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Background and Objective: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. Methods: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. Results: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19–2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. Conclusions: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes. [ABSTRACT FROM AUTHOR]

There is presently no efficient dose individualization strategy for the use of antiseizure medications in epileptic pregnant patients. This study aimed to develop a population pharmacokinetics model for levetiracetam and propose a tailored adaptive individualized dosage strategy for epileptic pregnant patients. A total of 322 levetiracetam plasma concentrations from 238 patients with epilepsy were included, including 216 women with epilepsy (20.83% of whom were pregnant). The levetiracetam plasma concentration was measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were modeled using a nonlinear mixed-effects model. The resultant model served as the basis for simulating the dosage adjustment strategy. A one-compartment model with first-order elimination best described the pharmacokinetic data of levetiracetam. The apparent clearance (CL/F) was 3.43 L/h (95% CI 3.30–3.56) and the apparent volume of distribution was 43.7 L (95% CI 40.4–47.0) for a typical individual of 57.2 kg. Pregnancy and body weight were found to be significant covariates of CL/F of levetiracetam. The recommended regimen of levetiracetam could be predicted by the population pharmacokinetic model based on body weight, gestational age, and the daily dose of levetiracetam taken before pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Long-term exposure to antiepileptics causes adverse effects on bone metabolism, but the available English literature regarding fracture healing is limited. In his study, we compare the effects of carbamazepine and levetiracetam on fracture healing. Material and Method: Thirty Sprague-Dawley rats were randomly assigned to three groups of ten. Carbamazepine and levetiracetam were administered to rats in the first (CAR) andsecond group (LEV), respectively; the third group (CONT) served as the control group. Drug administration was started four weeks before fracture model establishment. Then a closed fracture was created and fixed. In each group, half of the rats were sacrificed at 4 weeks and then at 6 weeks. All femurs were evaluated with plain radiography using radiographic union scale in tibial (RUST) fractures scoring, Lane & Sandhu scoring. Besides microtomography (micro-CT), and histological Huo scoring was performed. Results: Radiological scores were superior in all groups in the sixth week than in the fourth week (p<0.01). The group with the lowest bone mineral density (BMD) was the CAR group, followed by the LEV group in the 4"' and 6'1' weeks (p<0.01). The callus mineralization rate was lower in the drug groups in the 4th week (p=0.05). There was no significant difference between the groups at 6 weeks in micro-CT analysis (p=0.54). Histologic scores were similar to micro-CT in the 4"' week, but the carbamazepine group had the lowest scores in the. 6lh week (p<0.01). Conclusion: This study demonstrated that carbamazepine and levetiracetam adversely affect the early period of fracture healing. [ABSTRACT FROM AUTHOR]

The fast, accurate, and affordable determination of the anti-epileptic drug levetiracetam (LEV) is the need of time for human health. In this study, a novel electrochemical sensor platform was proposed for the cost-effective and sensitive determination of the levetiracetam based on molybdenum sulfide nano-flower-adorned pencil graphite electrode (MoS2/PGE). The nano-flowers of MoS2 were prepared by a cost-effective one-step facile hydrothermal method and the morphology of synthesized MoS2 micro-flowers was characterized via FESEM, XRD, and EDS techniques. The various electro-kinetics parameters like diffusion coefficient (Do =1.41 × 10−5 cm2 s−1), heterogeneous rate constant (Kh= 9.04 × 10−4 cm s−1), electron transfer coefficient (α = 0.66), the effective surface area of the fabricated electrode (A = 0.0767 cm2), and surface coverage (Γo = 2.98 × 10−11 mol cm−2) were evaluated for the oxidation of LEV at MoS2/PGE employing voltammetric techniques. The oxidative peak current in the optimized square wave stripping voltammetry varies linearly with LEV concentration within the range of 72.0 to 130.0 µM with detection limit (LOD) value of 14.20 µM. The proposed MoS2/PGE platform provides a sensitive, low cost and eco-friendly tool for the rapid detection of LEV in clinical samples. [ABSTRACT FROM AUTHOR]

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020–2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1–2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope =.85), with no significant change in the 2nd trimester (slope =.11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period. [ABSTRACT FROM AUTHOR]

