light. Additionally, the alga attempted to compensate for the CBZ-induced reduction in electron transfer efficiency at the PSII receptor side and light energy utilization by increasing its electron transfer from downstream. Principal component analysis (PCA) further verified that the parameters on non-photochemical dissipation, electron transport, and integrative performance were the most sensitive algal toxicological indicators for CBZ exposure, and algal PS has energy protection capability through negative feedback regulation. However, prolonged exposure to high doses of CBZ will eventually result in permanent damage to the algal PS. Hence, attention should be paid to the concentration of CBZ in the effluent and the exposure time, while methods to mitigate algal photodamage should be appropriately sought for algal treatment of dense effluents., 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 Ltd. All rights reserved.)

Background: Carbamazepine is one of the most commonly used antiseizure medications. Although carbamazepine pharmacokinetics in epileptic patients is well described, much less is known about these processes in the patients who experienced self-poisoning episode by this drug. Therefore, the aim of our investigation was to perform population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults., Research Design and Methods: Software program NONMEM and the ADVAN2 TRANS2 subroutine were used for establishing a population toxicokinetic model for the estimation of clearance and volume of distribution based on of the sum values of carbamazepine and carbamazepine-10,11-epoxide concentrations., Results: Our results indicated that the adult patients' ability to eliminate carbamazepine and carbamazepine-10,11-epoxide following acute carbamazepine self-poisoning was strongly associated with the high levels of CRP and ASP, as well as by the treatment with sedation., Conclusions: Our study should provide better understanding of the toxicokinetics of carbamazepine taken in overdose and better management of patient population admitted to hospital.

Standardization and validation of in vitro drug metabolism is essential for pre-clinical drug development as well as for in vitro toxicity assays including the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA). Use of isolated liver microsomes (MIC) in in vitro testing has been utilized for a long time; however, the effect of species of origin and induction agents on the metabolic capacities of MIC is not adequately evaluated. In this study we investigated the impact of species of origin and induction agent on the capacity of MICs to bioactivate carbamazepine (CBZ) using cytotoxicity as a gross endpoint to measure the levels of cytotoxic metabolites generated by each type of MICs. Jurkat E6.1 cell line was used and MICs from human, rat, mouse, minipig and rabbit origin as well as rat MICs that is either non-induced or induced by phenobarbitone (PHB), dexamethasone (DEXA), 3-methylcholanthrene (3MC), clofibrate (CLOF) and isoniazid (INH) were investigated. MICs from minipig and rat MICs induced with 3MC exhibited the highest capacity to produce cytotoxic metabolites of CBZ. These findings will help optimize and standardize in vitro toxicity assays and provide guidance to pre-clinical investigation of drugs., Competing Interests: Declaration of competing interest None of the authors of this manuscript have any conflict of interest to declare. Their affiliations and employers are as indicated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this research work, surface-modified nano zerovalent copper (nZVC) was prepared using a simple borohydride reduction method. The spectroscopic and crystallographic results revealed the successful synthesis of surface-modified nano zerovalent copper (nZVC) using solvents such as ethanol (ETOH), ethylene glycol (EG) and tween80 (T80). The as-synthesized material was fully characterized for morphological surface and crystal structural properties. The results indicated that EG provides an excellent synthesis environment to nZVC compared to ETOH and T80 in terms of good dispersion, high surface area and excellent catalytic properties. The catalytic efficiency of nZVC/EG was investigated alone and with peroxymonosulphate (PMS) in the absence of light. The degradation results demonstrated that the involvement of PMS synergistically boosted the catalytic efficiency of synthesized nZVC/EG material. Furthermore, the degradation products (DPs) of CBZ were determined by GC-MS and subsequently, the degradation pathways were proposed. The ecotoxicity analysis of the DPs was also explored. The proposed (nZVC/EG/PMS) system is economical and efficient and thus could be applied for the degradation of CBZ from an aquatic system after altering the degradation pathways in such a way that results in harmless products.

In this study, the impact of calcination of zeolites on the ecotoxicity of carbamazepine solutions in two matrices, water and synthetic sewage, was assessed. Two types of zeolites were tested: natural zeolite, in the form of a zeolite rock consisting mainly of clinoptilolite, and a synthetic zeolite type 5 A. Additionally, zeolites were calcined at a temperature of 200 °C. The kinetics of carbamazepine adsorption in aqueous solutions and in synthetic sewage matrix was determined. Higher adsorption capacity was obtained for carbamazepine aqueous solutions as well as zeolites after the calcination process. Considering type of zeolite, the highest and fastest uptake of carbamazepine was observed for natural zeolite after calcination. In the case of ecotoxicity, carbamazepine solutions before adsorption was the most toxic towards Raphidocelis subcapitata, next Aliivibrio fischeri and Daphnia magna, regardless to the matrix type. The differentiation in toxicity regarding the type of matrix was observed, in the case of algae and bacteria, higher toxicity was demonstrated by carbamazepine solutions in the water matrix, while in the case of crustaceans-the sewage matrix. After the adsorption process, the toxicity of carbamazepine solutions on zeolites decreased by 34.5-60.9 % for R. subcapitata, 33-39 % for A. fischeri and 55-60 % for D. magna, thus confirming the effectiveness of the proposed method of carbamazepine immobilization., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent attention on the detrimental effects of pharmaceutically active compounds (PhACs) in natural water has spurred researchers to develop advanced wastewater treatment methods. Carbamazepine (CBZ), a widely recognized anticonvulsant, has often been a primary focus in numerous studies due to its prevalence and resistance to breaking down. This study aims to explore the effectiveness of a bio-electrochemical system in breaking down CBZ in polluted water and to assess the potential harmful effects of the treated wastewater. The results revealed bio-electro degradation process demonstrated a collaborative effect, achieving the highest CBZ degradation compared to electrodegradation and biodegradation techniques. Notably, a maximum CBZ degradation efficiency of 92.01% was attained using the bio-electrochemical system under specific conditions: Initial CBZ concentration of 60 mg/L, pH level at 7, 0.5% (v/v) inoculum dose, and an applied potential of 10 mV. The degradation pathway established by identifying intermediate products via High-Performance Liquid Chromatography-Mass Spectrometry, revealed the complete breakdown of CBZ without any toxic intermediates or end products. This finding was further validated through in vitro and in vivo toxicity assays, confirming the absence of harmful remnants after the degradation 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 © 2024 Elsevier Ltd. All rights reserved.)

Carbamazepine (CBZ) is a widely used anticonvulsant drug that has been detected in aquatic environments. This study investigated the toxicity of its by-products (CBZ-BPs), which may surpass CBZ. Unlike the previous studies, this study offered a more systematic approach to identifying toxic BPs and inferring degradation pathways. Furthermore, quadrupole time-of-flight (QTOF) and density functional theory (DFT) calculations were employed to analyze CBZ-BP structures and degradation pathways. Evaluation of total organic carbon (TOC) and total nitrogen (TN) mineralization rates, revealed carbon (C) greater susceptibility to mineralization compared with nitrogen (N). Furthermore, three rules were established for CBZ decarbonization and N removal during degradation, observing the transformation of aromatic compounds into aliphatic hydrocarbons and stable N-containing organic matter over time. Five potentially highly toxic BPs were screened from 14 identified BPs, with toxicity predictions guiding the selection of commercial standards for quantification and true toxicity testing. Additionally, BP207 emerged as the most toxic, supported by the predictive toxicity accumulation model (PTAM). Notably, highly toxic BPs feature an acridine structure, indicating its significant contribution to toxicity. These findings offered valuable insights into the degradation mechanisms of emerging contaminants and the biosafety of aquatic environments during deep oxidation., 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 Ltd. All rights reserved.)

