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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., 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 (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug-drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4-sensitive index substrate midazolam (MDZ). This was a fixed-sequence arm of an open-label, phase I study (NCT04840888). Healthy participants (n = 15) aged 18-63 years received oral doses of 1.2 mg MDZ alone (Day 1), CBZ b.i.d. alone (100 mg Days 2-4; 200 mg Days 5-7; 300 mg Days 8-10 and 12-13), and 300 mg CBZ b.i.d. plus 1.2 mg MDZ (Days 11 and 14). One participant (6.7%) experienced constipation due to treatment with CBZ plus MDZ on Day 11. One participant (6.7%) experienced urticaria (Days 12-13), and two participants (13.3%) experienced somnolence (Days 8-10) due to treatment with 300 mg CBZ b.i.d. alone. All AEs were mild. For MDZ, the geometric mean (90% CI) ratio (vs. Day 1) of the area under the curve (AUC 0-∞) was 0.28 (0.24-0.31) on Day 11 and 0.26 (0.23-0.29) on Day 14. The AUC (0-12 hours) of CBZ was 114,000 ng∙h/mL on Day 11 and 105,000 ng∙h/mL on Day 14. Steady-state concentrations of CBZ and induction of CYP3A4 were achieved on Day 11. The data are consistent with predictions of physiologically-based pharmacokinetic models in Simcyp. The 9-day dosing regimen for CBZ induction was well-tolerated by healthy participants, supporting the use of a shorter CBZ regimen for CYP3A4 induction studies., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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/Viatel TM and low/ Viatel TM 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 Viatel TM PLGA showed a smoother surface and a stronger PLGA-drug intimacy than the implants with Viatel TM Ultrapure PLGA, due to the higher plasticity of the Viatel TM PLGA. Subsequently, the implants with Viatel TM PLGA exhibited less burst release than implants with Viatel TM Ultrapure PLGA, however, their onset and progress of the lag and substantial release phases were shorter and faster than the Viatel TM 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., 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.)

BACKGROUND Providing pain relief for patients with neuropathic pain syndrome (NPS) is difficult, as sodium-channel blockers pose serious adverse events (AEs). Intravenous (i.v.) lidocaine infusion responses may identify patients likely to benefit from oral sodium channel blockers. We evaluated i.v. lidocaine responses to predict oral oxcarbazepine (OXC) efficacy in patients with NPS. MATERIAL AND METHODS This prospective cohort study administered one-time 3 mg/kg i.v. lidocaine infusion to patients with NPS. Numeric rating scale (NRS) pain scores and AEs were observed. Next, OXC 150 mg was prescribed; dosages were increased by 150 mg every 3 days until ≥50% pain reduction or the maximum tolerable dose or 1800 mg/day was reached. NRS, rescue drug requirements, and AEs were evaluated by phone at 1, 3, and 5 weeks and clinic visits at 2, 4, and 6 weeks. Depression, Anxiety & Stress Scales 21 (DASS-21), and EuroQol-Five Dimensions-Five Levels (EQ-5D-5L) questionnaires were assessed at baseline and in week 6. RESULTS Of 46 patients, 14 discontinued due to intolerable AEs, and 32 were in the final analysis. Average post-intervention NRS significantly decreased from 6.8±1.7 (baseline) to 3.8±2.0 (lidocaine) and 4.1±2.3 (OXC); P<0.001. Negative and positive predictive values for OXC efficacy were 76.2% (95% CI: 61.6-86.5%) and 54.5% (95% CI: 32-75.4%), respectively. Six weeks after OXC treatment, 20 and 11 patients achieved ≥30% pain reduction and ≥50% pain relief, respectively. EQ-5D-5L (P=0.018) and DASS-21 stress dimension (P<0.001) significantly improved. CONCLUSIONS Negative responses to i.v. lidocaine predicted a lack of oral OXC response. AEs of OXC may have obscured an analgesic effect.

Introduction: Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients., Method: Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data., Results: Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses., Conclusion: We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population., (© 2024 Pharmacotherapy Publications, Inc.)

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.

Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (C max ) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC 168h , AUC last , AUC inf ), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided., (© 2024 Janssen Research & Development, LLC. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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.

Background: Trigeminal neuralgia (TN) is difficult to treat due to its severe pain intensity and recurring episodes, which significantly impact quality of life., Objectives: We aimed to assess the effectiveness of electroacupuncture (EA) in alleviating the pain intensity in TN, and to determine whether EA combined with low-dosage carbamazepine (CBZ) has a synergistic effect., Methods: A multi-centre, randomized, 2 × 2 factorial trial was conducted. Participants who met the inclusion criteria received active EA or sham EA for 60 min, three times a week for four weeks; CBZ (300 mg per day) or placebo for four weeks. The primary outcome was the change in visual analog scale (VAS) score from baseline to weeks 2, 4, 16, and 28. Secondary outcomes included quality of life and adverse events., Results: A total of 120 participants (75 females and 45 males; mean (SD) age, 58.5 (15.3) years) were included. The main effects of EA and CBZ were significant (P < 0.001), and there was a significant interaction was identified between the interventions (P = 0.041). Participants who received EA (mean difference [MD], -0.3 [95% CI, -0.40 to -0.20] at week 2; -1.6 [-1.70 to -1.50] at week 4; -1.1 [-1.31 to -0.89] at week 16; -0.8 [-1.01 to -0.59] at week 28), CBZ (MD, -0.6 [95% CI, -0.70 to -0.50] at week 2; -0.9 [-1.03 to -0.77] at week 4, -0.2 [-0.41 to 0.01] at week 16, 0.2 [-0.01 to 0.41] at week 28), and the combination of both (MD, -1.8 [95% CI, -1.90 to -1.70] at week 2; -3.7 [-3.83 to -3.57] at week 4, -3.4 [-3.61 to -3.19] at week 16, -2.9 [-3.11 to -2.69] at week 28) had a greater reduction in VAS score over the treatment phase than their respective control groups (sham EA, placebo, and sham EA plus placebo). EA-related adverse events (6/59, 10.17%) were lower than that of CBZ (15/59, 25.42%) during the whole phases., Conclusions: EA or CBZ alone are effective treatments for TN, while the combination of EA and low-dosage CBZ exerts a greater benefit. These findings in this trial demonstrate that the combination of EA and low-dosage CBZ may be clinically effective under certain circumstances., Trial Registration: NCT03580317., (© 2024. The Author(s).)

