Degradation of carbamazepine by the UVA-LED365/ClO2/NaClO process: Kinetics, mechanisms and DBPs yield.

A mixed oxidant of chlorine dioxide (ClO2) and NaClO was often used in water treatment. A novel UVA-LED (365 nm)-activated mixed ClO2/NaClO process was proposed for the degradation of micropollutants in this study. Carbamazepine (CBZ) was selected as the target pollutant. Compared with the UVA365/ClO2 process, the UVA365/ClO2/NaClO process can improve the degradation of CBZ, with the rate constant increasing from 2.11×10-4 sec-1 to 2.74×10-4 sec-1. In addition, the consumption of oxidants in the UVA365/ClO2/NaClO process (73.67%) can also be lower than that of UVA365/NaClO (86.42%). When the NaClO ratio increased, both the degradation efficiency of CBZ and the consumption of oxidants can increase in the UVA365/ClO2/NaClO process. The solution pH can affect the contribution of NaClO in the total oxidant ratio. When the pH range of 6.0-8.0, the combination process can generate more active species to promote the degradation of CBZ. The change of active species with oxidant molar ratio was investigated in the UVA365/ClO2/NaClO process. When ClO2 acted as the main oxidant, HO• and Cl• were the main active species, while when NaClO was the main oxidant, ClO• played a role in the system. Both chloride ion (Cl-), bicarbonate ion (HCO3-), and nitrate ion (NO3-) can promote the reaction system. As the concentration of NaClO in the reaction solution increased, the generation of chlorates will decrease. The UVA365/ClO2/NaClO process can effectively control the formation of volatile disinfection by-products (DBPs), and with the increase of ClO2 dosage, the formation of DBPs can also decrease.

Stevens-Johnson Syndrome/Toxic epidermal necrolysis complicated with fulminant type 1 diabetes mellitus: a case report and literature review.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening skin lesion triggered by hypersensitive drug reaction. They are characterized by extensive epidermal necrosis and skin exfoliation. Fulminant type 1 diabetes mellitus (FT1DM) is featured by a rapid-onset of hyperglycemia with ketoacidosis due to severely destroyed ß-cell function. Fulminant type 1 diabetes mellitus as a sequela of SJS/TEN has rarely been reported. CASE PRESENTATION: We present a 73-year-old female patient who developed SJS/TEN skin allergic reaction after taking carbamazepine and phenytoin for 35 days. Then, hyperglycemia and diabetic ketoacidosis occurred 20 days after discontinuation of antiepileptic drugs. A very low serum C-peptide level (8.79 pmol/l) and a near-normal glycosylated hemoglobin level met the diagnostic criteria for fulminant T1DM. Intravenous immunoglobulin (IVIG) and insulin were promptly administered, and the patient recovered finally. CONCLUSIONS: This rare case indicates that monitoring blood glucose is necessary in SJS/TEN drug reaction, and comprehensive therapy with rehydration, insulin, antibiotics, and IVIG may improve the prognosis.

Hybrid packed bed bioreactor using combined biodegradation and ozonation to enhance nitrogen and micropollutants removal from landfill leachate.

Landfill leachate contains ammonium and micropollutants. Ammonium can be biologically removed but bio-recalcitrant micropollutants removal requires post-treatment like ozonation. This study developed an expanded clay aggregates packed biofilm column (EBC) and demonstrated its feasibility of coupling biodegradation and ozonation (CBAO) to simultaneously remove nitrogen and bio-recalcitrant micropollutants. The first 60 days only had biodegradation process to start the bioreactor. 51 % nitrogen was biologically removed but the removal of micropollutant carbamazepine (CBZ) was only 30 %. From 61 d to 150 d, both biodegradation and ozonation were performed in the EBC. After 48 h-biodegradation, ozone gas was introduced and bubbling through EBC for 30 min to further remove residual micropollutants. At 0.4 gO3/gCOD, CBZ were completely removed. The average nitrogen removal efficiency (85 %) was increased by 34 % because the increased abundance of nitrifying and denitrifying bacteria in EBC. This study confirmed the promising potential of the CBAO process for treating landfill leachte.