Carbamazepine (CBZ) is an anticonvulsant medication used to treat epilepsy and bipolar disorder. Due to its persistence and low removal rate in wastewater treatment plants, it is frequently detected in the environment, raising concerns regarding its potential adverse effects on aquatic organisms and ecosystems. In this study, we aimed to assess the impact of CBZ on the behavior and growth of juvenile yellow catfish Tachysurus fulvidraco, a native and economically important species in China. Fish were exposed to CBZ at three concentrations of 1, 10, or 100 µg/L for 14 days. The fish exposed to 10 and 100 μg/L of CBZ exhibited decreased feeding, and a significant increase in cannibalistic tendencies was observed in fish exposed to 100 μg/L CBZ. Acetylcholinesterase activity was increased in the brain of fish exposed to 100 μg/L CBZ. CBZ also inhibited the growth of yellow catfish. To better elucidate mechanisms of toxicity, transcriptomics was conducted in both the brain and liver. In the brain, gene networks associated with neurotransmitter dysfunction were altered by CBZ, as well as networks associated with mitochondrial dysfunction and metabolism. In the liver, gene networks associated with the immune system were altered by CBZ. The current study improves comprehension of the sub-lethal effects of CBZ and reveals novel insight into molecular and biochemical pathways disrupted by CBZ, identifying putative key events associated with reduced growth and altered behavior. This study emphasizes the necessity for improved comprehension of the effects of pharmaceutical contaminants on fish at environmentally relevant levels., 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. Published by Elsevier B.V.)

Groundwater contamination by pharmaceutically active compounds (PhACs) has been considered a public health concern worldwide. Alongside the potential toxicological risk of these organic substances, many countries still rely on groundwater for drinking water supply. Thus, this study identified a priority list of seven licit PhACs, comprising acetaminophen (ACT), tramadol (TRA), carbamazepine (CBZ), erythromycin (ERY), sulfamethoxazole (SMX), metformin (MET), and oxazepam (OXZ). Consumption, concentration, and human toxicity in silico results were collected from open access databases. These three indicators were analyzed separately and grouped through a general risk index. The consumption index (data from the USA and Brazil) indicated that ACT, TRA, and MET are the most consumed. Monitoring samples from the USA and Europe (n = 816) indicated that OXZ and ERY stand out as the higher occurrence index considering both regions, but the ranking for each region showed considerable differences. When assessing toxicological risk, an index ≥ 0.5 was attributed to CBZ, MET, OXZ, SMX, and TRA. The general risk indicated the need to be attentive to MET, OXZ, and TRA as they presented ≥ 0.5 index values for at least two indicators., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Carbamazepine (CBZ) has been identified in the aquatic environment as an emerging contaminant. Its immune effect across generations at environmentally relevant concentrations is little known. We aim to elucidate the effects of CBZ on the immune system in zebrafish (Danio rerio), hypothesizing the effects caused by CBZ exposure in the parental generation can be passed on to its offspring, leading to impairment of innate immune function and defense against pathogen weakened. A suite of bioassays (including a test with added lipopolysaccharide) was used to measure the effects of environmentally relevant levels of CBZ (1, 10, and 100 μg/l) on zebrafish at multiple biological levels, and across 2 successive generations (21 days exposure for F0; 5 and 21 days exposure or nonexposure for F1). The results showed that CBZ affected homeostasis in the immune system, caused liver vacuolization, increased the inflammation-related microbiota proportion in gut, and decreased reproduction, by induction of oxidative stress and modulation of Toll-like receptors (TLR) signaling pathway on gut-liver axis. The effects of exposure to CBZ over 21 days in F0 could be passed to the next generation. Intergenerational effects on TLR and antioxidant defense system were also observed in nonexposed F1 at 5 days post-fertilization (5 dpf), but diminished at 21 dpf. The finding provided evidence to unravel immune response by gut-liver axis mediated and oxidative stress under 4 test conditions. The study has raised a potential concern about the multigenerational immune effects of environmental pollutants and calls for a focus on the risk of synergetic pathogen infection., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carbamazepine (CBZ) is a common antiepileptic drug. CBZ enters the environment through unreasonable and standardized ways such as human and animal metabolites, discarded drugs, and more than half of its metabolites are released into the environment. Since CBZ is not easy to be degraded, continuous input of CBZ into the water environment will cause long-term impact on the water ecological environment and seriously endanger human health. Aiming at how to degrade wastewater containing carbamazepine, studies were conducted on the degradation of carbamazepine by ultrasound/zero-valent iron/persulfate system (US/ F e 0 /PS). Firstly, the removal effects of carbamazepine by different systems, such as ultrasound/sodium persulfate (US/PS), zero-valent iron/persulfate system ( F e 0 /PS) and US/ F e 0 /PS, were compared; Secondly, the influence of factors, such as ultrasonic power, sodium persulfate dosage, zero-valent iron dosage, reaction temperature, pH, etc., on the reaction was investigated by the control variables method. Results show that ultrasound power, PS concentration, pH and temperature have a great influence on the removal of carbamazepine in US/Fe 0 /PS reaction system. Besides, the optimum parameters for degradation of carbamazepine with US/ F e 0 /PS reaction system were determined ([CBZ] 0  = 0.025 mM; [PS] 0  = 0.4 mM; Fe 0  = 4.0 mg/L; ultrasonic power = 40 W; T = 30 ℃; initial pH = 5.0). Finally, the intermediates and degradation pathways of carbamazepine by US/ F e 0 /PS system were analyzed and speculated. It was inferred that two intermediates were generated during the degradation of carbamazepine, mainly through the ring opening and decyclization of piperazine rings. It was proved that process US/ F e 0 /PS has a very important application value in the degradation of antibiotic-containing wastewater.

Exposure to single molecules under laboratory conditions has led to a better understanding of the mechanisms of action (MeOAs) and effects of pharmaceutical active compounds (PhACs) on non-target organisms. However, not taking the co-occurrence of contaminants in the environment and their possible interactions into account may lead to underestimation of their impacts. In this study, we combined untargeted metabolomics and proteogenomics approaches to assess the mixture effects of diclofenac, carbamazepine and venlafaxine on marine mussels (Mytilus galloprovincialis). Our multi-omics approach and data fusion strategy highlighted how such xenobiotic cocktails induce important cellular changes that can be harmful to marine bivalves. This response is mainly characterized by energy metabolism disruption, fatty acid degradation, protein synthesis and degradation, and the induction of endoplasmic reticulum stress and oxidative stress. The known MeOAs and molecular signatures of PhACs were taken into consideration to gain insight into the mixture effects, thereby revealing a potential additive effect. Multi-omics approaches on mussels as sentinels offer a comprehensive overview of molecular and cellular responses triggered by exposure to contaminant mixtures, even at environmental concentrations., 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.)

