Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines.

The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have been partially attributed to the epigenetic disinhibition of the transcription repressor RE1-Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). Additionally, VPA changes post-traumatic brain injury (TBI) brain metabolism to create a neuroprotective environment. To address the interconnection of neuroprotection, metabolism, inflammation and REST/NRSF after TBI, we subjected C57BL/6N mice to experimental TBI and intraperitoneal VPA administration or vehicle solution at 15 min, 1, 2, and 3 days post-injury (dpi). At 7 dpi, TBI-induced an up-regulation of REST/NRSF gene expression and HDACi function of VPA on histone H3 acetylation were confirmed. Neurological deficits, brain lesion size, blood-brain barrier permeability, or astrogliosis were not affected, and REST/NRSF target genes were only marginally influenced by VPA. However, VPA attenuated structural damage in the hippocampus, microgliosis and expression of the pro-inflammatory marker genes. Analyses of plasma lipidomic and polar metabolomic patterns revealed that VPA treatment increased lysophosphatidylcholines (LPCs), which were inversely associated with interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) gene expression in the brain. The results show that VPA has mild neuroprotective and anti-inflammatory effects likely originating from favorable systemic metabolic changes resulting in increased plasma LPCs that are known to be actively taken up by the brain and function as carriers for neuroprotective polyunsaturated fatty acids.

Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

Transcriptome analysis of Burkitt lymphoma cells treated with anti-convulsant drugs that are inhibitors of Epstein-Barr virus lytic reactivation.

Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression.

Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]). CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Treatments and Outcomes Among Patients with Sydenham Chorea: A Meta-Analysis.

Importance: Sydenham chorea is the most common acquired chorea of childhood worldwide; however, treatment is limited by a lack of high-quality evidence. Objectives: To evaluate historical changes in the clinical characteristics of Sydenham chorea and identify clinical and treatment factors at disease onset associated with chorea duration, relapsing disease course, and functional outcome. Data Sources: The systematic search for this meta-analysis was conducted in PubMed, Embase, CINAHL, Cochrane Library, and LILACS databases and registers of clinical trials from inception to November 1, 2022 (search terms: [Sydenham OR Sydenham's OR rheumatic OR minor] AND chorea). Study Selection: Published articles that included patients with a final diagnosis of Sydenham chorea (in selected languages). Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Individual patient data on clinical characteristics, treatments, chorea duration, relapse, and final outcome were extracted. Data from patients in the modern era (1945 through 2022) were entered into multivariable models and stratified by corticosteroid duration for survival analysis of chorea duration. Main Outcomes and Measures: The planned study outcomes were chorea duration at onset, monophasic course (absence of relapse after ≥24 months), and functional outcome (poor: modified Rankin Scale score 2-6 or persisting chorea, psychiatric, or behavioral symptoms at final follow-up after ≥6 months; good: modified Rankin Scale score 0-1 and no chorea, psychiatric, or behavioral symptoms at final follow-up). Results: In total, 1479 patients were included (from 307 articles), 1325 since 1945 (median [IQR] age at onset, 10 [8-13] years; 875 of 1272 female [68.8%]). Immunotherapy was associated with shorter chorea duration (hazard ratio for chorea resolution, 1.51 [95% CI, 1.05-2.19]; P = .03). The median chorea duration in patients receiving 1 or more months of corticosteroids was 1.2 months (95% CI, 1.2-2.0) vs 2.8 months (95% CI, 2.0-3.0) for patients receiving none (P = .004). Treatment factors associated with monophasic disease course were antibiotics (odds ratio [OR] for relapse, 0.28 [95% CI, 0.09-0.85]; P = .02), corticosteroids (OR, 0.32 [95% CI, 0.15-0.67]; P = .003), and sodium valproate (OR, 0.33 [95% CI, 0.15-0.71]; P = .004). Patients receiving at least 1 month of corticosteroids had significantly lower odds of relapsing course (OR, 0.10 [95% CI, 0.04-0.25]; P < .001). No treatment factor was associated with good functional outcome. Conclusions and Relevance: In this meta-analysis of treatments and outcomes in patients with Sydenham chorea, immunotherapy, in particular corticosteroid treatment, was associated with faster resolution of chorea. Antibiotics, corticosteroids and sodium valproate were associated with a monophasic disease course. This synthesis of retrospective data should support the development of evidence-based treatment guidelines for patients with Sydenham chorea.