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 (EC 50 136 μM) or inhibits (IC 50 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., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The field of nasal drug delivery gained enormously on interest over the past decade. Performing nasal in vivo studies is expensive and time-consuming, but also unfeasible for an initial high-throughput compound and formulation screening. Therefore, the development of fast and high-throughput in vitro models to screen compounds for their permeability through the nasal epithelium and mucosa is constantly expanding. Yet, the protocols used for nasal in vitro permeability studies are varying, which limits the comparability and reproducibility of generated data. This project aimed to elucidate the influence of different culture and assay parameters of RPMI 2650 cells grown under air-liquid interface (ALI) conditions on the transepithelial electrical resistance (TEER) and apparent permeability (P app ) values of five selected reference compounds, covering the range of low to moderate to high permeability. The influence of the passage number, seeding density, and timepoint of airlift was minimal in our approach, while the substrate pore density had a significant influence on the P app values of carbamazepine, propranolol, and metoprolol, classified as highly permeable compounds, but not on atenolol and aciclovir. Elevation of the experimental concentration of carbamazepine, propranolol, and metoprolol in the donor compartment had an increasing effect on the P app values, while prolonging the assay time did not have a significant influence. Based on the results reported here, RPMI 2650 cells cultured under ALI conditions offer the possibility of a standardized high-throughput screening model for small molecules and their formulations for in vitro drug permeation studies to predict and select optimal conditions for their nasal delivery., (© 2023. Controlled Release Society.)

Purpose: The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy., Methods: We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values., Results: Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate., Conclusions: Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: Carbamazepine (CBZ) is one of the oldest, yet first line drugs for treating epilepsy. However, there is a large inter-individual difference in requirement of maintenance dose and one third of persons treated with antiepileptic drugs (AEDs) exhibit drug resistance to therapy. One of the proposed mechanisms for the drug resistance was increased expression of efflux transporter P-glycoprotein. The pharmacogenetic studies of drug transporters ( ABCB1 ) done in combination therapies of AEDs were inconclusive. Hence, we have attempted to study the impact of ABCB1 3435C>T genetic polymorphism and CBZ monotherapy in persons with epilepsy (PWE) from South India, which is a genetically distinct population . With this background, this study was aimed to determine the dose of CBZ in ABCB1 3435C>T genotypes and to determine the distribution of ABCB1 3435C>T genotypes (which codes P-glycoprotein) between responders and non-responders to CBZ therapy., Methods: A cross sectional study was conducted in 200 persons with epilepsy, who were categorised as responders and non-responders according to ILAE (international league against epilepsy) criteria. Eligible participants were enrolled from the epilepsy clinic of the neurology department and five ml of blood was collected. DNA extraction and genotyping were done by phenol-chloroform method and real time polymerase chain reaction (RT-PCR), respectively., Results: The mean maintenance dose of carbamazepine was statistically significant among different genotypes (p<0.05) of ABCB1 3435C>T (526 vs. 637 mg/day in CC vs. TT genotype). There was no significant association between ABCB1 3435C>T polymorphism (p=0.827) and CBZ resistance in PWE. Duration of disease and age of onset were found to be significant in predicting the response to CBZ therapy., Conclusions: We report that ABCB1 3435C>T polymorphism is significantly associated with an increase in dose requirement of CBZ in persons with epilepsy from South India., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Temporal lobe epilepsy (TLE) has the highest probability of becoming resistant. One of the causes was Polymorphism in multidrug resistant-1 (MDR1) C3435T. In Dr. Cipto Mangunkusumo Hospital, potential drug-resistant epilepsy prevalence was 84.51%; 66.6% of them used carbamazepine (CBZ) as antiseizure medication. This comparative cross-sectional study aimed to investigate MDR1 C3435T polymorphism and CBZ plasma level (plCBZ) in Indonesian TLE patients., Methods: TLE patient was selected consecutively; divided into drug-responsive (DRV) and drugresistant (DRE) groups. Healthy subjects were included as a control for the gene polymorphism comparison. MDR1 was identified using the restriction fragment length polymorphism PCR technique; C allele at 159 and 57bp while T allele at 216bp. High-performance liquid chromatography was used to determine plCBZ., Results: There were 86 subjects; 61 in the study group and 25 controls. The genotype distribution between them was 0.58 vs 0.42, x 2 =0.54, p=0.000. In the study group, CBZ within therapeutic doses (dCBZ) had outreached the therapeutic plCBZ and found similar in all genotypes. DRE criteria were found in 37 subjects. Distribution of C and T in DRV was 0.63 vs 0.37, x 2 =10.4; and DRE 0.55 vs 0.45 x 2 =6.17 (p=0.019). In Tukey's multiple comparison post hoc test, CT in DRV had significantly lower dCBZ (330,36 ± 174,91 mg) and plCBZ (7.15 ± 2.64 mcg/mL) compared to all genotypes in DRE. Whereas mean dCBZ was around 800mg and plCBZ outreached the toxic level; TT was the highest., Conclusion: The genotype MDR1 distribution was similar in the normal population and DRE. Therapeutic plCBZ was achieved using the low dose. CT genotype responds to lower dCBZ, while TT genotype outreached the highest toxic plCBZ., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Antiepileptic drugs may cause systemic and metabolic side effects. The aim of our study was to investigate the effects of valproic acid and carbamazepine monotherapy used in the treatment of epilepsy patients on serum adiponectin and carnitine levels. The study included 60 patients, of which 30 patients receiving valproic acid monotherapy and 30 patients receiving carbamazepine monotherapy, who were followed up by the epilepsy outpatient clinic with the diagnosis of idiopathic epilepsy, and 30 healthy volunteers. Patients, who used drugs for at least 6 months, were selected. Venous blood samples were collected from the patients and healthy volunteers after their consent was obtained. Serum carnitine and adiponectin levels in the collected samples were measured using the ELISA method. Serum carnitine levels were 5166.55 ng/ml (± 1954.92) in patients receiving carbamazepine, 4224.56 ng/ml (± 2055.54) in patients using valproic acid, and 5802.64 ng/ml (± 3422.57) in the control group. Serum adiponectin levels were 13,606.51 ng/ml (± 5915.92) in patients using carbamazepine, 11,986.58 ng/ml (± 5367.82) in patients receiving valproic acid, and 14,033.43 ng/ml (± 5646.34) in the control group. In both groups, both serum carnitine and serum adiponectin levels were lower than the control group. There was a negative but insignificant correlation between the duration and dose of carbamazepine and valproic acid drug use and serum adiponectin and carnitine levels. There is a need for more extensive studies with larger sample size to investigate the effect of antiepileptic drugs used on serum adiponectin and carnitine levels., (© 2020. Belgian Neurological Society.)