The Adverse Effects of Commonly Prescribed Antiseizure Medications in Adults With Newly Diagnosed Focal Epilepsy.

BACKGROUND AND OBJECTIVES: Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy. METHODS: The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses ("never/rarely" vs "sometimes/always"). RESULTS: A total of 225 adults initiated on levetiracetam (n = 132, 59%), lamotrigine (n = 55, 24%), carbamazepine (n = 19, 8.4%), or oxcarbazepine (n = 19, 8.4%) were included. There were no significant differences in AEP total scores between ASMs. Patients with depression (adjusted marginal score ratio [aMSR] 1.23, 95% CI 1.09-1.39, p = 0.001) and anxiety (aMSR 1.15, 95% CI 1.04-1.26, p = 0.007) had worse AEP total scores than those without. After adjusting for depression and anxiety, levetiracetam users were >3 times more likely to report feelings of aggression (adjusted odds ratio [aOR] 3.38, 95% CI 1.07-10.7, p = 0.038) and almost half as likely to experience unsteadiness (aOR 0.45, 95% CI 0.21-0.99, p = 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%). DISCUSSION: Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.

Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol.

PURPOSE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs: A Systematic Review and Meta-Analysis.

Importance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization. Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions. Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis. Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant. Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers. Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

Effective peroxymonosulfate activation by lithium cobaltite recovered from spent lithium-ion batteries for enhanced carbamazepine degradation in a wide pH range.

Considering the high cost and complicated recycling process of spent lithium-ion batteries (SLIBs), transforming SLIBs into environment functional materials may be a wise approach. Herein, lithium cobaltite (LCO) cathode powders recovered from SLIBs were used to activate peroxymonosulfate (PMS) for removing carbamazepine (CBZ). The recovered LCO enables a 98.2% removal efficiency of CBZ (2.5 mg/L) within 10 min, which was effective at a broader pH range (pH = 5.0-11.0). The influence of key factors (initial pH, PMS, and catalyst dosage) and coexisting substances (SO42-, H2PO4-, NO3-, Cl-, HCO3-, and HA) on CBZ degradation were examined in detail. The primary radical species during the degradation of CBZ were proved to be 1O2, SO4-, and.OH that generated from PMS activation initiated by the valence change of Co in recovered LCO. The recovered LCO displayed excellent reusability with about 80.0% removal of CBZ after six cycles. Homogeneous activation of PMS mainly contributed to CBZ degradation in the first run, but the recovered LCO catalyst dominated the heterogeneous activation of PMS for the degradation of CBZ in the second to sixth run. Finally, the CBZ degradation pathways were presented based on the identified intermediates. This research has offered a new strategy of "treating wastes with wastes" to maximize the recycling of electronic wastes to remove emerging pollutants.

The electro-responsive nanoliposome as an on-demand drug delivery platform for epilepsy treatment.

Nano-based drug delivery systems are regarded as a promising tool for efficient epilepsy treatment and seizure medication with the least general side effects and socioeconomic challenges. In the current study, we have designed a smart nanoscale drug delivery platform and applied it in the kindling model of epilepsy that is triggered rapidly by epileptic discharges and releases anticonvulsant drugs in situ, such as carbamazepine (CBZ). The CBZ-loaded electroactive ferrocene nanoliposomes had an average diameter of 100.6 nm, a surface charge of -7.08 mV, and high drug encapsulation efficiency (85.4 %). A significant increase in liposome size was observed in response to direct current (50-500 µA) application. This liposome-based drug delivery system can release CBZ at a fast rate in response to both direct current and pulsatile electrical stimulation in vitro. The CBZ-liposome can release the anticonvulsant drug upon epileptiform activity in the kindled rat model and can decline electrographic and behavioral seizure activity in response to electrical stimulation of the hippocampus with an initially subconvulsive current. With satisfactory biosafety results, this "smart" nanocarrier has promising potential as an effective and safe drug delivery system to improve the therapeutic index of antiepileptic drugs.

Bioaccumulation and behavioral response patterns of crucian carp (Carassius carassius) after carbamazepine exposure and elimination.