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway.

BACKGROUND: According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid. METHODS: In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring. RESULTS: The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. CONCLUSION: Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Social Behavior in Animal Models of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and stereotyped, repetitive patterns of behaviors, limited interests, and cognitive impairment. Especially, social deficit has been considered a core feature of ASD. Because of the limitations of the experimental approach in humans, valid animal models are essential in an effort to identify novel therapeutics for social deficits in ASD. The genetic and environmental factors are clinically relevant to the pathophysiology of ASD. Epidemiological studies demonstrate environmental interventions such as prenatal exposure to valproic acid (VPA). Prenatal exposure to VPA represents a robust model of ASD exhibiting face, construct, and predictive validity. Here, we introduce protocols of the social interaction test and the three-chamber test for evaluating social deficits in mice prenatally exposed to VPA.

Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross-sectional study.

INTRODUCTION: The debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM. METHODS: The present cross-sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non-remission on Young's mania rating scale (YMRS). RESULTS: The intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non-remission, but the comparison between the two ROC analyses was not statistically significant. CONCLUSION: Free valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring.

Sex-dependent alterations of inflammatory factors, oxidative stress, and histopathology of the brain-gut axis in a VPA-induced autistic-like model of rats.

INTRODUCTION: In this study, we aimed to investigate the inflammatory factors, oxidative stress, and histopathological consequences of the brain-gut axis in male and female rats prenatally exposed to VPA. METHODS: Pregnant Wistar rats were randomly divided into two groups. The animals received saline, and valproic acid (VPA) (600 mg/kg, i.p.) on embryonic day 12.5 (E12.5). All offspring were weaned on postnatal day 21, and the experiments were done in male and female rats on day 60. The brain and intestine tissues were extracted to assess histopathology, inflammation, and oxidative stress. RESULTS: An increase of interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) and a decrease of interleukin-10 (IL-10) were observed in the two sexes and two tissues of the autistic rats. In the VPA-exposed animals, malondialdehyde (MDA) and protein carbonyl (PC) increased in the brain of both sexes and the intestines of only the males. The total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT) significantly decreased in both tissues of male and female autistic groups. Histopathological evaluation showed that the %apoptosis of the cortex in the autistic male and female groups was more than in controls whereas this parameter in the CA1 and CA3 was significant only in the male rats. In the intestine, histopathologic changes were seen only in the male autistic animals. CONCLUSION: The inflammatory and antioxidant factors were in line in the brain-gut axis in male and female rats prenatally exposed to VPA. Histopathological consequences were more significant in the VPA-exposed male animals.

Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles.

Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness of low-frequency repeated TMS (LF-rTMS) in a rat model of autism spectrum disorder (ASD) induced by prenatal valproic acid (VPA) exposure through the injection of superparamagnetic iron oxide nanoparticles (SPIONs). For the induction of ASD, we administered prenatal VPA (600 mg/kg, I.P.) on the 12.5th day of pregnancy. At postnatal day 30, SPIONs were injected directly into the lateral ventricle of the brain. Subsequently, LF-rTMS treatment was applied for 14 consecutive days. Following the treatment period, behavioral analyses were conducted. At postnatal day 60, brain tissue was extracted, and both biochemical and histological analyses were performed. Our data revealed that prenatal VPA exposure led to behavioral alterations, including changes in social interactions, increased anxiety, and repetitive behavior, along with dysfunction in stress coping strategies. Additionally, we observed reduced levels of SYN, MAP2, and BDNF. These changes were accompanied by a decrease in dendritic spine density in the hippocampal CA1 area. However, LF-rTMS treatment combined with SPIONs successfully reversed these dysfunctions at the behavioral, biochemical, and histological levels, introducing a successful approach for the treatment of ASD.