Objective: Traumatic brain injury is a major health and socioeconomic problem and the first cause of young death worldwide. For this reason, the prevention of post-traumatic brain injury and the research of new methods for it are important today. In this study, we aimed to determine whether the use of antiepileptic drugs contributed to axonal healing after traumatic brain injury., Methods: Thirty-six Long-Evans rats, each weighing 300-350 g, were used in this study. A total of 6 groups, including the sham, control, and 4 study groups, were determined. A 1.5 mm-sized trauma was created in the biparietal area with a blunt-tipped dissector. Carbamazepine phenytoin valproic acid and levetiracetam (phenytoin: 30 mg/kg, valproic acid: 60 mg/kg, levetiracetam: 80 mg/kg, and carbamazepine: 36 mg/kg) were intraperitoneally administered to the study groups, and the control group intraperitoneally received a physiological saline solution (15 ml/kg) twice daily for 3 days. After 72 h, hemispheres of the sacrificed subjects were taken for examination in biochemistry and histology. Glutathione, malondialdehyde, and NG2 levels in the samples were determined., Results: No significant difference was found in biochemical measurements. Histopathological examination revealed that the NG2 expression was more intense in the group treated with phenytoin and levetiracetam (phenytoin was partly higher) and the amount of edema decreased. The NG2 expression increased and the edema decreased, though lower in the group treated with carbamazepine and valproic acid, compared with phenytoin and levetiracetam. An increase in the NG2 expression and edema intensity were determined in the control and sham groups., Conclusion: Antiepileptic drug selection after traumatic brain injury is an important medical matter. Although the patient-oriented selection is essential, the study suggests that the choice of phenytoin, levetiracetam carbamazepine, and valproic acid will, respectively, have an accelerating effect for axonal healing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels., Methods: We retrospectively identified hospitalized patients simultaneously receiving a DOAC and carbamazepine, phenobarbital, phenytoin, or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady state were included. DOAC peak or trough levels were compared with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified., Results: We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch)., Conclusion: Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Unilateral-onset spike-wave discharges (SWDs) following fluid percussion injury (FPI) in rats have been used for nearly two decades as a model for complex partial seizures in human posttraumatic epilepsy (PTE). This study determined if SWDs with a unilateral versus bilateral cortical onset differed. In this experiment, 2-mo-old rats received severe FPI (3 atm) or sham surgery and were instrumented for chronic video-electrocorticography (ECoG) recording (up to 9 mo). The antiseizure drug, carbamazepine (CBZ), and the antiabsence drug, ethosuximide (ETX), were administered separately to determine if they selectively suppressed unilateral- versus bilateral-onset SWDs, respectively. SWDs did not significantly differ between FPI and sham rats on any measured parameter (wave-shape, frequency spectrum, duration, or age-related progression), including unilateral (∼17%) versus bilateral (∼83%) onsets. SWDs with a unilateral onset preferentially originated ipsilateral to the craniotomy in both FPI and sham rats, suggesting that the unilateral-onset SWDs were related to surgical injury and not specifically to FPI. ETX profoundly suppressed SWDs with either unilateral or bilateral onsets, and CBZ had no effect on either type of SWD. These results suggest that SWDs with either a unilateral or bilateral onset have a pharmacosensitivity similar to absence seizures and are very different from the complex partial seizures of PTE. Therefore, SWDs with a unilateral onset after FPI are not a model of the complex partial seizures that occur in PTE, and their use for finding new treatments for PTE could be counterproductive, particularly if their close similarity to normal brain oscillations is not acknowledged. NEW & NOTEWORTHY Unilateral-onset spike-wave discharges (SWDs) in rats have been used to model complex partial seizures in human posttraumatic epilepsy (PTE), compared to bilateral-onset SWDs thought to reflect human absence seizures. Here, we show that both unilateral- and bilateral-onset SWDs following traumatic brain injury are suppressed by the antiabsence drug ethosuximide and are unaffected by the antiseizure drug carbamazepine. We propose that unilateral-onset SWDs are not useful for studying mechanisms of, or treatments for, PTE.

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser 261 -AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser 261 . NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser 261 and accelerated AQP2 transcription.

This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration-time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC (p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.