Background: Mental health in people with epilepsy (PWE) is often overlooked, especially in developing countries. Purpose: Consequently, the current work had two objectives: (1) to estimate the burden of depression, anxiety, insomnia, and stress, and (2) to examine the association of these psychiatric/psychological symptoms with levetiracetam and other relevant clinical factors in a cohort of Jordanian PWE. Research Design: This is a cross-sectional study. The demographic and clinical data were recorded. Depression was measured by the Patient Health Questionnaire-9 (PHQ-9, Arabic-validated version) and anxiety by the General Anxiety Disorder-7 (GAD-7, Arabic-validated version). The insomnia severity index (ISI-A, Arabic version) was used to assess sleep quality, and the Perceived Stress Scale (PSS-A, Arabic version) was used to measure perceived stress. Study Sample: Data were analyzed from 280 patients, of which 178 (63.6%) received levetiracetam as monotherapy or as adjuvant. Results: Depression was reported in 150 (53.6%), anxiety in 110 (39.3%), insomnia in 131 (46.8%), and clinically significant stress in 211 (75.4%). At univariate analysis, levetiracetam was not associated with psychiatric symptoms. Multivariate logistic regression revealed that severe depressive symptoms were associated with family history (OR = 2.47, 95% CI = 1.42-4.33, P = .001) and seizure type (OR = 1.69, 95% CI = 1.01-2.80, P = .04), severe anxiety symptoms were associated with family history (OR = 1.90, 95% CI = 1.12-3.23, P = .01), severe insomnia was associated with seizure type (OR = 2.16, 95% CI = 1.33-3.5, P = .002) and severe stress was associated with marital status (OR = 2.37, 95% CI = 1.31-4.29, P = .004). Conclusions: The high psychological burden of PWE is a challenging issue that requires attention and prompt action to control its risk factors. Levetiracetam was not associated with psychiatric symptoms in this study. [ABSTRACT FROM AUTHOR]

Background & Objective: Febrile seizure (FS) is the most common childhood seizure disorder that occurs in 3-4% of children .The aim of this study was to determine the effect of intermittent oral anticonvulsant Levetiracetam in prevention of the recurrence of febrile seizure (FS) in children. Materials & Methods: This a randomized clinical trial study was conducted on 108 children with FS referred to the pediatric department of Mohammad Kermanshahi Hospital in Kermanshah in 2020. Then, eligible patients were divided into intervention (Levetiracetam; n= 72) and control (Acetaminophen; n= 36) groups using balanced block randomization. The intervention group received a dose of 30-60 mg/kg Levetiracetam during the febrile illness for prophylaxis for 9 months. In contrast, in the control group, only acetaminophen was prescribed just to reduce fever. Finally, the number of FS recurrences were studied in two groups. The data were analyzed using SPSS 26. Results: The mean (±S.D) age were 2.37 (±1.01) vs. 2.30 (±0.95) years in the intervention and control groups; respectively. The number (%) of boys in the two groups under study was 39 (54.1) and 19 (52.7), respectively. The mean time to first seizure recurrence after the intervention was significantly longer in the intervention group (5.70 ± 0.82 months) than in the control group (2.32 ± 0.75 months) (P-Value<0.05). Also, the mean number of recurrences of FS in the intervention group (2.25 ± 0.80) was significantly lower than the control group (4.13 ± 0.79) (P-Value<0.05). Conclusion: The administration of oral anticonvulsant Levetiracetam may be effective in the reduction of the recurrences of FS, however, detailed studies in this field is recommended. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications (ASMs). Although dozens of ASMs are available in the clinic, approximately 30% of epileptic patients have medically refractory seizures; other limitations in most traditional ASMs include poor tolerability and drug-drug interactions. Therefore, there is an urgent need to develop alternative ASMs. Levetiracetam (LEV) is a first-line ASM that is well tolerated, has promising efficacy, and has little drug-drug interaction. Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein (SV) 2A, the molecular basis of its action remains unknown. Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs. [ABSTRACT FROM AUTHOR]

Introduction: Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Methods: Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72 h later-at time at which drug is expected to be cleared. Results: We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers pvalb and opalin, and increased the marker of activated microglia, cd68 and the astrocyte-associated gene vegfa. These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. Discussion: The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity. [ABSTRACT FROM AUTHOR]