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.

Pharmaceutical residues in plastic tablet containers: Impacts on recycling and the environment.

High-density polyethylene tablet containers are potentially very suitable for recycling, but no data are publicly available on active pharmaceutical ingredients' (API) residues in empty containers and if they affect the recyclability of pharmaceutical packaging. Plastic tablet containers represented 15 % of pharmaceutical primary packages sold in Finland in 2020 and 2021, equalling 350 tons of plastic per year. We studied the residues of six APIs remaining or adsorbed inside plastic tablet containers. The effects of tablet coating and usage in dose-dispensing services versus households on the API residues, and rinsing water's ability to remove the residues were evaluated. Up to 940,000 µg/kg of carbamazepine was detected in a container of uncoated carbamazepine tablets. The residues from coated tablets containing the other five APIs were 2.4-6,100 µg/kg. Ten times higher paracetamol residues were obtained in containers from household use than from a dose-dispensing unit. Rinsing can remove most API residues, but it leads to environmental emissions. For example, rinsing water can double carbamazepine emissions from a Finnish wastewater treatment plant where plastic packaging waste effluents are processed. Considering the API concentrations, decreasing residues by rinsing and dilution with other plastic packaging waste, the residues of the studied APIs are not considered an obstacle to the recycling of plastic tablet containers. However, further research is needed on more toxic APIs and the fate of APIs in the plastics recycling process.

A Cross-Sectional Study Comparing Oxidative Stress in Patients with Epilepsy Treated with Old and New Generation Antiseizure Medications.

Background and Objectives: Oxidative stress resulting from a disturbance of the endogenous redox system is suspected in numerous diseases of the central nervous system, including epilepsy. In addition, antiseizure medications (ASMs), especially those of the old generation, may further increase oxidative stress. To evaluate the effects of ASM generation on oxidative stress, we conducted a cross-sectional study in patients with epilepsy treated with old, new, and polytherapy. Materials and Methods: The antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, as well as the concentrations of malondialdehyde, protein carbonyl, nitrate, nitrite, and glutathione in reduced and oxidized forms, were measured in 49 patients with epilepsy and 14 healthy controls. In addition, the plasma concentrations of ASMs and metabolites of carbamazepine and valproic acid were measured in the patients. Results: Patients with epilepsy showed increased activities of superoxide dismutase and catalase (p < 0.001), concentrations of glutathione disulfide and markers of nitric oxide metabolism (p < 0.001), and decreased activities of glutathione peroxidase, glutathione reductase, glutathione, and nitrite concentrations (p ≤ 0.005) compared to healthy controls. A comparison of ASM generations revealed increased levels of superoxide dismutase and catalase (p ≤ 0.007) and decreased levels of glutathione peroxidase and glutathione reductase (p ≤ 0.01) in patients treated with old ASMs compared to those treated with new generation ASMs. In addition, an increase in protein carbonyl and nitric oxide metabolites (p ≤ 0.002) was observed in patients treated with old generation ASMs compared to those treated with new generation ASMs. Most oxidative stress parameters in patients receiving polytherapy with ASMs were intermediate between the results of patients treated with the old and new generations of ASMs. Conclusions: An increase in oxidative stress markers and modulation of antioxidant enzyme activities was observed in patients with epilepsy compared to controls. The results of our study showed significantly higher oxidative stress in patients treated with old ASMs compared to those treated with new generation ASMs.

Development of poly (lactic-co-glycolic acid) (PLGA) based implants using hot melt extrusion (HME) for sustained release of drugs: The impacts of PLGA's material characteristics.