Purpose: Drug-resistant epilepsy is a problem worldwide. Xenobiotic receptors may play a significant role in the establishment of resistance to antiepileptic agents. Previous studies have confirmed that the metabolism and efficacy of carbamazepine (CBZ) can be influenced by xenobiotic receptors, especially pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AHR). Therefore, this study intends to elucidate the pharmacogenomic associations of polymorphisms of these xenobiotic receptors with the CBZ response in epilepsy patients, and these genetic data may be useful for the treatment of clinical prophylaxis and individualized treatment of intractable epilepsy., Methods: Adult patients with epilepsy who were on CBZ-based monotherapy and combination therapy (n = 257) were genotyped, and the patients were divided into drug-responsive and drug-resistant groups according to the International League Against Epilepsy criteria. We sought to tag single-nucleotide polymorphisms (SNPs) of PXR, CAR and AHR that principally represent alleles associated with drug resistance risk; in addition, a gene interaction analysis reference panel was constructed for SNP-based imputation., Results: No significant effects of PXR or AHR polymorphisms were observed. However, an interaction between the CAR rs2502815 variant and CBZ response was observed: in CBZ-based monotherapy and combination therapy patients, the GG genotype of the CAR rs2502815 variant (vs. wild-type homozygous) was independently associated with CBZ response after adjusting for variables [odds ratio (OR) = 0.389, 95% confidence interval (CI) 0.203-0.743, p = 0.004]. The results of the haplotype and gene interaction case-control analyses of the CBZ response were negative. Our results provide clinical data regarding the genetic possibilities of drug responses related to CAR variation in epilepsy patients., Conclusion: This study is the first to indicate a potentially relevant interaction between the CAR rs2502815 polymorphism and the CBZ response in epilepsy patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Due to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin., Methods: The effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay., Results: Given acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5-75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment., Conclusions: Acute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Carbamazepine, an anticonvulsant drug, has shown antidepressant effects in clinical and experimental models. Nitric oxide (NO) is a neurotransmitter in the central nervous system and has been involved in a variety of diseases including depression. In the present study, the involvement of NO/cyclic GMP/KATP channels pathway in the antidepressant action of carbamazepine was investigated in mice. The antidepressant-like activity was assessed in the forced swim test (FST) behavioral paradigm. Carbamazepine reduced (40 mg/kg, intraperitoneal) immobility period. The antidepressant-like effect of carbamazepine (40 mg/kg, intraperitoneal) was prevented by pretreatment with L-arginine [substrate for NO synthase (NOS), 750 mg/kg, intraperitoneal], sildenafil (a PDE-5 inhibitor, 5 mg/kg, intraperitoneal) and diazoxide (K+ channels opener, 10 mg/kg). Pretreatment of mice with L-NAME (a non-selective NOS inhibitor, 10 mg/kg, intraperitoneal), methylene blue (direct inhibitor of both NOS and soluble guanylate cyclase, 10 mg/kg, intraperitoneal) and glibenclamide (an ATP-sensitive K+ channel blocker, 1 mg/kg, intraperitoneal) produced potentiation of the action of a sub-effective dose of carbamazepine (30 mg/kg, intraperitoneal). Also, carbamazepine (30 mg/kg) potentiated the antidepressant-like effect of fluoxetine through NO modulation. The various modulators used in the study did not produce any changes in locomotor activity per se. The results demonstrated that the antidepressant-like effect of carbamazepine in the FST involved an interaction with the NO/cGMP/KATP channels pathway., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The study is aimed at comparing effects of older drugs like carbamazepine (CBZ) and newer agent like levetiracetam (LEV) on polycystic ovarian syndrome (PCOS) in women with epilepsy (WWE)., Methods: An interviewer-based questionnaire was used to obtain relevant clinical information from 50 WWE on CBZ and LEV monotherapy, respectively, and 50 age-matched controls. The diagnosis of epilepsy was clinical with electroencephalographic features taken into consideration and the seizures classified using the 2017 International League Against Epilepsy classification. The diagnosis of PCOS was based on the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine., Results: The frequency of PCOS and its subcomponent were higher among WWE compare to controls. PCOS was present in 22 (44%) of LEV group compare to 8 (16%) CBZ group. The frequency of its subcomponent was higher among those on LEV except for comparable effect with regard to oligomenorrhea. The levels of the sex steroid hormone were comparable in both groups of WWE except luteal phase luteinizing hormone, which was lower among the LEV group (P .001). The follicular phase estradiol level was lower (P .021), and follicle-stimulating hormone level was about 2-fold higher (P .03) among WWE compare to controls. The mean value testosterone was significantly lower among controls compared to WWE., Conclusions: The increased frequency of PCOS and its subcomponent and the unsatisfactory effect of LEV compared to CBZ on reproductive endocrine function underscore the need for routine reproductive endocrine evaluation to improve overall quality of life., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Carbamazepine (CBZ) is mainly metabolized by CYP3A4 into carbamazepine-10,11-epoxide (CBZE). Cannabidiol (CBD) is a potent inhibitor of the CYP3A family. The aim of this study is to determine the effect of acute and chronic administration of CBD on the pharmacokinetics of CBZ and CBZE. Male SD rats were assigned into four acute and four chronic groups: control (CBZ only), positive control (ketoconazole), low-dose cannabidiol (l-CBD), and high-dose cannabidiol (h-CBD). Acute CBD groups were administered a single dose of CBD, while chronic CBD groups were given multiple doses of CBD for 14 days (q.d.) before CBZ administration. Plasma samples had been collected and analyzed for CBZ and CBZE, then their noncompartmental pharmacokinetic parameters before and after CBD administration were determined. The co-administration of a single l-CBD has significantly increased CBZ's [Formula: see text] by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in C max by 31.8%. Acute h-CBD caused similar effects on CBZ's [Formula: see text] with 40.4% significant decrease in CBZE's C max , when compared to the control. Chronic h-CBD caused a significant decrease in CBZ's C max and [Formula: see text] by 75.3% and 65.7%, respectively. Besides, [Formula: see text] and C max of CBZE significantly decreased by 75.3% and 78.3%, respectively. These results demonstrated that the pharmacokinetics of CBZ and CBZE had been significantly affected by CBD. When CBD has been administered as a single dose, the effect is believed to be mainly caused by the inhibition of CBZ metabolism through CYP3A. The effect of chronic administration of CBD probably includes kinetic pathways other than the inhibition of CYP3A-dependent pathways. Graphical abstract.

Objectives: The objectives of this study were to determine the relationship between genetic polymorphisms in gene encodings for CYP3A4 and carbamazepine (CBZ)-induced dose-related side effects in North Indian people with epilepsy., Patients and Methods: The current prospective study included 37 patients with CBZ-induced dose-related side effects and 102 patients who did not experience side effects while on CBZ. The genotyping for CYP3A4 allele (CYP3A4*16) was done using real-time polymerase chain reaction (RT-PCR) in Applied Biosystems 7500 RT-PCR System (USA). CBZ was administered in all patients at a dose varying from 15 to 20 mg/kg daily., Results: Various demographic variables were comparable between the groups except that control of seizures was far better in controls. After testing, it was found that none of our patients had the presence of CYP3A4*16 allele., Conclusion: CYP3A4*16 allele is not represented significantly in North Indian people with CBZ-induced dose-related side effects., Competing Interests: None