Background: Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome. Methods: This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam. Results: Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644). Conclusions: Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome. Trial registration: The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. Methods: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. Results: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. Conclusions: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. Clinical trial registration: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838. [ABSTRACT FROM AUTHOR]

Background: Levetiracetam is a readily available, safe anticonvulsive medication. It is frequently administered as IV piggyback with a pump, carrier fluid, and tubing. The Established Status Epilepticus Treatment Trial demonstrated levetiracetam being similarly effective to previously used treatments in doses up to 4500 mg administered over 10 minutes. Objective: We sought to compare usage, cost, and waste of IV piggyback with IV push administration of levetiractam following implementation of an IV push protocol in an academic emergency department. Methods: A three-month review of levetiracetam administration was done following protocol implementation using IV push for initial treatment of benzodiazepine-refractory status epilepticus. The review quantified the number of IV push vs IV piggyback doses for all indications and evaluated cost of supplies necessary for administration. Results: During the study period, 137 patients received 142 doses of IV levetiracetam. Fifty-one doses (36%) were given as IV push rather than IV piggyback. The majority of doses 116 (82%) were 1000-2000 mg and 11 doses (8%) 3500-4500 mg. Estimated three-month savings with complete transition of IV piggyback to IV push would exceed $6000 just in our ED. The amount of sterile solution carrier fluid was also reduced and IV pump time freed. Conclusion: Implementation of an emergency department IV push levetiracetam protocol resulted in cost savings. Opportunities remain to improve clinical implementation practices. Medication administration represents one crucial target area where healthcare systems can implement policies to reduce waste and commit to climate-smart health care. [ABSTRACT FROM AUTHOR]

Introduction: The study aimed to evaluate the effectiveness and safety of brivaracetam (BRV) as conversion monotherapy in adults with focal epilepsy treated in the context of real-world clinical practice. Methods: This was a retrospective, observational, non-interventional study in adults with focal epilepsy who converted to BRV monotherapy following the withdrawal of background antiseizure medications (ASMs). Primary effectiveness outcome was the retention rate of BRV as single ASM at 6 and 12 months. Secondary outcomes included the 6- and 12-month rates of seizure freedom. Safety and tolerability outcomes included the frequency and type of adverse events (AEs) and the occurrence of treatment discontinuation due to AEs. Results: A total of 44 participants with a median age of 63.5 (interquartile range 44–73.5) years were included; 17 subjects were seizure free at baseline, and 9 of them switched from levetiracetam because of lack of tolerability. The retention rate of BRV monotherapy was 88.6% (39/44) at 6 months and 83.9% (26/31) at 12 months. The rates of seizure freedom were 72.7% (32/44) in subjects with 6-month follow-up and 58.1% (18/31) in subjects with 12-month follow-up. The median maintenance dosage of BRV monotherapy was 150 (100–200) mg/day at 6 months and 125 (100–200) mg/day in subjects with 12-month follow-up. Adverse events were recorded in 6/44 (13.6%) participants and led to BRV discontinuation in 2/44 (4.5%) cases. The reported AEs were somnolence (n = 3), fatigue (n = 2), and irritability (n = 1); no serious AEs were experienced. In 21/44 (47.7%) participants, BRV monotherapy resulted from the direct switch from levetiracetam. The rates of treatment retention and seizure freedom at 6 and 12 months were higher among people who switched from levetiracetam to BRV monotherapy. Conclusion: Brivaracetam may be a valuable treatment of focal seizures in people who converted to monotherapy in a real-life setting. [ABSTRACT FROM AUTHOR]