Hot melt extrusion (HME) processed Poly (lactic-co-glycolic acid) (PLGA) implant is one of the commercialized drug delivery products, which has solid, well-designed shape and rigid structures that afford efficient locoregional drug delivery on the spot of interest for months. In general, there are a variety of material, processing, and physiological factors that impact the degradation rates of PLGA-based implants and concurrent drug release kinetics. The objective of this study was to investigate the impacts of PLGA's material characteristics on PLGA degradation and subsequent drug release behavior from the implants. Three model drugs (Dexamethasone, Carbamazepine, and Metformin hydrochloride) with different water solubility and property were formulated with different grades of PLGAs possessing distinct co-polymer ratios, molecular weights, end groups, and levels of residual monomer (high/ViatelTM and low/ ViatelTM Ultrapure). Physicochemical characterizations revealed that the plasticity of PLGA was inversely proportional to its molecular weight; moreover, the residual monomer could impose a plasticizing effect on PLGA, which increased its thermal plasticity and enhanced its thermal processability. Although the morphology and microstructure of the implants were affected by many factors, such as processing parameters, polymer and drug particle size and distribution, polymer properties and polymer-drug interactions, implants prepared with ViatelTM PLGA showed a smoother surface and a stronger PLGA-drug intimacy than the implants with ViatelTM Ultrapure PLGA, due to the higher plasticity of the ViatelTM PLGA. Subsequently, the implants with ViatelTM PLGA exhibited less burst release than implants with ViatelTM Ultrapure PLGA, however, their onset and progress of the lag and substantial release phases were shorter and faster than the ViatelTM Ultrapure PLGA-based implants, owing to the residual monomer accelerated the water diffusion and autocatalyzed PLGA hydrolysis. Even though the drug release profiles were also influenced by other factors, such as composition, drug properties and polymer-drug interaction, all three cases revealed that the residual monomer accelerated the swelling and degradation of PLGA and impaired the implant's integrity, which could negatively affect the subsequent drug release behavior and performance of the implants. These results provided insights to formulators on rational PLGA implant design and polymer selection.

Rationalising the dose threshold for severe carbamazepine toxicity: a retrospective series.

INTRODUCTION: Carbamazepine causes dose-dependent toxicity in overdose. Resources commonly state that severe toxicity occurs with ingestions >50 mg/kg without supporting evidence. We aimed to compare ingested dose with clinical toxicity. METHODS: This was a retrospective series of patients reportedly ingesting carbamazepine >2,000 mg referred to a clinical toxicology unit and state poisons information centre. Medical records were reviewed to extract patient demographics, ingestion details, clinical effects and management. Severe toxicity was defined as the presence of coma (Glasgow Coma Scale <9), seizure, or hypotension (systolic blood pressure <90 mmHg). RESULTS: There were 69 presentations in 42 patients with a median ingested carbamazepine dose of 113 mg/kg (IQR: 71-151 mg/kg). Coma occurred in 10 cases, eight having ingested >200 mg/kg and the remaining two ingesting 113 mg/kg and 151 mg/kg, respectively. Seizures occurred in four cases (lowest ingested dose 143 mg/kg). Hypotension occurred in five cases (lowest ingested dose 113 mg/kg). DISCUSSION: Severe carbamazepine toxicity did not occur with reported ingestions <100 mg/kg and was uncommon in ingestions <200 mg/kg. CONCLUSION: Severe toxicity was common in ingestions >200 mg/kg. Using the suggested threshold of severe toxicity of >50 mg/kg appeared overly conservative in this series.

Interdisciplinary strategies for diagnosis and treatment of trigeminal neuralgia.

Temporary, sudden, shooting and recurrent unilateral facial pain in the supply area of one or more trigeminal nerve branches characterises trigeminal neuralgia. Innocuous stimuli trigger the pain, e.g. chewing, speaking or brushing teeth. In some patients, paroxysms superimpose on continuous pain. In aetiological terms, idiopathic, classic (due to neurovascular compression) and secondary trigeminal neuralgia (e.g. due to multiple sclerosis, brainstem ischaemia and space-occupying lesions) are defined. Many drugs may be efficacious, with carbamazepine being first-choice therapy. However, non-pharmacological and invasive procedures may also help. To reach the correct diagnosis and determine the best therapeutic measures, adequate pain characterisation and interdisciplinary collaboration are essential. We hereby present our experience of an interdisciplinary approach for the diagnosis and treatment of trigeminal neuralgia.

Spectral changes in electroencephalography linked to neuroactive medications: A computational pipeline for data mining and analysis.