Objectives: This study was performed to evaluate the efficacy and tolerability of lacosamide (LCM) for paroxysmal kinesigenic dyskinesia (PKD) in children., Methods: We retrospectively reviewed the medical charts of pediatric PKD patients (aged <16 years) treated with LCM. Data regarding demographic characteristics, proline-rich transmembrane protein 2 (PRRT2) gene variant, clinical features of PKD, dose of LCM, efficacy, and adverse events were recorded., Results: Four eligible patients (3 males, 1 female) were identified, with an age of onset ranging from 8.3 to 14.7 years. PRRT2 variant was evaluated in three children and a c.649dupC variant was identified in one child with a positive family history. Attacks were bilateral in three children and left-sided in one. Two children had a family history of PKD and one child had a family history of benign infantile epilepsy. Treatment with carbamazepine failed in two children due to drowsiness and auditory disturbance. The initial dose of LCM was 50 mg/day in three children and 100 mg/day in one. All patients were attack-free within a few days. The maintenance dose was mostly similar to the initial dose. No adverse events related to LCM were reported during follow-up., Conclusions: LCM is an effective and well-tolerated treatment for PKD in children, and low-dose treatment may be viable., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the time course of changes in perampanel levels when co-administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model., Methods: The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down-titration (75 mg twice daily [bid]/wk) of co-administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8-4 mg) and up-titration (2-6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations., Results: The PBPK model accurately reproduced perampanel plasma concentration-time profiles from clinical studies in single- and multiple-dose regimen simulations, including multiple-dose carbamazepine co-administration. The time course of return to pre-induced perampanel levels occurred more slowly following carbamazepine down-titration (~48 days after first down-titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8-4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady-state concentrations, which returned to the levels observed during carbamazepine co-administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up-titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down-titrated weekly (~45 days) vs abrupt discontinuation (~24 days)., Conclusion: This PBPK model simulated and predicted optimal perampanel dose tapering and up-titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme-inducing anti-seizure medications to monotherapy., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

To evaluate changes in the pharmacokinetics of perampanel after discontinuation of carbamazepine. We enrolled 13 patients receiving perampanel who discontinued carbamazepine therapy between June 2016 and December 2018. Data on serum concentrations were obtained from the therapeutic drug monitoring database of the National Epilepsy Center (Shizuoka, Japan). To compare the pharmacokinetics of perampanel before and after discontinuation of carbamazepine, we determined the concentration/dose (CD) ratio of perampanel (serum level [ng/mL] divided by the dose [mg/kg]). The follow-up period was set to eight weeks following the discontinuation of carbamazepine therapy. The mean baseline CD ratio of perampanel was 1,247 ng/mL/mg/kg which increased markedly over time after discontinuation of carbamazepine, with a mean CD ratio at Weeks 1-2, Weeks 3-4, and Weeks 5-8 of 2,683, 3,914, and 4,220, respectively. At eight weeks, the mean CD ratio of perampanel had increased by 276%. Eleven patients developed adverse events, including dizziness, somnolence, irritability, and ataxia. Five of these 11 patients required perampanel dose reduction within eight weeks after discontinuation of carbamazepine. Two patients achieved seizure-free status at Weeks 5-8. The serum perampanel concentration began to increase from one week after discontinuation of carbamazepine, and continued to rise for eight weeks. Based on these findings, we recommend frequent monitoring of serum perampanel concentration for at least eight weeks after stopping carbamazepine therapy. Monitoring is required as a guide for dose adjustment in order to achieve a safe and effective therapeutic dose of perampanel.

Background: Benign childhood epilepsy with centrotemporal spikes (BECTS) or benign rolandic epilepsy is the most common epileptic syndrome in school-age children. Genetics is an important factor in BECTS pathogenesis, and <10 genes were associated with BECTS. This study aimed to identify novel genetic causes of BECTS., Methods: We conducted whole-exome sequencing on a patient with BECTS and validated the findings by Sanger sequencing in a pedigree with three patients., Results: CHRNA4 c.1007G>A was identified in three patients with BECTS in a pedigree. Carbamazepine, which should be carefully used in BECTS, was observed to be effective in the treatment of our atypical BECTS proband based on the molecular diagnosis of CHRNA4., Conclusion: This is the first study on CHRNA4 variant in BECTS, which widened the genetic spectrum of BECTS and contributed to precise medicine in BECTS., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

This work tested the role of carbamazepine in alleviating alloxan-induced diabetic neuropathy and the enhancement of spinal plasticity. Mice were randomized into four groups: normal, control, carbamazepine (25-mg/kg) and carbamazepine (50-mg/kg). Nine weeks after induction of diabetes, symptoms of neuropathy were confirmed and carbamazepine (or vehicle) was given every other day for five weeks. After completing the treatment period, mice were sacrificed and the pathologic features in the spinal cord and the sciatic nerves were determined. The spinal cords were evaluated for synaptic plasticity (growth associated protein-43, GAP43), microglia cell expression (by CD11b) and astrocyte expression (glial fibrillary acidic protein, GFAP). Further, sciatic nerve expression of Nav1.5 was measured. Results revealed that carbamazepine 50 mg/kg prolonged the withdrawal threshold of von-Frey filaments and increased the hot plate jumping time. Carbamazepine improved the histopathologic pictures of the sciatic nerves and spinal cords. Spinal cord of carbamazepine-treated groups had enhanced expression of GAP43 but lower content of CD11b and GFAP. Furthermore, specimens from the sciatic nerve indicated low expression of Nav1.5. In conclusion, this work provided evidence, for the first time, that the preventive effect of carbamazepine against diabetic neuropathy involves correction of spinal neuronal plasticity and glia cell expression.