• Real-world safety of Levetiracetam based on FAERS and disproportionality analysis. • Levetiracetam carries a potential risk of causing rhabdomyolysis, SJS, TEN, DRESS. • Be mindful of spontaneous abortion and stillbirth in pregnant women. • Suspicious signals such as drug interaction warrant heightened attention. Levetiracetam is a relatively new and widely utilized anti-seizure medication; however, limited information is available regarding its adverse effects. This study aims to thoroughly investigate, evaluate, and present evidence on the safety profile of Levetiracetam, relying on data from the FDA Adverse Event Reporting System (FAERS) database to facilitate informed clinical decision-making. We employed various statistical measures, including Reporting Odds Ratio (ROR), Proportionate Reporting Ratio (PRR), and analysis by the Medicines and Healthcare Products Regulatory Agency (MHRA), to identify signals of adverse reactions associated with Levetiracetam. Positive signals consistent with Designated Medical Event (DME) were singled out for focused comparison and discussion. The analysis of 26,182 adverse events linked to Levetiracetam as the primary suspected drug revealed 692 positive signals spanning 22 System Organ Classes (SOCs). Nervous system disorders were the most frequently reported, followed by psychiatric disorders, and general disorders and administration site conditions. 11 positive signals consistent with Preferred Terms (PTs) in DME were identified, predominantly concentrated in 6 SOCs. Among these, rhabdomyolysis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) exhibited relatively large values of A, ROR, and Chi-squared. Additionally, PTs related to spontaneous abortion, drug interaction, urethral atresia, ventricular septal defect, and atrial septal defect showed significant strength. The study indicates that Levetiracetam carries a potential risk of causing rhabdomyolysis, SJS, TEN, DRESS as well as spontaneous abortion. Signals related to drug interaction, urethral atresia, ventricular septal defect, and atrial septal defect warrant heightened attention in clinical use. [ABSTRACT FROM AUTHOR]

• Prospective controlled study in difficult-to-treat patients with epilepsy. • Switch from levetiracetam to brivaracetam versus ongoing levetiracetam treatment. • Psychiatric adverse events prior to and after the switch and among the controls. • Elevated scores for anxiety and psychoticism prior to the switch. • No significant differences anymore between the two groups after one week. Brivaracetam is often used as an alternative to levetiracetam in patients with epilepsy (PWE) encountering efficacy issues or adverse events with levetiracetam. This study evaluated the psychological status of PWE who were switched from levetiracetam to brivaracetam due to psychiatric tolerability concerns in comparison to those who remained on levetiracetam. We used various psychological assessments including the Symptom Checklist SCL-90-R, the Beck Depression Inventory-II, and the adverse event profile. Eligible participants completed the questionnaires at baseline and again 8 days later. Psychological changes were assessed using standard statistical methods to show differences between a group that immediately switched from levetiracetam to brivaracetam and another group with unchanged levetiracetam. Between May 2020 and May 2021, 63 patients participated in the study, of whom 34 switched from levetiracetam to brivaracetam. At baseline, participants who switched to brivaracetam had fewer antiseizure medications but experienced more monthly seizures. Baseline scores for anxiety (p = 0.020) and psychoticism (p = 0.046) on SCL-90-R in PWE switched to brivaracetam were higher than in the remaining group. In the subsequent assessment, all psychological scores were reduced and were no longer significantly different between both groups. Using multiple regression, initial treatment with a single antiseizure medication and male gender emerged as predictors of psychological improvement. Our study found no increased risk of adverse events or psychiatric symptoms after switching from levetiracetam to brivaracetam. Though statistically non-significant, a trend towards improved psychiatric outcomes in the switch group warrants further investigation in future trials with stronger designs for enhanced statistical power. [ABSTRACT FROM AUTHOR]