Acetic acid is an organic acid that can be used in the food industry, which normally has an insignificant rate of adverse reactions when used rationally. However, irrational use can cause serious toxic effects and even death. In this context, the case of a death of a 52-year-old woman, involving the suspected voluntary use of food acetic acid, is presented, while toxicological and histopathological aspects were addressed for death mechanism elucidation. In this case, the pH value of 6.75 in blood, has shown severe metabolic acidosis after the ingestion of the large quantity of dietary acetic acid - about a liter. Also, the victim suffers from mental illness, carbamazepine being one of the treatment drugs. Liver damage, demonstrated by histopathological examination may be a consequence of both massive accumulation of carbamazepine in the liver and toxicity of food acetic acid. In conclusion, the hepatotoxicity induced by high level of carbamazepine was suspected of increasing the risk of multiple organ failure, in the context of acetic acid acute toxicity, highlighting the particularities of the case.

Dreissena polymorpha is a bivalve promising for biomonitoring in freshwater ecosystems thanks to its abundance and high filtration activity allowing rapid uptake of toxicants and identification of their negative effects. Nonetheless, we still lack knowledge on its molecular responses to stress under realistic scenario, e.g. multi-contamination. Carbamazepine (CBZ) and Hg are ubiquitous pollutants sharing molecular toxicity pathways, e.g. oxidative stress. A previous study in zebra mussels showed their co-exposure to cause more alterations than single exposures, but molecular toxicity pathways remained unidentified. D. polymorpha was exposed 24 h (T24) and 72 h (T72) to CBZ (6.1 ± 0.1 μg L -1 ), MeHg (430 ± 10 ng L -1 ) and the co-exposure (6.1 ± 0.1 μg L -1 CBZ and 500 ± 10 ng L -1 MeHg) at concentrations representative of polluted areas (~10× EQS). RedOx system at the gene and enzyme level, the proteome and the metabolome were compared. The co-exposure resulted in 108 differential abundant proteins (DAPs), as well as 9 and 10 modulated metabolites at T24 and T72, respectively. The co-exposure specifically modulated DAPs and metabolites involved in neurotransmission, e.g. dopaminergic synapse and GABA. CBZ specifically modulated 46 DAPs involved in calcium signaling pathways and 7 amino acids at T24. MeHg specifically modulated 55 DAPs involved in the cytoskeleton remodeling and hypoxia-induced factor 1 pathway, without altering the metabolome. Single and co-exposures commonly modulated proteins and metabolites involved in energy and amino acid metabolisms, response to stress and development. Concomitantly, lipid peroxidation and antioxidant activities were unchanged, supporting that D. polymorpha tolerated experimental conditions. The co-exposure was confirmed to cause more alterations than single exposures. This was attributed to the combined toxicity of CBZ and MeHg. Altogether, this study underlined the necessity to better characterize molecular toxicity pathways of multi-contamination that are not predictable on responses to single exposures, to better anticipate adverse effects in biota and improve risk assessment., 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.)

Globally, the prevalence and pollution of pharmaceutical drugs in aquatic environments have been steadily increasing. This study sought to evaluate the effects of 14 days of exposure to environmental-relevant doses (ibuprofen 0.5, 5, and 50 µg/L, and carbamazepine 0.005, 1, and 10 µg/L) of the nonsteroidal anti-inflammatory drugs ibuprofen and carbamazepine in the freshwater fish Oreochromis mossambicus. The results showed a significant (P < 0.05) decrease in O. mossambicus superoxide dismutase, catalase, biotransformation enzymes, glutathione-s-transferase, glutathione peroxidase, oxidative stress lipid peroxidation, protein carbonyl activity, cellular damage metallothionine, reduced glutathione, immunological activities, and respiratory burst activity. Consequently, the acquired data revealed that O. mossambicus treated with ibuprofen and carbamazepine shows more significant alterations in metabolic depression, biochemical parameters, and oxidative stress. In addition, increased neurotoxic effects were observed in ibuprofen and carbamazepine treated O. mossambicus., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Epilepsy, a neurological disorder, is characterized by seizures that are an appearance of excessive brain activity and is symptomatically treated with antiepileptic drugs (AEDs). Oxcarbazepine (OCBZ), lamotrigine (LTG), and carbamazepine (CBZ) are widely used AEDs in clinics and are very often detected in aquatic environments. However, neither the sub-lethal effects nor the specific mechanisms of these AEDs' action on the fish are well understood. In this study, juvenile zebrafish were exposed to a sub-lethal concentration (100 μg/L) of OCBZ, LTG, and CBZ for 28 d, after which indicators of oxidative stress (i.e. superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) level) and neurotoxicity (i.e. acetylcholinesterase (AChE) activity, γ-aminobutyric acid (GABA) level, and glutamic acid (Glu) level) were measured. Brain SOD activity was significantly increased by three AEDs, while brain CAT activity was significantly inhibited by LTG and CBZ. Liver SOD activity was significantly enhanced by CBZ, and liver CAT activity was significantly induced by OCBZ and LTG. Liver MDA level was significantly increased by three AEDs. Brain AChE activity was significantly increased by LTG and CBZ, and brain GABA level was significantly enhanced by three AEDs. However, there were no significant alterations in the levels of MDA and Glu in zebrafish brain. To ascertain mechanisms of AEDs-induced toxicity, brain transcriptomics and liver metabolomics were conducted in zebrafish. The brain transcriptomics results showed that lots of differentially expressed genes (DEGs) were enriched in the sensory system, the immune system, the digestive system, the metabolic processes, and others in three AEDs treated groups. The metabolomics data indicated dysregulation of glycerophospholipid signaling and lipid homeostasis in zebrafish liver after three AEDs exposure. The overall results of this study improve understanding of the sub-lethal effects and potential molecular mechanisms of action of AEDs in fish., 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. Published by Elsevier B.V.)

Carbamazepine (CBZ), a pharmaceutical compound, has been proposed as an anthropogenic marker to assess water quality due to its persistence in conventional treatment plants and widespread presence in water bodies. This paper presents a comprehensive literature review on sources and occurrences of CBZ in water bodies, as well as toxicological effects and regulations of the drug. Given the documented side effects of CBZ on the human body when taken medicinally, its careful monitoring in water is recommended. CBZ residues in drinking water may provide a pathway to embryos and infants via intrauterine exposure or breast-feeding, which may cause congenital malformations and/or neurodevelopmental problems over long term exposure. An in-depth technical assessment of the conventional and advanced treatment technologies revealed the inadequacy of the standalone technologies. Compared to conventional activated sludge and membrane bioreactor processes, effective removal of CBZ can be achieved by nanofiltration and reverse osmosis membranes. However, recent studies have revealed that harsh chemical cleaning, as required to mitigate membrane fouling, can often reduce the long-term removal efficiency. Furthermore, despite the efficient performance of activated carbon adsorption and advanced oxidation processes, a few challenges such as cost of chemicals and regeneration of activated carbon need to be carefully considered. The limitations of the individual technologies point to the advantages of combined and hybrid systems, namely, membrane bioreactor coupled with nanofiltration, adsorption or advanced oxidation process. [ABSTRACT FROM AUTHOR]