BACKGROUND AND OBJECTIVES: The increasing amount of open-access medical data provides new opportunities to gain clinically relevant information without recruiting new patients. We developed an open-source computational pipeline, that utilizes the publicly available electroencephalographic (EEG) data of the Temple University Hospital to identify EEG profiles associated with the usage of neuroactive medications. It facilitates access to the data and ensures consistency in data processing and analysis, thus reducing the risk of errors and creating comparable and reproducible results. Using this pipeline, we analyze the influence of common neuroactive medications on brain activity. METHODS: The pipeline is constructed using easily controlled modules. The user defines the medications of interest and comparison groups. The data is downloaded and preprocessed, spectral features are extracted, and statistical group comparison with visualization through a topographic EEG map is performed. The pipeline is adjustable to answer a variety of research questions. Here, the effects of carbamazepine and risperidone were statistically compared with control data and with other medications from the same classes (anticonvulsants and antipsychotics). RESULTS: The comparison between carbamazepine and the control group showed an increase in absolute and relative power for delta and theta, and a decrease in relative power for alpha, beta, and gamma. Compared to antiseizure medications, carbamazepine showed an increase in alpha and theta for absolute powers, and for relative powers an increase in alpha and theta, and a decrease in gamma and delta. Risperidone compared with the control group showed a decrease in absolute and relative power for alpha and beta and an increase in theta for relative power. Compared to antipsychotic medications, risperidone showed a decrease in delta for absolute powers. These results show good agreement with state-of-the-art research. The database allows to create large groups for many different medications. Additionally, it provides a collection of records labeled as "normal" after expert assessment, which is convenient for the creation of control groups. CONCLUSIONS: The pipeline allows fast testing of different hypotheses regarding links between medications and EEG spectrum through ecological usage of readily available data. It can be utilized to make informed decisions about the design of new clinical studies.

Experimentally derived partitioning coefficients of carbamazepine and sulfadiazine in landfill refuse-leachate phase: Effects of refuse and leachate properties.

Pharmaceuticals have been detected at high concentrations in landfill leachate and refuse, which may pose potential long-term environmental impacts. The interaction of pharmaceuticals between leachate and refuse contributes to their retention through in situ sorption, thereby mitigating this impact. However, limited efforts have been made to describe the distribution characteristics of pharmaceuticals in the refuse-leachate phase. In this study, two refuse and three leachate samples were used to obtain partitioning coefficients (Kd) for two typical pharmaceuticals, carbamazepine (CBZ) and sulfadiazine (SD), with campus soil as a comparison. Landfill refuse exhibited higher Kd values (12.36 ± 0.90 and 19.76 ± 1.96 mL/g for CBZ and 1.90 ± 0.34 and 6.27 ± 0.58 mL/g for SD in two samples, respectively) than campus soil (3.73 ± 1.31 mL/g for CBZ and 0.81 ± 0.26 mL/g for SD), influenced by refuse properties such as higher organic matter (OM) content and specific surface area (SSA). The influence of leachate pH on Kd values depended on the electrostatic interaction between the species of target pollutants and negatively charged refuse. The effect of humic acid (HA) was related to its binding with target pollutants in solution and its competition with them for sorption sites. Electrostatic repulsion, hydrogen bonding and π-π interaction were the proposed mechanisms in SD sorption on refuse, while hydrogen bonding participated in the sorption of CBZ. The results will help aid the understanding of the distribution of pharmaceuticals in the refuse-leachate system and improve corresponding management strategies.

Embryo-fetal developmental toxicity of carbamazepine administered orally in wistar rat.

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.

Pharmacokinetic drug-drug interactions of JBPOS0101 mediated by cytochrome P450 3A4 and UDP-glucuronosyltransferases.