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Objectives and Aim: The primary aim of this study was to conduct a comparative analysis of the safety and efficacy of levetiracetam (LEV) and phenobarbital (PB) as first-line treatments for neonatal seizure management. This study was designed to measure and compare the incidence of adverse effects and to determine the discharge and mortality rates associated with the use of these antiseizure medications (ASMs). Through this comparison, this research sought to provide insights to optimise care for neonates experiencing seizures. Materials and Methods: This retrospective cohort study evaluated 104 neonates treated for seizures at Zeynep Kamil Hospital from 2015 to 2020 after excluding those on non-PB/LEV antiseizure medications. Seizures were characterised using electroencephalogram (EEG) and categorised according to aetiology and frequency. Treatment efficacy was gauged by seizure cessation, as confirmed using EEG. Adverse effects and demographic data were recorded. Statistical analyses were conducted using SPSS, employing the Shapiro–Wilk, independent t-test, Mann–Whitney U test, and chi-square test, with a significance threshold of p < 0.05. Results: Overall, 104 neonates treated with first-line ASM were evaluated for efficacy; PB was administered in 68.26% of the cases, while LEV was utilised in 31.74%. The total complete response rate was 40.38%, with no significant difference between the PB and LEV groups (p = 0.309). The incidence rate ratios (IRRs) demonstrated that seizure frequency profoundly influenced treatment effectiveness, with IRRs of 2.09 for rare seizures, 3.25 for frequent seizures, and 4.01 for status epilepticus, indicating a higher treatment response rate with increasing seizure frequency. For second-line treatment, among a subset of 62 patients, PB had a slight, non-significant advantage over LEV, with an odds ratio of 1.09, suggesting a marginally better response to LEV. Adverse events were significantly more frequent in the PB group, affecting 19 of 67 neonates (28.36%), compared to only 2 of 71 neonates (2.82%) in the LEV group (p < 0.001). No significant difference was observed in the discharge rates between the two groups (PB, 67.61%; LEV, 75.76%; p = 0.674). Interestingly, the mortality rate was significantly higher in the LEV group (45.45%) than that in the PB group (22.54%; p = 0.045). Conclusion: This study underscores LEV's superior safety profile over PB in neonatal seizure management, evidenced by a significantly lower rate of adverse events. PB seems to be more effective in the second-line treatment of neonatal seizures. Despite the lack of significant differences in the discharge rates, the higher mortality rate associated with LEV warrants further investigation. These findings advocate the cautious selection of antiepileptic drugs in neonatal care, with a preference for LEV based on its safety profile. [ABSTRACT FROM AUTHOR]

Objective: The determination of pKa values holds paramount importance in the field of medicinal chemistry, serving as a critical parameter for understanding the ionization behavior of pharmaceutical compounds. This study employs potentiometric titration as a precise method to elucidate the pKa values of diverse molecules. The experimental methodology involved a carefully controlled titration setup, utilizing a pH meter to monitor the titration curve and identify inflection points corresponding to the dissociation of acidic or basic functional groups. Methods: Potentiometric titration was conducted using a standardized protocol. Each compound was titrated with a titrant solution of known concentration, and pH measurements were recorded throughout the titration process. The titration curves were analyzed to determine the pKa values of the compounds based on the points of inflection. Results: The potentiometric titration method successfully provided accurate and reproducible pKa values for the studied compounds. The pKa values for the active ingredients Diclofenac, Clavunate potassium, and Levetiracetam are 3.31, 3.53, and 11.3, respectively. Compounds with pKa values below 7 are unlikely to be significantly protonated at physiological pH, which is approximately 7.4. Conclusion: The study underscores the critical role of pKa values in guiding medicinal chemistry efforts. The potentiometric titration method proved to be an effective tool for determining these constants, contributing essential data for rational drug design. The correlation between pKa values and pharmacokinetic properties emphasizes the relevance of this approach in optimizing drug candidates for enhanced therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Demyelinating diseases are commonly associated with epileptic seizures and have limited management options. Hence, the need to investigate potential options for management of such seizures. Antiaris Africana extract (AE) was investigated for effect in chronic demyelinating seizures. Cuprizone treatment induced short but frequent spike discharges in mice. Antiaris Africana extract (300 mg/kg) treatment abolished epileptiform discharges. Cuprizone administration caused severe demyelination in the corpus callosum. After the demyelination phase, myelin content decreased to 22.86 ± 1.92 % in the cuprizone-only group. However, there was an increase to 52.14 ± 3.91 % in cuprizone-only group and 62.00 ± 2.78 % in the Antiaris africana extract group respectively, after a 4-week cuprizone cessation period. Treatment with AE and LEV visibly altered myelin growth. Antiaris africana extract treatment produced significant (P

Author(s): Ankita Dey (corresponding author) [1]; Anju Grewal [1]; Manisha Patlan [1] Dear Editor, Opitz-Kaveggia syndrome was identified by Opitz and Kaveggia in 1974 in a family of five affected [...]