This study examined the potential effects of Mucuna pruriens (MP) seed powder on the disruptions of the hypothalamic-pituitary-testicular axis caused by the carbamazepine (CBZ) treatment in male Wistar rats. A total of 35 male Wistar rats were randomized into 5 groups (n=7). The animal in group 1 received normal saline (0.2 ml) orally, while groups 2-5 received carbamazepine (CBZ) 25 mg/kg per oral. Groups 1, and 2 were fed with standard rats' chow, while groups 3-5 rats were supplied with a diet containing MP seed powder at 2.25 g, 1.5 g, and 0.75 g respectively. The serum level of male reproductive hormones, estradiol, seminal profiles, and histoarchitecture of the hypothalamus, pituitary, and testis was delineated. Descriptive and inferential statistics were used to analyze the result. There was a marked decrease in the testicular weight, follicle-stimulating hormone, testosterone concentration, and normal sperm cells in the CBZ, and CBZ + MP (2.25 mg/kg) treatment groups.  There was a marked increase in the testicular tissue lipid peroxidation in the CBZ, and CBZ + MP (g) treated rats in addition to various morphological alterations in the hypothalamus, pituitary, and testis. These anomalies were receded in the CBZ + MP (1.5 g), and CBZ + MP (0.75 g) treatment groups. Consumption of MP (1.5 g, and 0.75 g) may alleviate the injurious effects of CBZ treatment on the hypothalamic-pituitary-testicular functions.

مقدمه: مصرف روز افزون کاربامازپین منجر به افزایش مسمومیت با این دارو شده است. در خصوص میزان تغییرات و گرفتاری سیستم قلبی و عروقی در مسمومیت با کاربامازپین اختلاف نظر وجود دارد. روش‌ها: در یک مطالعه‌ی مقطعی، 77 نفر از بیماران مراجعه کننده به بخش مسمومین بیمارستان نور اصفهان، که دچار مسمومیت با کاربامازپین شده بودند، به صورت غیراحتمالی آسان انتخاب شدند. تغییرات ECG، نبض و فشار خون و ارتباط این تغییرات با سطح هوشیاری در بدو ورود و 12 و 24 ساعت بعد ارزیابی شد. یافته‌ها: در میان بیماران، 49 نفر (6/63 درصد) زن و مابقی مرد بودند. ارتباط معنی‌داری بین تغییرات QT Interval و QRS complex و تغییرات نبض با مسمومیت با کاربامازپین وجود نداشت. فشار خون سیستولی، دیاستولی و متوسط شریانی (MABP) به صورت کاهنده و PR Interval به صورت افزاینده تغییرات معنی‌داری از بدو ورود تا 24 ساعت بعد نشان داد. همچنین فشار خون سیستولی، دیاستولی و MABP در افراد دچار کما در مقایسه با سایر سطوح هوشیاری کمتر و پهنای کمپلکس QRS در آن‌ها به صورت معنی‌داری بیشتر بود. بین کاهش سطح هوشیاری و فشار خون دیاستولی، QT Interval و PR Interval در بدو ورود و 12 و 24 ساعت بعد ارتباط معنی‌داری وجود نداشت. نتیجه‌گیری: با توجه به ارتباط سطح هوشیاری و تغییرات نبض (برادی‌کاردی)، فشار خون سیستولی، MABP و QRS Complex در ساعت 12 بستری، پایش بیماران از لحاظ فشار خون، نبض و تغییرات الکتروکاردیوگرام به ویژه در سطوح پایین‌تر هوشیاری لازم به نظر می‌رسد تا بتوانیم از عوارض ناخواسته و مرگ و میر بیماران پیش‌گیری کنیم و از طول مدت بستری بکاهیم.

Carbamazepine (CBZ), a pharmaceutical compound, has been proposed as an anthropogenic marker to assess water quality due to its persistence in conventional treatment plants and widespread presence in water bodies. This paper presents a comprehensive literature review on sources and occurrences of CBZ in water bodies, as well as toxicological effects and regulations of the drug. Given the documented side effects of CBZ on the human body when taken medicinally, its careful monitoring in water is recommended. CBZ residues in drinking water may provide a pathway to embryos and infants via intrauterine exposure or breast-feeding, which may cause congenital malformations and/or neurodevelopmental problems over long term exposure. An in-depth technical assessment of the conventional and advanced treatment technologies revealed the inadequacy of the standalone technologies. Compared to conventional activated sludge and membrane bioreactor processes, effective removal of CBZ can be achieved by nanofiltration and reverse osmosis membranes. However, recent studies have revealed that harsh chemical cleaning, as required to mitigate membrane fouling, can often reduce the long-term removal efficiency. Furthermore, despite the efficient performance of activated carbon adsorption and advanced oxidation processes, a few challenges such as cost of chemicals and regeneration of activated carbon need to be carefully considered. The limitations of the individual technologies point to the advantages of combined and hybrid systems, namely, membrane bioreactor coupled with nanofiltration, adsorption or advanced oxidation process.

For the first time, several pharmaceuticals have been defined as priority substances in the new proposal of the revision of the Water Framework Directive (WFD). Consequently, environmental quality standards have been determined for several drugs. This is the case with the antiepileptic carbamazepine, which is considered as hazardous in healthcare settings by The National Institute for Occupational Safety and Health (NIOSH). This organism considers as such drugs that have shown teratogenicity, carcinogenicity, genotoxicity or other developmental, reproductive, or organ toxicity at low doses in studies with animals or humans. This study has been focused on the non-carcinogenic drugs classified in group 2, and their presence in the environment. This group contains many different therapeutic agents such as antineoplastics, psychoactive drugs, immunosuppressants and antivirals, among others. Of the 116 drugs included in the list, 26 have been found in aquatic environmental matrices. Certain drugs have received most attention (e.g., the antiepileptic carbamazepine, progesterone and the antidepressant paroxetine) while others completely lack environmental monitoring. Carbamazepine, fluconazole, paroxetine and warfarin have been found in invertebrates' tissues, whereas carbamazepine, oxazepam and paroxetine have been found in fish tissues. The main aim of the NIOSH's hazardous drug list is to inform healthcare professionals about adequate protection measures to prevent occupational exposure to these pharmaceuticals. However, this list contains useful information for other professionals and researchers such as environmental scientists. The paucity of relevant environmental data of certain hazardous pharmaceuticals might be important to help in the prioritization of compounds that may demand further research., 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. Published by Elsevier B.V.)