JBPOS0101 is a new antiepileptic drug and is a substrate of UDP-glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC50 136 µM) or inhibits (IC50 95.4-386.5 µM) cytochrome P450 (CYP) 3A4. As co-medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug-drug interactions (DDIs) between them should be determined. This study aimed to investigate pharmacokinetic (PK) interactions of JBPOS0101 influenced by CYP3A4 and UGTs using midazolam (MDZ) and CBZ. A two-cohort, open-label, fixed-sequence study was conducted in healthy Koreans. In cohort A, subjects received MDZ IV alone, and then JBPOS0101 were co-administered with MDZ after oral doses of JBPOS0101 for 7 days. In cohort B, multiple doses of JBPOS0101 and CBZ were administered respectively, and subjects received both together for 7 days. Serial blood samples were collected for PK analysis. When MDZ and JBPOS0101 were co-administered, the systemic exposure of MDZ decreased by 30%. Meanwhile, JBPOS0101 did not significantly changed the PK of CBZ. CBZ decreased the systemic exposure of JBPOS0101 at steady state by 40%, respectively. With IV administration of MDZ, JBPOS0101 acted as a weak inducer of hepatic CYP3A4 and decreased systemic exposure of MDZ. The ability of JBPOS0101 to similarly modulate gut CYP3A4 activity will require further evaluation. Co-administration of multiple doses of JBPOS0101 and CBZ did not significantly alter CBZ pharmacokinetics, but the clinical impact of decreased systemic exposure of JBPOS0101 by CBZ should be further considered.

Metabolomic and sphingolipidomic profiling of human hepatoma cells exposed to widely used pharmaceuticals.

Pharmaceutical compounds have become one of the main contaminants of emerging concern (CECs) due to their high usage and increased release into the environment. This study aims to assess the effects caused by three widely consumed hepatotoxic pharmaceutical compounds: an antibiotic (amoxicillin), an antiepileptic (carbamazepine), and an antidepressant (trazodone), on human health when indirectly exposed to toxicologically relevant concentrations (30, 15, and 7.5 µM for amoxicillin and carbamazepine, and 4, 2, and 1 µM for trazodone). A combination of semi-targeted metabolomic and targeted sphingolipid analyses was chosen to unravel the metabolic alterations in human hepatic cells exposed to these CECs at three concentrations for 24 h. HepG2 hepatoma cells were encapsulated in sodium alginate spheroids to improve the physiological relevance of this in vitro approach. Statistical analysis was used to identify the most affected metabolites and sphingolipids for each drug exposure. The results revealed small but significant changes in response to carbamazepine and trazodone exposures, affecting sphingolipid, glycerophospholipid precursors, and amino acid metabolism. Under both drug treatments, a decrease in various ceramide species (related to cell signaling) was observed, along with reduced taurine levels (related to the biosynthesis of bile acid conjugates) and carnitine levels (suggesting an impact on energy production). These and other drug-specific changes indicate that cellular functions in liver cells might be altered under low doses of these CECs, potentially affecting the health of other organs.

Carbamazepine responsive episodic dystonia and hallucination due to pyruvate dehydrogenase E2 (DLAT) gene mutation.

Pyruvate Dehydrogenase (PDH) E2 deficiency due to Dihydrolipoamide acetyltransferase (DLAT) mutations is a very rare condition with only nine reported cases to date. We describe a 15-year-old girl with mild intellectual disability, paroxysmal dystonia and bilateral basal ganglia signal abnormalities on brain magnetic resonance imaging (MRI). Additionally, neurophysiological, imaging, metabolic and exome sequencing studies were performed. Routine metabolite testing, and GLUT1 and PRRT2 mutation analysis were negative. A repeat brain MRI revealed 'Eye-of-the-tiger-sign'. Exome sequencing identified homozygous valine to glycine alteration at amino acid position 157 in the DLAT gene. Bioinformatic and family analyses indicated that the alteration was likely pathogenic. Patient's dystonia was responsive to low-dose carbamazepine. On weaning carbamazepine, patient developed hallucinations which resolved after carbamazepine was restarted. PDH E2 deficiency due to DLAT mutation has a more benign course compared to common forms of PDH E1 deficiency due to X-linked PDHA1 mutations. All known cases of PDH E2 deficiency due to DLAT mutations share the features of episodic dystonia and intellectual disability. Our patient's dystonia and hallucinations responded well to low-dose carbamazepine.