Abstract Background The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. Methods This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. Results Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (

Abstract Background The long-term use of anti-seizure medications (ASMs) adversely affects thyroid, lipid profile and other metabolic functions. Subclinical hypothyroidism and alterations in thyroid hormone serum levels are reported with older ASMs in adults with limited and conflicting data of the influence of ASMs especially newer one on thyroid function in children. This study aimed to investigate the effects of conventional and newer ASMs whether mono or polytherapy on thyroid profile in children with epilepsy and its impact on lipid profile and metabolic functions. Results This study included 155 children with epilepsy (76 on monotherapy and 79 on polytherapy) with mean age of 9.677 ± 3.981 years (54.84% euthyroid, 31.61% hypothyroid, 9.68% subclinical hyperthyroid and 3.87% subclinical hypothyroid) and 78 healthy controls. Children with epilepsy whether on monotherapy or on polytherapy had a statistically significant thyroid profile abnormalities (hypothyroidism, sub-clinical hypothyroidism or sub-clinical hyperthyroidism), dyslipidemia, delayed growth and increase in DBP compared to control group. There was a statistically significant positive correlation between hypothyroidism and dyslipidemia as well as between hypothyroidism and delayed growth and increase in DBP. There was no statistically significant difference between polytherapy and monotherapy regarding thyroid and lipid parameters but children with epilepsy on polytherapy were associated with more statistically significant delay in growth and increase in DBP compared to monotherapy group. Carbamazepine had a statistically significant association with hypothyroidism, increase in DBP and higher total and LDL-cholesterol. Valproic acid had a statistically significant association with sub-clinical hypothyroidism with a positive dose correlation. Levetiracetam (LEV) was associated with a statistically significant lower HDL-cholesterol. All echocardiography data showed no abnormality. Conclusion ASMs whether older or newer generations can affect thyroid and lipid profile differently through different mechanisms that are dose and duration dependent regardless of the seizure type and age of the patient. ASMs mainly conventional ones are associated with hypothyroidism, sub-clinical hypothyroidism, sub-clinical hyperthyroidism, dyslipidemia and consequently delayed growth and diastolic blood pressure abnormalities.

On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far‐reaching recommendations. [ABSTRACT FROM AUTHOR]

AbstractObjective: To observe the efficacy and safety of sodium valproate (VPA) compared to levetiracetam (LEV) in the treatment of severe traumatic brain injury (sTBI).Methods: In this blind, prospective study, eighty-four sTBI patients who had craniotomy from August 2021 to August 2023 were randomly split into two groups through random number table method: LEV and VPA, each with 42 patients. Both received comprehensive treatment post-craniotomy. LEV group: LEV injection on surgery day, transitioning to LEV tablets from day two. VPA group: VPA injection on surgery day, switching to VPA extended-release tablets from day two. The study compared hospital stay, neurological function, clinical outcomes, seizures, and drug reactions between groups.Results: The length of hospital stay showed no significant difference between the LEV and VPA groups. Both groups demonstrated improved neurological function post-treatment (NIHSS and BI scores), with no significant between-group differences. Clinical outcomes at 3 months post-treatment were similar in both groups. Seizure occurrence within 3 months after treatment showed no significant difference between the LEV (19.05%) and VPA (23.81%) groups. However, the VPA group experienced a significantly higher rate of drug-related adverse reactions (40.48%) compared to the LEV group (21.43%).Conclusion: Both VPA and LEV are effective in treating sTBI, showing no significant difference in improving neurological function, daily life abilities, treatment outcomes, and seizure occurrence. However, VPA treatment exhibited a significantly higher incidence of drug-related adverse reactions compared to LEV, indicating that LEV might be a safer option for sTBI treatment. [ABSTRACT FROM AUTHOR]

Introduction: Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. Methods: Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. Results: Pharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. Discussion: This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design. [ABSTRACT FROM AUTHOR]

Introduction: There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add-on therapy with LEV for achieving >80% seizure reduction after phenobarbital (PB) treatment. Methods: Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG-confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd-, 3rd- or 4th-line treatment. Antiseizure medication was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography. The total seizure burden in minutes, 2 h before and 4 h after administration of LEV, was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving >80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated. Results: A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36–44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (n = 11), hemorrhagic or ischemic stroke (n = 16), central nervous system infection (n = 8), genetic (n = 8), metabolic disorders (n = 3), and unknown (n = 1). Following LEV administration, >80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration. Discussion: Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration. [ABSTRACT FROM AUTHOR]