Polystyrene microplastics (PS MPs) and carbamazepine (CBZ) are frequently detected in freshwater ecosystems. However, the transgenerational effects of PS MPs and CBZ on the reproduction of aquatic organisms and the corresponding mechanisms are still unclear. In the present study, Daphnia magna was used to evaluate the reproductive toxicity in two consecutive generations (F0, F1). The molting and reproduction parameters, the expression of reproduction, and the toxic metabolism genes were examined after 21-day exposure. A significantly enhanced toxicity was observed in the presence of 5 μm PS MPs and CBZ. Chronic exposure results showed that the 5 μm PS MPs alone, CBZ alone, and their mixtures exerted significant reproductive toxicity of D. magna. The results of RT-qPCR showed transcripts of genes related to reproduction (cyp314, ecr-b, cut, vtg1, vtg2, dmrt93b) and toxic metabolism (cyp4, gst) were altered in both the F0 and F1. In addition, for the F0, gene transcriptional changes of reproduction were not fully translated into physiological performance, probably due to the compensatory responses caused by the low dose of PS MPs alone, CBZ alone, and their mixtures. Whereas for the F1, the trade-off between reproduction and toxic metabolism at gene levels was observed, which translated into a significant reduction in the total neonate number of F1. These findings suggest that long-term exposure to MPs and CBZ can cause serious reproduction damage to aquatic animals, which needs to be given sufficient attention., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pharmaceuticals can be considered a global threat to aquatic ecosystems due to their pseudo-persistence and their potential toxicity towards non-target species. Amoxicillin (AMX) and carbamazepine (CBZ) and their mixture (1:1) were investigated on the marine copepod Tigriopus fulvus (Fischer, 1860) considering both acute and chronic endpoints. While acute and chronic exposure did not directly affect survival, reproductive endpoints were affected like the mean egg hatching time that was significantly longer than the negative control for treatments with AMX (0.789 ± 0.079 μg/L), CBZ (8.88 ± 0.89 μg/L), and AMX and CMZ as a mixture (1.03 ± 0.10 μg/L and 0.941 ± 0.094 μg/L), in that order., (© 2023. The Author(s).)

Pharmaceutical compounds and their metabolites are found in natural and wastewater. However, investigation of their toxic effects on aquatic animals has been neglected, especially for metabolites. This work investigated the effects of the main metabolites of carbamazepine, venlafaxine and tramadol. Zebrafish embryos were exposed (0.1-100 µg/L) for 168hpf exposures to each metabolite (carbamazepine-10,11-epoxide, 10,11-dihydrocarbamazepine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, O-desmethyltramadol, N-desmethyltramadol) or the parental compound. A concentration-response relationship was found for the effects of some embryonic malformations. Carbamazepine-10,11-epoxide, O-desmethylvenlafaxine and tramadol elicited the highest malformation rates. All compounds significantly decreased larvae responses on a sensorimotor assay compared to controls. Altered expression was found for most of the 32 tested genes. In particular, abcc1, abcc2, abcg2a, nrf2, pparg and raraa were found to be affected by all three drug groups. For each group, the modelled expression patterns showed differences in expression between parental compounds and metabolites. Potential biomarkers of exposure were identified for the venlafaxine and carbamazepine groups. These results are worrying, indicating that such contamination in aquatic systems may put natural populations at significant risk. Furthermore, metabolites represent a real risk that needs more scrutinising by the scientific community., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Carbamazepine (CBZ) is one of the widely distributed pharmaceutical residues in aquatic environments, yet few researches have addressed its chronic effect on the anxiety of fish, and the mechanisms possibly involved remained elusive. In this study, adult female zebrafish (Danio rerio) were exposed to environmental relevant concentrations of CBZ (CBZ-low, 10 μg/L; CBZ-high, 100 μg/L) for 28 days. After exposure, CBZ-high didn't affect the anxiety of fish. However, the onset time to the higher half of the tank was delayed and the total duration in the lower half of the tank was increased in CBZ-low fish, suggesting an increased anxiety. Further investigation indicated that CBZ-low significantly decreased the gamma-aminobutyric acid (GABA) level in the brain, while increased the serotonin (5-HT) level in the brain and cortisol level in plasma. Accordingly, the mRNA levels of genes in GABA (gad2, abat, gabrb2, gabrg2, gria1a and slc12a2) pathway and HPI (crha, actha, pc1 and pc2) axis were also altered. Despite the upregulation of tph2 was consistent with increased 5-HT level in the brain, significantly downregulated htr1aa and htr1b may indicate attenuated 5-HT potency. Although CBZ-high significantly reduced GABA level in the brain and increased cortisol level in plasma, the effects were dramatically alleviated than that of CBZ-low. Consistently, the expression of genes in HPI (crha, actha, pc1 and pc2) axis and GABA (gad2 and abat) pathway were also altered by CBZ-high, probably due to inconspicuous anxiety response of CBZ-high. Briefly, our data suggested that low concentration of CBZ disrupted zebrafish anxiety by interfering with neurotransmission and endocrine system, thereby bringing about adverse ecological consequences., 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 Inc. All rights reserved.)