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

OBJECTIVE: This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA. METHODS: We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group. RESULTS: The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 µg/mL) compared with that before co-administration (88.8 ± 13.6 µg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 µg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291). CONCLUSIONS: In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study.

INTRODUCTION: There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome. MATERIAL AND METHODS: A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors. RESULTS: There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862). CONCLUSIONS: Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Effectiveness analysis of three-drug combination therapies for refractory focal epilepsy.

Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical approach, especially in patients receiving polytherapy. We aimed to analyze the effectiveness of various three-drug combinations in a group of patients with DRE under real-world conditions. This single-center, longitudinal observational study investigated patients with drug-resistant focal epilepsy who received three-drug regimens in the outpatient clinic of Tongji Hospital from September 2019 to December 2022. The effectiveness of each triple regimen was evaluated by the seizure-free rate and within-patient ratio of the seizure frequency (a seizure frequency ratio [SFR]<1 indicated superior efficacy). The independent t-test or Mann-Whitney U test was used for effectiveness analysis, and P values were adjusted by the Benjamini-Hochberg method for multiple comparisons. A total of 511 triple trials comprising 76 different regimens were conducted among 323 enrolled patients. Among these triple regimens, lamotrigine (LTG)/valproic acid (VPA)/topiramate (TPM) was the most frequently prescribed (29.4%, n â€‹= â€‹95). At the last clinical visit, 14.9% (n â€‹= â€‹48) of patients achieved seizure freedom after receiving triple therapy. LTG/VPA/TPM and LTG/VPA/levetiracetam (LEV) exhibited the highest seizure-free rates at 17.9% and 12.8%, respectively. These two regimens also had significantly lower median SFRs of 0.48 (interquartile range [IQR], 0.17-0.85; adjusted P â€‹< â€‹0.001) and 0.63 (IQR, 0.21-1.04; adjusted P â€‹< â€‹0.01), respectively. LTG/VPA/perampanel (PER) was another promising regimen that showed marginal effectiveness (median SFR â€‹= â€‹0.67; adjusted P â€‹= â€‹0.053). LTG/VPA/phenobarbital had the highest incidence of regimen-specific side effects (40.0%, 4/10), while the incidence of side effects from LTG/VPA/LEV was minimal (5.1%, 2/39). In conclusion, LTG/VPA/TPM and LTG/VPA/LEV exhibited superior efficacy and good tolerability in treating patients with DRE. Our results provide preliminary insights into the selection of ASMs for three-drug combination therapies in this clinically challenging population.

Reversal of Valproate-Induced Major Salivary Gland Changes By Moringa Oleifera Extract in Rats.

This study aimed to explore the potential protective impacts of Moringa oleifera extract on major alteration in salivary glands of rats exposed to sodium valproate (VA). Groups were defined as control, control+moringa extract, sodium valproate, and sodium valproate+moringa extract. Antioxidant and oxidant status, activities of digestive and metabolic enzymes were examined. VA treatment led to various biochemical changes in the salivary glands, including decreased levels of antioxidants like glutathione, glutathione-S-transferase, and superoxide dismutase (except for sublingual superoxide dismutase). Conversely, a decrease in alpha-amylase, alkaline and acid phosphatase, lactate dehydrogenase, protease, and maltase activities were observed. The study also demonstrated that VA induces oxidative stress, increases lipid peroxidation, sialic acid, and nitric oxide levels in the salivary glands. Total oxidant capacity was raised in all glands except in the sublingual gland. The electrophoretic patterns of proteins were similar. Moringa oleifera extract exhibited protective properties, reversing these VA-induced biochemical changes due to its antioxidant and therapeutic attributes. This research suggests that moringa extract might serve as an alternative treatment approach for individuals using VA and experiencing salivary gland issues, although further research is necessary to confirm these findings in human subjects.