Epilepsy affects cognition through several mechanisms in a complex relationship. Valproic acid (VPA) and levetiracetam (LEV) are widely used due to their good efficacy and tolerability profiles. However, VPA may cause impairment of spatial working memory. There has not been much explanation regarding the negative cognitive side effects of LEV, few research suggests that LEV may even have a stimulating effect on cognition. Evidence of the comparative effects of anti-epileptic drugs on cognitive function is still limited. Objective: To investigate the effects of VPA monotherapy and LEV monotherapy on idiopathic generalized epilepsy patients. Methods: This was a cross-sectional observational study of patients with IGE taking either VPA monotherapy (n=28) or LEV (n=25). All patients underwent cognitive function assessment using MoCA-Ina, CDT, TMT A and B. Results: There was a significant association between 64.3% of patients taking VPA having MoCA-Ina score <26 vs. only 12% in patients taking LEV (OR 13.2, 95% CI 3.150-56.309, p<0.001), 35.7% of patients taking VPA vs. 0% in patients taking LEV on TMT-A score (p<0,001), and 46.4% of patients taking VPA vs. 4% in patients taking LEV on TMT-B score (OR 20.80, 95% CI 2.462-175.696, p 0,001). Neither patients with VPA monotherapy nor LEV monotherapy was statistically significant in CDT score (57.1% vs 36%, OR 0.422, 95% CI 0.139-1.277, p 0.170). Conclusion: This study showed patients with VPA have lower cognitive function than LEV. Further studies on cognitive function in epilepsy are recommended to provide information to assist in efficient drug selection decision-making for patients. [ABSTRACT FROM AUTHOR]

Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first‐line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population. [ABSTRACT FROM AUTHOR]

Objective: Rapid administration of antiseizure medications is a critical concept in the treatment of status epilepticus. Although undiluted levetiracetam (LEV) doses of up to 2500 mg have been evaluated, minimal data exist to support the safety of loading doses up to 4500 mg. This study will evaluate intravenous (IV) push administration of undiluted LEV from 2500 to 4500 mg for safety outcomes as well as tolerability. Methods: This is a retrospective, observational, cohort analysis of adult patients who received at least one loading dose of undiluted IV push LEV from October 15, 2019, to April 30, 2022, at a large academic medical center in Phoenix, Arizona. Relevant outcomes include the safety and tolerability of rapid administration of undiluted LEV at higher loading doses. Results: We evaluated 518 loading doses in 518 unique patients included during the study period. LEV was a new medication for witnessed or suspected seizures in 80.3% of patients, with 31.2% having a documented history of epilepsy or seizure disorder. At the time of LEV administration, 52.9% of patients were on a general medicine floor, 34.3% were in the intensive care unit, and 12.7% were in the emergency department. The median loading dose of LEV was 3600 mg (3000–4000 mg), with 4000 mg being the most common loading dose given. Peripheral IV lines were documented as the only available line in 78.6% of patients for loading dose administration. No adverse events associated with LEV administration were documented. Significance: Rapid IV administration of undiluted doses of LEV is both safe and tolerable in loading doses of 2500–4500 mg, allowing for rapid drug administration in the setting of status epilepticus. [ABSTRACT FROM AUTHOR]

Levetiracetam may cause acute renal failure and myoclonic encephalopathy at high plasma levels, particularly in patients with renal impairment. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict levetiracetam pharmacokinetics in Chinese adults with epilepsy and renal impairment and define appropriate levetiracetam dosing regimen.PBPK models for healthy subjects and epilepsy patients with renal impairment were developed, validated, and adapted. Furthermore, we predicted the steady-state trough and peak concentrations of levetiracetam in patients with renal impairment using the final PBPK model, thereby recommending appropriate levetiracetam dosing regimens for different renal function stages. The predicted maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration–time curve (AUC) were in agreement (0.8 ≤ fold error ≤ 1.2) with the observed, and the fold error of the trough concentrations in end-stage renal disease (ESRD) was 0.77 − 1.22. The prediction simulations indicated that the recommended doses of 1000, 750, 500, and 500 mg twice daily for epilepsy patients with mild, moderate, severe renal impairment, and ESRD, respectively, were sufficient to achieve the target plasma concentration of levetiracetam. [ABSTRACT FROM AUTHOR]