Antiepileptic drugs (AEDs) are globally prescribed to treat epilepsy and many other psychiatric disorders in humans. Their high consumption, low metabolic rate in the human body and low efficiency of wastewater treatment plants (WWTPs) in eliminating these chemicals results in the frequent occurrence of these pharmaceutical drugs in aquatic systems. Therefore, aquatic organisms, including ecologically and economically important teleost fishes, may be inadvertently exposed to these chemicals. Due to their physiological similarity with humans, fishes may be particularly vulnerable to AEDs. Almost all AED drugs are detectable in natural aquatic ecosystems, but diazepam (DZP) and carbamazepine (CBZ) are among the most widely detected AEDs to date. Recent studies suggest that these drugs have a substantial capacity to induce neurotoxicity and behavioral abnormality in fishes. Here we review the current state of knowledge regarding the potential mode of action of DZP and CBZ as well as that of some other AEDs on teleosts and put observable behavioral effects into a mechanistic context. We find that following their intended mode of action in humans, AEDs also disrupt the GABAergic, glutamatergic and serotonergic systems as well as parasympathetic neurotransmitters in fishes. Moreover, AEDs have non-specific modes of action in teleosts ranging from estrogenic activity to oxidative stress. These physiological changes are often accompanied by dose-dependent disruptions of anxiety, locomotor activity, social behaviors, food uptake, and learning and memory, but DZP and CBZ consistently induced anxiolytic effects. Thereby, AED exposure severely compromises individual fitness across teleost fish species, which may lead to population and ecosystem impairment. We also showcase promising avenues for future research by highlighting where we lack data when it comes to effects of certain AEDs, AED concentrations and behavioral endpoints., Competing Interests: Declaration of competing interest We declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Unravelling the adverse outcomes of pharmaceuticals mixture represents a research priority to characterize the risk for marine ecosystems. The present study investigated, for the first time, the interactions between two of the most largely detected pharmaceuticals in marine species: carbamazepine (CBZ) and valsartan (VAL), elucidating mechanisms that can modulate bioaccumulation, excretion and the onset of toxicity. Mytilus galloprovincialis were exposed to environmental levels of CBZ and VAL dosed alone or in combination: measurement of drug bioaccumulation was integrated with changes in the whole transcriptome and responsiveness of various biochemical and cellular biomarkers. Interactive and competing mechanisms between tested drugs were revealed by the much higher CBZ accumulation in mussels exposed to this compound alone, while an opposite trend was observed for VAL. A complex network of responses was observed as variations of gene expression, functional effects on neurotransmission, cell cycle, immune responses and redox homeostasis. The elaboration of results through a quantitative Weight of Evidence model summarized a greater biological reactivity of CBZ compared to VAL and antagonistic interactions between these compounds, resulting in a reduced effect of the antiepileptic when combined with valsartan. Overall, new perspectives are highlighted for a more comprehensive risk assessment of environmental mixtures of pharmaceuticals., Competing Interests: Declaration of competing interest The authors (Marica Mezzelani, Luca Peruzza, Giuseppe d'Errico, Massimo Milan, Stefania Gorbi and Francesco Regoli) 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Carbamazepine (CBZ) is widely used as an anti-epileptic drug. Vitamin B12 has been shown to protect against DNA damage caused by several mutagenic agents., Objective: This study aimed to investigate the effect of vitamin B12 on CBZ-induced genotoxicity in cultured human lymphocytes., Methods: Sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) genotoxic assays were utilized to achieve the study objective., Results: The results showed significantly higher frequencies of CAs and SCEs in the CBZ-treated cultures (12 μg/mL) compared to the control group (P<0.01). The genotoxic effects of CBZ were reduced by pre-treatment of cultures with vitamin B12 (13.5μg/ml, P<0.05). Neither CBZ nor vitamin B-12 showed any effects on mitotic and proliferative indices., Conclusion: CBZ is genotoxic to lymphocyte cells, and this genotoxicity can be reduced by vitamin B12., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Carbamazepine (CBZ) is the antiepileptic drug used in epilepsy and some psychiatric disorders. Besides its widely used, many adverse effects have been reported including hematotoxicity, hepatotoxicity, endocrine disorders, and testicular damages due to oxidative stress. However, the role of CBZ on renal toxicity is not fully known. In this study, we attempted to explain the connected mechanisms by focusing on the metabolism of CBZ-induced renal toxicity in rats. Twenty male Wistar-Albino rats were randomized into 2 groups ( n  = 10); control (1 mL/day distilled water, orally) and CBZ (25 mg/kg/day CBZ, orally) groups. After 60 days, TAS (total oxidant status) and TOS (total oxidant status) levels, histopathological features, some genes involved in apoptosis, 8-hydroxy-2-deoxyguanosine (8-OHdG) activity, and apoptotic cells were assessed of kidney tissue. The oxidative stress index (OSI) was measured from TAS and TOS levels. TOS levels and OSI significantly increased, while TAS levels decreased in the CBZ group relative to the control group. Histopathological observations, Caspase-3 (Casp3), Poly [ADP-ribose] polymerase-1 (PARP-1), 8-OHdG immunoreactivities, and apoptotic cells markedly raised in the CBZ group compared with the control group. Also, mRNA expression of Cytochrome c (Cytc) and CASP3 significantly increased in the CBZ group compared to the control group. In conclusion, long-term use of CBZ may promote renal damage in rats by inducing oxidative stress and apoptosis.

Carbamazepine overdose is a common, toxic ingestion, manifesting as central nervous system (CNS) and respiratory depression. Carbamazepine is highly protein bound with a large volume of distribution and, therefore, inefficiently removed by conventional hemodialysis. We describe the successful use of continuous venovenous hemodialysis (CVVHD) with 5 % albumin enhanced dialysate in a 31-year-old female who developed CNS depression, hypotension and respiratory failure, requiring mechanical ventilation, after an intentional ingestion of approximately 10 g of extended release carbamazepine, Tegretol CR. The peak drug level was 26 mcg/ml, therapeutic range 8-12 mcg/ml, with toxicity often developing a level above 15 mcg/ml. Normal half-life of drug elimination is 35-60 h in carbamazepine naïve patients. In contrast, with albumin-enhanced dialysis, we observed a drug half-life of 18 h. She was extubated on day two and was transferred to inpatient psychiatry by day 3 without significant neurologic sequelae. In vitro studies have been done with bovine blood demonstrating significant carbamazepine removal using CVVHD with albumin-enhanced dialysate. There has been very limited experience using albumin-enhanced CVVHD in an adult patient with carbamazepine toxicity. [ABSTRACT FROM AUTHOR]

Forming calcareous exoskeletons is crucial for the health and survival of calcifiers such as bivalves. However, the impacts of waterborne emergent pollutants on this important process remain largely unknown. In this study, the effects of two types of emergent pollutants, microplastics (MPs) and carbamazepine (CBZ), which are ubiquitously present in ocean environments, on shell formation were assessed in the thick-shell mussel (Mytilus coruscus) with a shell regeneration experiment. In addition, their impacts on the in vivo contents of ATP, Ca 2+ , carbonic anhydrase (CA), and bone morphogenetic protein receptor type-2 (BMPR2), the activity of phosphofructokinase (PFK) and Ca 2+ -ATPase, and the expression of shell-formation related genes were analyzed. The data collected demonstrated that shell regeneration after mechanical injury was significantly arrested by CBZ and/or MPs. Besides, all the physiological and molecular parameters investigated were markedly suppressed by these two pollutants. Furthermore, synergistic impacts on most of the parameters examined were observed between CBZ and MPs. Our results indicate that these two pollutants may disrupt shell formation by constraining the availability of raw materials and energy, inhibiting the formation of the organic shell matrix, and interfering with the regulation of crystallization, which may have far-reaching impacts on the health of marine calcifiers., 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 B.V. All rights reserved.)