The present study aims to evaluate the efficacy of selenium (Se) alone or combined with carbamazepine (CBZ) against the adverse effects induced by the chemoconvulsant pentylenetetrazole (PTZ) in the cortex of adult male rats. Electrocorticogram (ECoG) and oxidative stress markers were implemented to evaluate the differences between treated and untreated animals. Animals were divided into five groups: control group that received i.p. saline injection, PTZ-treated group that received a single i.p. injection of PTZ (60 mg/kg) for induction of seizures followed by a daily i.p. injection of saline, Se-treated group that received an i.p. injection of sodium selenite (0.3 mg/kg/day) after PTZ administration, CBZ-treated group that received orally CBZ (80 mg/kg/day) after PTZ administration, and combination (Se plus CBZ)-treated group that received an oral administration of CBZ (80 mg/kg/day) followed by an i.p. injection of sodium selenite (0.3 mg/kg/day) after PTZ administration. Quantitative analyses of the ECoG indices and the neurochemical parameters revealed that Se and CBZ have mitigated the adverse effects induced by PTZ. The main results were decrease in the number of epileptic spikes, restoring the normal distribution of slow and fast ECoG frequencies and attenuation of most of the oxidative stress markers. However, there was an increase in lipid perioxidation marker in combined treatment of CBZ and Se. The electrophysiological and neurochemical data proved the potential of these techniques in evaluating the treatment's efficiency and suggest that supplementation of Se with antiepileptic drugs (AEDs) may be beneficial in ameliorating most of the alterations induced in the brain as a result of seizure insults and could be recommended as an adjunct therapy with AEDs.

The purpose of this research was to investigate drug dose, solubility, permeability, and their interplay, as key factors in oral formulation development for lipophilic drugs. A PEG400-based formulation was studied for five doses of the lipophilic drug carbamazepine, accounting for biorelevant dissolution of the dose in the GIT, and in-vivo bioavailability in rats. With the three lower doses (10, 25 and 50 mg/kg), complete in-vitro dissolution was achieved and maintained throughout the experiment with this formulation, while significant precipitation was obtained with higher doses (100 and 200 mg/kg). Likewise, the studied formulation allowed complete bioavailability in-vivo with the three lower doses, while the same formulation allowed only 76% and 42% bioavailability for the 100 and 200 mg/kg doses, respectively. There was good correlation between the in-vitro and in-vivo results. In conclusion, this work demonstrates that the dose is a crucial factor in formulation development; while a given formulation may be optimal for a certain drug dose, it may no longer be optimal for higher doses of the same drug. Hence, the solubility, the permeability, and their interplay, have to be considered in light of the drug dose intended to be administered in order to achieve successful oral formulation development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, -49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level-to-dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences., (© 2020 International League Against Epilepsy.)

Introduction: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations., Methods: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4., Results: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction., Conclusions: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs., (Copyright © 2018 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

The most important limits of oxaliplatin treatment is its peripheral neurotoxicity. The aim of our study was to evaluate the oxaliplatin-induced peripheral neuropathy, its impact on treatment and its management. One hundred chemo-naive patients treated with oxaliplatin-based regimen in the medical oncology department of the military hospital of Tunis between 2012 and 2017 were recruited retrospectively. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). Fifty-six patients were aged more than 60 years. The sex-ratio was 1.56. Twenty-seven patients were overweight, 17 were obese and 56 had a BMI inferior to 25 kg/m 2 . Two patients were consuming alcohol. Twenty-three patients had diabetes. Sixty-four patients developed chronic peripheral neuropathy because of oxaliplatin (grade 1-2 in 58 cases and grade 3 in 6 cases). Sex, BMI, diabetes and alcohol consumption were not associated with the development of peripheral neuropathy. No association was found between grades of neuropathy and sex, alcohol consumption and diabetes. The median cumulative dose of oxaliplatin that induced neuropathy was 432.4 mg/m 2 . The most prescribed treatment was gabapentin (81%) and carbamazepine (16.8%). The treatment was not sufficient to stop neuropathy in 82.6% of cases. Dose reduction was done in 64.2% of cases, treatment delay in 10.7% of cases and treatment interruption in 10.7% of cases. We didn't find any association between known risk factors and peripheral neuropathy. The cumulative dose is interesting to define or to predict the timing of neurotoxicity., Competing Interests: The authors declare no competing interests., (© Aref Zribi et al.)

The aim of this work was to develop a mathematical model to estimate the drug release from a conventional single-compartment reservoir pellet and extend its applicability to multi-compartment reservoir pellets. Conventional pellets were prepared by layering the drug onto starter-core then applying various ethylcellulose/HPC coatings for drug release control. Multi-layered pellets comprised a first drug layer of propranolol HCl (D 1 ) followed by a first controlled release coating (C 1 ) and consecutively a second drug layer of carbamazepine or caffeine (D 2 ) and then a second controlled-release coating (C 2 ). Drug release from single- and multi-compartment pellets generally increased with an increase of the water-soluble HPC in the coatings. The response described a sigmoidal curve, which agreed with a cumulative normal distribution function. The developed mathematical model facilitated quantification of the drug release of pellets as a function of the porogen content and the coating level. Additionally, the model was applied successfully in multi-compartment pellets to calculate theses effects on the release of drugs with a broad range of aqueous solubility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Prostaglandin E 2 (PGE 2 ), a physiologically active lipid compound, is increased in several diseases characterized by chronic inflammation. To determine its significance in epilepsy-associated inflammation and response to antiepileptic drug (AED), we evaluated the plasma PGE 2 (median, pg/ml) levels in drug-free patients with epilepsy (N = 34) and patients receiving AED monotherapy (N = 55) in addition to that in healthy controls (N = 34). When compared to controls, plasma PGE 2 levels were significantly elevated in all drug-free patients independent of the type of epilepsy (137.2 versus 475.7 pg/ml, p < 0.0001). Among the patients receiving AED monotherapy, only valproate responders showed a significant decrease compared to both drug-free patients (232.1 versus 475.7 pg/ml, p < 0.01) as well as valproate non-responders (232.1 versus 611.9 pg/ml, p < 0.0001). Both responders and non-responders on phenytoin or carbamazepine monotherapy had elevated PGE 2 levels similar to drug-free patients. In addition, no difference was observed in plasma profiles of PGE 2 precursor, arachidonic acid among the groups. Our work presents the clinical evidence of the association between plasma PGE 2 levels and valproate efficacy in patients with epilepsy., Competing Interests: Declaration of Competing Interest None of the authors has any competing interest to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The development of orodispersible tablets (ODTs) for poorly soluble and poorly flowable drugs via direct compression is still a challenge. This work aimed to develop ODTs of poorly soluble drugs by combining cyclodextrins that form inclusion complexes to improve wetting and release properties, and directly compressible co-processed excipients able to promote rapid disintegration and solve the poor flowability typical of inclusion complexes. Carbamazepine (CBZ) and hydroxypropyl-β-cyclodextrin (HPβCD) were used, respectively, as a model of a poorly soluble drug with poor flowability and as a solubilizing agent. Specifically, CBZ-an antiepileptic and anticonvulsant drug-may benefit from the studied formulation approach, since some patients have swallowing difficulties or fear of choking and are non-cooperative. Prosolv® ODT G2 and F-Melt® type C were the studied five-in-one co-processed excipients. The complex was prepared by kneading. Flow properties of all materials and main properties of the tablets were characterized. The obtained results showed that ODTs containing CBZ/HPβCD complex can be prepared by direct compression through the addition of co-processed excipients. The simultaneous use of co-processing and cyclodextrin technologies rendered ODTs with an in vitro disintegration time in accordance with the European Pharmacopoeia requirement and with a fast and complete drug dissolution. In conclusion, the combination of five-in-one co-processed excipients and hydrophilic cyclodextrins may help addressing the ODT formulation of poorly soluble drugs with poor flowability, by direct compression and with desired release properties.