Background: Levetiracetam is the most commonly used antiepileptic drug in pregnant women due to its low teratogenic risk profile, favorable pharmacokinetic characteristics, and safety profile. Serum levels of levetiracetam vary in epilepsy during pregnancy. Therefore, the aim of the study was to evaluate the serum levels of levetiracetam during different trimesters of pregnancy by using therapeutic drug monitoring (TDM). Materials and Methods: This was a single-center, prospective study. Pregnant women with epilepsy on levetiracetam were enrolled after getting written informed consent from them. Serum trough levels of levetiracetam were estimated at all trimesters by high-performance liquid chromatography (HPLC). Results: The study included 16 participants with mean ± standard deviation (SD) age of 27.75 ± 4 years. There were nine (56.2%) participants with generalized seizure disorder and seven (43.8%) participants of focal seizure disorder. Among 16 patients, 10 (62.5%) participants were on levetiracetam alone and six (37.5%) participants were on levetiracetam combined with other antiepileptic drugs. In a total of 48 trough samples, 45 sample concentrations were below the therapeutic range of 12-46 mg/l and three sample concentrations were within the therapeutic range. There was a statistically significant difference in the concentration-dose ratio (CDR) of levetiracetam between the third and first trimesters (P-value 0.018). Conclusion: There was a statistically significant difference in serum levetiracetam concentration between the third and first trimesters. A well-conducted, intensive pharmacokinetic sampling study in PWWE with a control group is needed in future to evaluate the whole pharmacokinetic profile of levetiracetam and to correlate the clinical outcome. [ABSTRACT FROM AUTHOR]

• 111 (7.8%) of 1412 patients taking levetiracetam had severe psychotic disorders. • Some patients also showed suicidal and self-harm behaviors. 3 reducing or stopping the drug to control symptoms were necessary. • Psychiatric symptoms caused by levetiracetam require high attention. : Drug-induced psychiatric symptoms are an important cause of treatment failure. Worldwide, levetiracetam has been widely used to treat epilepsy; however, associated psychobehavioral abnormalities have been observed. This study aimed to characterize levetiracetam-induced severe psychiatric symptoms and to propose preventive and therapeutic measures. : In this retrospective cluster sampling study, psychiatric symptoms of patients who had taken levetiracetam for at least 1 month were analyzed. : 111(7.8%) of the 1,412 included patients exhibited severe psychiatric symptoms. Hallucinations, delusions, aggressive behavior, and agitation were the most common manifestations. Some patients also showed suicidal and self-harm behaviors. These symptoms were mainly controlled by reducing the dose of levetiracetam, stopping the drug, or adding antipsychotic drugs to the treatment regimen. : The severe psychiatric symptoms caused by levetiracetam require special attention. [ABSTRACT FROM AUTHOR]

Opinion statement: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor–related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel. [ABSTRACT FROM AUTHOR]

Epilepsy is the most common neurological disorder in childhood which often requires long-term or sometimes lifelong treatment. In this study, we aimed to evaluate the change in hematological and biochemical laboratory parameters at the 24th month compared to the treatment baseline values in pediatric epilepsy patients receiving levetiracetam (LEV) and valproic acid (VPA) monotherapy. Complete blood count panel, biochemical and hormonal parameters were investigated retrospectively at baseline and at 24 months in patients diagnosed with epilepsy at the Balıkesir University Medical Faculty pediatric neurology clinic, Türkiye, and started on LEV and VPA monotherapy between 01.08.2019 and 01.08.2022. Forty-nine patients were using LEV and 14 VPA. A statistically significant difference in terms of the complete blood count parameters mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) was observed in the cases using LEV between baseline and the 24th month of treatment (p=0.006, p=0.004). Among the cases using VPA, significant differences between baseline and the 24th month of treatment were determined in the complete blood count parameters red blood cell (RBC), MCV, and monocyte (MON)% values (p=0.004, p=0.022, and p=0.01). In conclusion, epilepsy treatment is a lengthy process in pediatric patients, and patients need to be monitored using hematological and biochemical parameters at specific intervals in terms of potential seizure drug side effects. [ABSTRACT FROM AUTHOR]