The chronic toxicity of diclofenac (DCF) and carbamazepine (CBZ) as separate substances and in conjunction with their mixture on Daphnia magna was assessed in the parental (F0) and first filial (F1) generations. The second (F1-B2) and fifth (F1-B5) broods of F1 offspring were investigated and compared. Both drugs and their mixture were exposed to each generation of Daphnia magna for 21 days with life history, behavioural and gene expressions as measured endpoints. After the parental exposure, offspring from these two broods were transferred to a clean medium for a 21-day recovery. Exposure to diclofenac, carbamazepine and their mixture significantly inhibited growth, reproduction, swimming activities, heart rate, thoracic limb activities, reproductive and antioxidant-related genes in the parental as well as the first filial generations. These effects were relatively greater in the F1 generation. This indicates that Daphnia magna's sensitivity improved while its fitness declined over the two generations, which is an indicator of greater energy requirements for maintenance. Besides, the significant inhibition in the antioxidant-related genes implies that oxidative stress occurred in Daphnia magna under the exposure to these drugs. The significant reduction in the reproductive output, moulting frequency and cyp314 gene expression as a result of exposure to CBZ simultaneously obtained herein may indicate that this drug could act as an endocrine disruptor. Most of these significant effects were not recoverable after the 21-day recovery period. The findings reported herein highlight the necessity to include maternal effects in environmental risk assessment processes, considering that pollutant effects are underestimated during single-generational exposure., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The combination of certain human leukocyte antigen (HLA) polymorphisms with administration of certain drugs shows a strong correlation with developing drug hypersensitivity. Examples of typical combinations are HLA-B*57:01 with abacavir and HLA-B*15:02 with carbamazepine. However, despite belonging to the same serotype, HLA-B*57:03 and HLA-B*15:01 are not associated with drug hypersensitivity. Recent studies have shown that several HLA polymorphisms are associated with multiple drugs rather than a single drug, all resulting in drug hypersensitivity. In this study, we compared the molecular structures and intracellular localization of HLA-B*57:01, HLA-B*58:01, and HLA-B*15:02, which pose risks for developing drug hypersensitivity, as well as HLA-B*57:03 and HLA-B*15:01 that do not present such risks. We found that HLA molecules posing risks have a low affinity for the subunit β 2 -microglobulin; notably, the weak hydrogen bond formed via Gln96 of the HLA molecule contributes to this behavior. We also clarified that these HLA molecules are easily accumulated in the endoplasmic reticulum, exhibiting a low expression on the cell surface. Considering that these hypersensitivity risk-associated HLA molecules form complexes with β 2 -microglobulin and peptides in the endoplasmic reticulum, we assumed that their low complex formation ability in the endoplasmic reticulum facilitates the interaction with multiple drugs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Due to significant effects of carbamazepine toxicity on the cardiovascular system and the present contraversy about the frequency of cardiovascular manifestations in such patients, this study was designed to evaluate this issue more throughly. Methods: In a cross-sectional study, patients with carbamazepine poisoning referred to Nour Hospital, Isfahan, were recruited using convinience sampling method. ECG parameters (QRS complex, QT interval, and PR interval), pulse rate, and blood pressure changes, as well as consciousness alterations, were measured in patients on admission and 12 and 24 hours later. Finding: Among 77 patients 49 (63.6%) were women. There was no significant relationship between QT interval and QRS complex changes and pulse rate alteration and carbamazepine toxicity; but there was meaningful association between pulse rate, blood pressure (systolic and diastolic), and PR interval changes. Furtheremore, there was significant decreasing relationship between loss of consciousness (coma) and blood pressure [systolic and mean arterial blood pressure (MABP)], pulse rate, QRS complex changes at 12 hours after admission. QRS complex had much more width in these patients in comparison with others. There was no correlation between loss of consciousness and diastolic blood pressure, QT interval and PR interval on admisson and 12 hours and 24 hours later. Conclusion: Regarding the founded relation between level of consciousness and changes at 12 hours after admission, evaluation of patients about vital sign and ECG monitoring, specialy in lower level of consciousness, should be considered; it will lead to prevent unexpected complication, mortality and to reduce the length of hospitalisation. [ABSTRACT FROM AUTHOR]

Carbamazepine (CBZ) and Hg are widespread and persistent micropollutants in aquatic environments. Both pollutants are known to trigger similar toxicity mechanisms, e.g. reactive oxygen species (ROS) production. Here, their effects were assessed in the zebra mussel Dreissena polymorpha, frequently used as a freshwater model in ecotoxicology and biomonitoring. Single and co-exposures to CBZ (3.9 μg L -1 ) and MeHg (280 ng L -1 ) were performed for 1 and 7 days. Metabolomics analyses evidenced that the co-exposure was the most disturbing after 7 days, reducing the amount of 25 metabolites involved in protein synthesis, energy metabolism, antioxidant response and osmoregulation, and significantly altering cells and organelles' structure supporting a reduction of functions of gills and digestive glands. CBZ alone after 7 days decreased the amount of α-aminobutyric acid and had a moderate effect on the structure of mitochondria in digestive glands. MeHg alone had no effect on mussels' metabolome, but caused a significant alteration of cells and organelles' structure in gills and digestive glands. Single exposures and the co-exposure increased antioxidant responses vs control in gills and digestive glands, without resulting in lipid peroxidation, suggesting an increased ROS production caused by both pollutants. Data globally supported that a higher number of hyperactive cells compensated cellular alterations in the digestive gland of mussels exposed to CBZ or MeHg alone, while CBZ + MeHg co-exposure overwhelmed this compensation after 7 days. Those effects were unpredictable based on cellular responses to CBZ and MeHg alone, highlighting the need to consider molecular toxicity pathways for a better anticipation of effects of pollutants in biota in complex environmental conditions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The increased frequency and intensity of short-term extreme warming phenomena have been associated to harsh biological and ecosystem outcomes (i.e., mass mortalities in marine organisms). Marine heatwaves (MHWs), occurring when seasonal temperature threshold is exceeded for at least 5 consecutive days, may reduce the tolerance of coastal species toward additional pressures, but interactions between such multiple stressors are virtually unexplored. The present study aimed to characterize in Mytilus galloprovincialis the influence of a simulated MHW scenario on the toxicological effects of the pharmaceutical carbamazepine (CBZ), ubiquitously detected in the marine environment and chosen as model compound for this relevant class of emerging contaminants. The bioaccumulation of CBZ and responsiveness of various biological parameters, including immune system, antioxidant status, lipid metabolism and cellular integrity, were analyzed in exposed mussels both during and after the end of the heatwave. MHW appeared to strongly modulate accumulation of CBZ, paralleled by weakened immunocompetence and onset of oxidative disturbance that finally evolved to cellular damages and lipid metabolism disorders. Elaboration of the overall results through a quantitative Weight of Evidence model, revealed the highest hazard in organisms exposed to both the stressors 10 days after the end of the heatwave, suggesting that MHWs could leave a footprint on the capability of mussels to counteract CBZ toxicity, thus affecting their vulnerability and predisposition to adverse effects toward multiple stressors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Contaminants of emerging concern (CEC) are routinely detected in aquatic environments, especially pharmaceuticals, such as carbamazepine (CBZ), and neonicotinoid pesticides, like acetamiprid (ACT). CECs can interact with each other and with other legislated contaminants like Cd, resulting in unknown effects. Most studies evaluate only the effects of single contaminant exposures on aquatic biota. Therefore, the aim of the present study was to assess the effects of both single and combined CBZ, ACT and Cd exposures on zebrafish brain and liver oxidative stress parameters and metal homeostasis. The biomarkers catalase (CAT), glutathione-S-transferase (GST), total thiols (TOT), metallothionein (MT) and malondialdehyde (MDA) and the essential elements Ca, Cu, K, Na, Mg, Mn and Zn were evaluated after 96-hour static exposures. CBZ, ACT and Cd single (brain and liver) and combined (liver) treatments resulted in oxidative effects in both fish organs, also leading to metal (Ca, Mg, K, Mn, Zn and Cu) homeostasis alterations. ACT exposure resulted in the greatest adverse effects in the brain, while CBZ was the cause of major element homeostasis and oxidative stress alterations in the liver. Lower LPO levels were observed in the combined treatments compared to single treatments, suggesting interactions and contaminant effect attenuation. This study is the first to evaluate the initial effects of combined CBZ, ACT and Cd exposures in zebrafish, paving the way for further investigations concerning other biomarkers during longer exposure times., (Copyright © 2022. Published by Elsevier B.V.)