Up-regulation of efflux transporters in brain capillaries may lead to the decreased therapeutic efficacy of antiepileptic drugs in patients with Drug Resistant Epilepsy. Adenosine receptor activation in brain capillaries can modulate blood-brain barrier permeability by decreasing the protein levels and function of efflux transporters. Therefore, we aimed to investigate whether the activation of adenosine receptors improves convulsions outcome in carbamazepine (CBZ) resistant animals and modulates the protein levels of efflux transporters (P-GP, MRP1, MRP2) in brain capillaries. We employed the window-pentylenetetrazol (PTZ) kindling model to develop CBZ resistant rats by CBZ administration during the post-kindling phase, and tested if these animals displayed subsequent resistance to other antiepileptic drugs. Crucially, we investigated if the administration of a broad-spectrum adenosine agonist (NECA) improves convulsions control in CBZ resistant rats. Of potential therapeutic relevance, in CBZ resistant rats NECA restored the anticonvulsant effect of CBZ. We also evaluated how the resistance to CBZ and the activation of adenosine receptors with NECA affect protein levels of efflux transporters in brain capillaries, as quantified by western blot. While CBZ resistance was associated with the up-regulation of both P-GP/MRP2 in brain capillaries, with the administration of NECA in CBZ resistant rats, we observed a decrease of P-GP and an increase of MRP2 levels, in brain capillaries. Since the activation of adenosine receptors improves the outcome of convulsions probably through the modulation of the efflux transporters protein levels in brain capillaries, adenosine agonists could be useful as an adjunct therapy for the control of Drug Resistant Epilepsy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Psychiatric comorbidities are common in patients with epilepsy. A double-blind noninferiority monotherapy trial (SP0993; NCT01243177) enrolled newly diagnosed patients (≥16 years) with focal or generalized tonic-clonic seizures. Patients were randomized 1:1 to lacosamide or carbamazepine controlled-release (carbamazepine-CR). Here, we report data from an exploratory post hoc analysis of patients who reported ongoing psychiatric conditions (Medical Dictionary for Regulatory Activities System Organ Class). Of 886 treated patients in the trial, 126 (14.2%; 64 on lacosamide; 62 on carbamazepine-CR) reported at least one ongoing psychiatric condition at screening, most commonly depression (38.1%), insomnia (27.8%), and anxiety (26.2%). In this subgroup, 32/64 (50.0%) patients on lacosamide and 22/62 (35.5%) on carbamazepine-CR completed the trial. The most common reasons for discontinuation in patients on lacosamide and carbamazepine-CR were adverse events (10.9%, 24.2%) and lack of efficacy (18.8%, 11.3%). Treatment-emergent adverse events (TEAEs) were reported in 52 (81.3%) of patients on lacosamide and 56 (90.3%) of patients on carbamazepine-CR, most commonly (≥10% patients in either treatment group; lacosamide, carbamazepine-CR) dizziness (12.5%, 16.1%), headache (12.5%, 14.5%), nasopharyngitis (12.5%, 9.7%), fatigue (7.8%, 14.5%), nausea (7.8%, 11.3%), somnolence (1.6%, 12.9%), and gamma-glutamyltransferase increase (1.6%, 12.9%). Overall, 15 (23.4%) lacosamide-treated and 10 (16.1%) carbamazepine-CR treated patients reported psychiatric TEAEs, most commonly (≥3 patients in either treatment group; lacosamide, carbamazepine-CR) depression (4.7%, 0) and anxiety (3.1%, 6.5%). There were no reports of psychotic disorder, epileptic psychosis, acute psychosis, or serious psychiatric TEAEs. Stratified Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose were similar with lacosamide and carbamazepine-CR (6 months 81.0%, 75.6%; 12 months 62.5%, 66.6%). A higher proportion of patients on lacosamide than carbamazepine-CR completed 6 (67.2%, 45.2%) and 12 months (50.0%, 37.1%) of treatment at the last evaluated dose without a seizure. This exploratory post hoc analysis indicated that lacosamide monotherapy was efficacious and generally well tolerated in patients with newly diagnosed epilepsy and concomitant psychiatric conditions. In this subpopulation, lacosamide showed similar efficacy and numerically better effectiveness than carbamazepine-CR., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

BackgroundEPHX1 gene polymorphisms were recently acknowledged as an important source of individual variability in carbamazepine metabolism, but the result of that association still remains controversial. Aim of the review To obtain a more precise estimation of the associations between EPHX1 polymorphisms and carbamazepine metabolism and resistance. Methods The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched for appropriate studies regarding the rs1051740 and rs2234922 polymorphisms of EPHX1 up to September 2019. The meta-analysis was carried out using the Review Manager 5.3 software. The mean difference and 95% confidence interval were applied to assess the strength of the relationship. Results A total of 7 studies involving 1118 related epilepsy patients were included. EPHX1 rs1051740 polymorphism was significantly associated with adjusted concentrations of both carbamazepine (CC vs. TT: P = 0.02; CC vs. CT + TT: P = 0.005) and carbamazepine-10,11-epoxide (CC vs. CT + TT: P = 0.03). Furthermore, EPHX1 rs2234922 polymorphism was also observed to be significantly associated with decreased adjusted concentrations of carbamazepine-10,11-trans dihydrodiol (GG vs. GA + AA: P = 0.04) and CBZD:CBZE ratio (GG vs. AA: P = 0.008; GG vs. GA + AA: P = 0.0008). Nevertheless, the pooled analysis showed that the EPHX1 polymorphisms had no significant effect on CBZ resistance. Conclusion EPHX1 rs1051740 and rs2234922 polymorphisms may affect the carbamazepine metabolism; but carbamazepine resistance was not related to any of the single nucleotide polymorphisms investigated. These findings provided further evidence for individualized therapy of epilepsy patients in clinics.