Sex differences in the susceptibility to valproic acid-associated liver injury in epileptic patients.

BACKGROUND: Valproic acid has been widely used as an antiepileptic drug for several decades. Long-term valproic acid treatment is usually accompanied by liver injury. Although both men and women are susceptible to valproic acid-associated liver injury, hepatotoxicity differs between the sexes. However, the mechanisms underlying sex differences in valproic acid-associated liver injury remain unclear. METHODS: To explore potential risk factors for the susceptibility to valproic acid-associated liver injury, 231 pediatric patients with epilepsy (119 males, 112 females) were enrolled for laboratory and genetic analysis. RESULTS: Heterozygous genotype of catalase C-262T (P = 0.045) and the concentrations of glutathione (P = 0.002) and thiobarbituric acid-reactive substances (P = 0.011) were associated with the sex-specific susceptibility to valproic acid-associated liver injury. Meanwhile, logistic regression analysis revealed that carriers of heterozygous genotype of catalase C-262T (P = 0.010, odds ratio: 4.163; 95 percent confidence interval 1.400 - 7.378), glutathione concentration (P = 0.001, odds ratio: 2.421; 95 percent confidence interval 2.262 - 2.591) and male patients (P = 0.005, odds ratio: 1.344; 95% confidence interval 0.782 - 2.309) had a higher risk for valproic acid-associated liver injury. DISCUSSION: The mechanism underlying valproic acid-induced hepatotoxicity remains unclear. Additionally, factors that may contribute to the observed differences in the incidence of hepatotoxicity between males and females have yet to be defined. This study identifies several genetic factors that may predispose patients to valproic acid-associated hepatotoxicity. LIMITATIONS: This relatively small sample size of children with one ethnicity some of whom were taking other antiepileptics that are potentially hepatotoxic. CONCLUSION: Catalase C-262T genotype, glutathione concentration and gender (male) are potential risk factors for the susceptibility to valproic acid-associated liver injury.

[Experimental study of the influence of phenozanic acid and its combination with valproic acid on the development of the epileptic system]. / Izuchenie vliyaniya fenozanovoi kisloty i ee kombinatsii s val'proevoi kislotoi na razvitie epilepticheskoi sistemy v eksperimente.

OBJECTIVE: To study the effect of phenosanic acid (PA) and its combination with valproic acid (VA) on the development of the Epi system. MATERIAL AND METHODS: A model of focal chronic epilepsy in rats was created by applying metallic cobalt to the surface of the sensorimotor area of the cortex. Long-term electrodes were implanted in the sensorimotor cortex of the left and right hemispheres, the hippocampus, and the hypothalamus. The effect of PA (80 mg/kg) and its combination with VA (200 mg/kg) on discharge activity was carried out on the 2nd day and at the stage of generalization of the Epi system - on the 6th day. The stability of the Epi system on day 10 was assessed by provoking the development of epileptic status (Epi status) in response to the administration of thiolactone homocysteine (HMC) at a dose of 5.5 mmol/kg. RESULTS: In rats treated with PA, low discharge activity is observed, which is confirmed by the absence of EEG and motor manifestations of status epilepticus caused by HMC. PA does not suppress paroxysmal activity at the stages of development of the Epi system. VA significantly suppresses paroxysmal activity, but does not affect the formation of new foci of Epi activity in subcortical structures and the contralateral cortex. The epi system of rats treated with VA is characterized by high discharge activity by the 10th day of the experiment and lability to provocation of epi status. The combination of drugs is more pronounced than PA, but less than VA, reduces the numerical characteristics of paroxysmal activity in the brain structures of rats. CONCLUSION: PA when administered alone, in combination with VA, causes a slowdown in the generalization of convulsive foci of Epi activity and prevents the formation of a stable Epi system. VA, having a pronounced anticonvulsant effect, does not weaken the development of the Epi system in the model of focal cobalt-induced epilepsy.