Toxicometabolomics and biotransformation product (bioTP) elucidation were carried out in single zebrafish (ZF) embryos exposed to carbamazepine (CBZ). Exposures were conducted in 96-well plates containing six CBZ concentrations ranging from 0.5 μg/L to 50 mg/L ( n = 12 embryos per dose). In the 50 mg/L dose group, 33% of embryos developed edema during the exposure (120 hpf), while hatching was significantly delayed in three of the lower-dose groups (0.46, 3.85, and 445 μg/L) compared to the control at 48 hpf. Toxicometabolomic analysis together with random forest modeling revealed a total of 80 significantly affected metabolites (22 identified via targeted lipidomics and 58 via nontarget analysis). The wide range of doses enabled the observation of both monotonic and nonmonotonic dose responses in the metabolome, which ultimately produced a unique and comprehensive biochemical picture that aligns with existing knowledge on the mode of action of CBZ. The combination of high dose exposures and apical endpoint assessment in single embryos also enabled hypothesis generation regarding the target organ for the morphologically altering insult. In addition, two CBZ bioTPs were identified without additional exposure experiments. Overall, this work showcases the potential of toxicometabolomics and bioTP determination in single ZF embryos for rapid and comprehensive chemical hazard assessment.

Millions of people rely on active pharmaceutical ingredients (APIs) to prevent and cure a wide variety of illnesses in humans and animals, which has led to a steadily increasing consumption of APIs across the globe and concurrent releases of APIs into the environment. In the environment, APIs can have a detrimental impact on wildlife, particularly aquatic wildlife. Therefore, it is essential to assess their potential adverse effects to aquatic ecosystems. The European Water Framework Directive sets out that risk assessment should be performed at the catchment level, crossing borders where needed. The present study defines ecological risk profiles for surface water concentrations of 8 APIs (carbamazepine, ciprofloxacin, cyclophosphamide, diclofenac, erythromycin, 17α-ethinylestradiol, metformin, and metoprolol) in the Vecht River, a transboundary river that crosses several German and Dutch regions. Ultimately, 3 main goals were achieved: 1) the geo-referenced estimation of API concentrations in surface water using the geography-referenced regional exposure assessment tool for European rivers; 2) the derivation of new predicted-no-effect concentrations for 7 of the studied APIs, of which 3 were lower than previously derived values; and 3) the creation of detailed spatially explicit ecological risk profiles of APIs under 2 distinct water flow scenarios. Under average flow conditions, carbamazepine, diclofenac, and 17α-ethinylestradiol were systematically estimated to surpass safe ecological concentration thresholds in at least 68% of the catchment's water volume. This increases to 98% under dry summer conditions. Environ Toxicol Chem 2022;41:648-662. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Carbamazepine (CBZ) is one of the most common pharmaceuticals found in the aquatic environment. Here, we reviewed studies in aquatic animals highlighting that CBZ affected ROS homeostasis but also the neuroendocrine system, cell viability, immunity, reproduction, feeding behavior and growth. Notably, the acetylcholinesterase activity was modified by concentrations of the order of ng L -1 CBZ. At ≥10 μg L -1 , data pointed that CBZ triggered the production of ROS, modifying the activity of antioxidant enzymes and produced a significant cellular stress at concentrations ≥100 μg L -1 . However, the response appeared species-, organ- and time-dependent, and was impacted by different experimental conditions and the origin of animals. In this context, this review discusses the available data and proposes future research priorities.

Monochloramine (NH 2 Cl) oxidant combined with a Ultraviolet (UV)-Light-emitting-diode (LED) light source forms a new advanced oxidation process (AOP), which can achieve high-efficiency degradation of carbamazepine (CBZ). The degradation of CBZ displayed pseudo-first-order reaction kinetics (R 2  > 0.98, k CBZ  = 0.0043 cm 2  mJ -1 at pH 7). The degradation of CBZ was dependent on UV-LED wavelength, with maximum degradation efficiency observed at 265 nm since it was the lowest wavelength studied among UV-LEDs. Variation in pH across the range, which might be expected under normal environmental conditions (pH 6-8), and the presence of Cl - had no significant effect on the degradation efficiency of CBZ, while the presence of HCO 3 - and natural organic matter (NOM) inhibited degradation. Electron paramagnetic resonance (EPR) experiments detected OH in the system. Probe compounds were used to distinguish the contribution of reactive chlorine species (RCS). It was proved that OH and Cl played major roles and OH was responsible for around 50% of the observed degradation of CBZ. Eight transformative products (TPs) in the degradation process of CBZ were identified, with a generally decreasing toxicity. The concentration of disinfection by-products (DBPs) formed during CBZ degradation was all within limits of WHO and China standard for drinking water. Although the concentration of nitrogen-containing DBPs (N-DBPs) was the lowest, N-DBPs were the main contributors to toxicity, and these would require more attention in practical applications. UV-LED/NH 2 Cl AOP was identified as an effective way to degrade pharmaceutically active 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 © 2021 Elsevier B.V. All rights reserved.)

Carbamazepine is one of the most abundant pharmaceutical active compounds detected in aquatic systems. Based on laboratory exposures, carbamazepine has been proven to adversely affect aquatic organisms. However, the underlying molecular events remain poorly understood. This study aims to investigate the molecular mechanisms potentially associated with toxicological effects of carbamazepine on the mussel Mytilus galloprovincialis exposed for 3 days at realistic concentrations encountered in coastal environments (80 ng/L and 8 μg/L). An integrated metabolomics and proteogenomics approach, including data fusion strategy, was applied to gain more insight in molecular events and cellular processes triggered by carbamazepine exposure. Consistent metabolic and protein signatures revealed a metabolic rewiring and cellular stress at both concentrations (e.g. intensification of protein synthesis, transport and catabolism processes, disruption of lipid and amino acid metabolisms). These highlighted molecular signatures point to the induction of autophagy, closely related with carbamazepine mechanism of action, as well as a destabilization of the lysosomal membranes and an enzymatic overactivity of the peroxisomes. Induction of programmed cell death was highlighted by the modulation of apoptotic cognate proteins. The proposed integrative omics data analysis was shown to be highly relevant to identify the modulations of the two molecular levels, i.e. metabolites and proteins. Multi-omics approach is able to explain the resulting complex biological system, and document stronger toxicological pieces of evidence on pharmaceutical active compounds at environmental concentrations in sentinel organisms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Reclaimed water (RW) obtained from wastewater treatment plants (WWTP) is used for irrigation, groundwater recharge, among other potential uses. Although most pollutants are removed, traces of them are frequently found, which can affect organisms and alter the environment. The presence of a myriad of contaminants in RW makes it a complex mixture with very diverse effects and interactions. A previous study, in which tadpoles were exposed to RW and RW spiked with Carbamazepine (CBZ), presented slight thyroid gland stimulation, as suggested by the development acceleration of tadpoles and histological findings in the gland provoked by RW, regardless of the CBZ concentration. To complement this study, the present work analysed the putative molecular working mechanism by selecting six genes coding for the thyroid-stimulating hormone (TSHβ), thyroid hormone metabolising enzymes (DIO2, DIO3), thyroid receptors (THRA, THRB), and a thyroid hormone-induced DNA binding protein (Kfl9). Transcriptional activity was studied by Real-Time PCR (RT-PCR) in brains, hind limbs, and tails on exposure days 1, 7, and 21. No significant differences were observed between treatments for each time point, but slight alterations were noted when the time response was analysed. The obtained results indicate that the effects of RW or RW spiked with CBZ are negligible for the genes analysed during the selected exposure periods., (Copyright © 2021 Elsevier Ltd. All rights reserved.)