Purpose: To evaluate the risk factors and prevalence of hyponatremia among epilepsy patients in relation to use of antiepileptic drugs (AEDs)., Methods: We retrospectively reviewed 14,620 adult patients (aged 18-103 years) and classified them into the following 3 groups: patients without AED treatment (n = 2165, Group I), patients receiving antiepileptic drugs other than carbamazepine (n = 7442, Group II), and patients treated with carbamazepine (n = 5013, Group III). This study did not include the patients receiving oxcarbazepine or eslicarbazepine acetate because these AEDs are not marketed in Japan. Severe hyponatremia was defined as a serum sodium level < 130 mEq/L., Results: In Groups I, II, and III, the mean sodium level was 140, 139, and 137 mEq/L, respectively. The highest frequency of severe hyponatremia was observed in Group III (7%), and it was much higher than in Group I (0.8%) or Group II (1.2%). In Groups II and III, old age, low body weight, and concomitant use of phenobarbital, benzodiazepines, or antipsychotics were risk factors for hyponatremia. In Group III, the sodium level decreased as the carbamazepine dose increased. At a carbamazepine dose exceeding 600 mg/day, there was 10.9-fold higher prevalence of hyponatremia, and the risk was potentiated by concomitant use of valproate., Conclusion: The serum sodium level should be monitored carefully when patients are receiving AED polypharmacy combined with antipsychotics. In particular, concomitant administration of valproate enhances the risk of hyperammonemia in patients receiving carbamazepine. These findings may help clinicians to avoid hyponatremia in patients with epilepsy., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: A large-scale, double-blind trial (SP0993; NCT01243177) demonstrated that lacosamide was noninferior to controlled-release carbamazepine (carbamazepine-CR) in terms of efficacy, and well tolerated as first-line monotherapy in patients (≥16 years of age) with newly diagnosed epilepsy. We report primary safety outcomes from the double-blind extension of the noninferiority trial (SP0994; NCT01465997) and post hoc analyses of pooled long-term safety and efficacy data from both trials., Methods: Patients were randomized 1:1 to lacosamide or carbamazepine-CR. Doses were escalated (lacosamide: 200/400/600 mg/d; carbamazepine-CR: 400/800/1200 mg/d) based on seizure control. Eligible patients continued randomized treatment in the extension. Primary outcomes of the extension were treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Post hoc analyses of data from combined trials included 12- and 24-month seizure freedom and TEAEs by number of comorbid conditions., Results: A total of 886 patients were treated in the initial trial and 548 in the extension; 211 of 279 patients (75.6%) on lacosamide and 180/269 (66.9%) on carbamazepine-CR completed the extension. In the extension, 181 patients (64.9%) on lacosamide and 182 (67.7%) on carbamazepine-CR reported TEAEs; in both groups, nasopharyngitis, headache, and dizziness were most common. Serious TEAEs were reported by 32 patients (11.5%) on lacosamide and 22 (8.2%) on carbamazepine-CR; 12 (4.3%) and 21 (7.8%) discontinued due to TEAEs. In the combined trials (median exposure: lacosamide 630 days; carbamazepine-CR 589 days), Kaplan-Meier estimated proportions of patients with 12- and 24-month seizure freedom from first dose were 50.8% (95% confidence interval 46.2%-55.4%) and 47.0% (42.2%-51.7%) on lacosamide, and 54.9% (50.3%-59.6%) and 50.9% (46.0%-55.7%) on carbamazepine-CR. Incidences of drug-related TEAEs and discontinuations due to TEAEs increased by number of comorbid conditions and were lower in patients on lacosamide., Significance: Long-term (median ~2 years) lacosamide monotherapy was efficacious and generally well tolerated in adults with newly diagnosed epilepsy. Seizure freedom rates were similar with lacosamide and carbamazepine-CR., (© 2019 UCB Biopharma SPRL. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: To estimate the comparative efficacy and safety of antiepileptic drugs (AEDs) in the elderly with new-onset epilepsy., Methods: We searched electronic databases for randomized controlled trials (RCTs) of monotherapy AEDs to treat epilepsy in elderly. The following outcomes were analyzed: seizure freedom and withdrawal from the study for any cause at 6 and 12 months; withdrawal from the study for any adverse event (AE) at 12 months; and occurrence of any AE at 12 months. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA) and mean ranks., Results: Five RCTs (1425 patients) were included. Included AEDs were carbamazepine immediate- and controlled-release (CBZ-IR, CBZ-CR), gabapentin (GBP), lacosamide (LCM), lamotrigine (LTG), levetiracetam (LEV), phenytoin (PHT), and valproic acid (VPA). At the pairwise and network meta-analyses, there were no differences in any of the comparison according to 6- and 12-month seizure freedom. The treatment with CBZ-IR and CBZ-CR was associated with a higher risk of withdrawal than LTG, LEV, or VPA, and CBZ-IR had the overall highest probability of discontinuation across all AEDs. According to SUCRA, the following had the greatest likelihood ranking best for seizure freedom at 6 and 12 months: LCM, LTG, and LEV. CBZ-CR and CBZ-IR had the highest probabilities of being worst for the 12-month retention. CBZ-IR, CBZ-CR, and GBP had the highest probabilities of withdrawal from the study for AEs, , and VPA had the highest probability of being the best-tolerated option., Significance: Although no significant difference in efficacy was found across treatments, LCM, LTG, and LEV had the highest probability of ranking best for achieving seizure freedom. CBZ-IR and CBZ-CR showed a poor tolerability profile, leading to higher withdrawal rates compared to LEV and VPA., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)