Paralytic ileus in a patient on clozapine therapy showing an inverted clozapine/norclozapine ratio after switching valproic acid to carbamazepine: a case report.

This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.

Autistic-like behaviour and changes in thalamic cell numbers a rat model of valproic acid-induced autism; A behavioural and stereological study.

The contribution of the thalamus to the development and behavioural changes in autism spectrum disorders (ASD), a neurodevelopmental syndrome, remains unclear. The aim of this study was to determine the changes in thalamic volume and cell number in the valproic acid (VPA)-induced ASD model using stereological methods and to clarify the relationship between thalamus and ASD-like behaviour. Ten pregnant rats were administered a single dose (600 mg/kg) of VPA intraperitoneally on G12.5 (VPA group), while five pregnant rats were injected with 5 ml saline (control group). Behavioural tests were performed to determine appropriate subjects and ASD-like behaviours. At P55, the brains of the subjects were removed. The sagittal sections were stained with cresyl violet and toluidine blue. The thalamic and hemispheric volumes with their ratios, the total number of thalamic cells, neurons and non-neuronal cells were calculated using stereological methods. Data were compared using a t-test and a Pearson correlation analysis was performed to examine the relationship between behaviour and stereological outcomes. VPA-treated rats had lower sociability and sociability indexes. There was no difference in social novelty preference and anxiety. The VPA group had larger hemispheric volume, lower thalamic volume, and fewer neurons. The highest percentage decrease was in non-neuronal cells. There was a moderate positive correlation between the number of non-neuronal cells and sociability, thalamic volume and the number of neurons as well as the time spent in the light box. The correlation between behaviour and stereological data suggests that the thalamus is associated with ASD-like behaviour.

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model.

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Low-frequency repetitive transcranial magnetic stimulation alleviates abnormal behavior in valproic acid rat model of autism through rescuing synaptic plasticity and inhibiting neuroinflammation.

Autism is a complex neurodevelopmental disorder with no effective treatment available currently. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising neuromodulation technique to treat autism. However, the mechanism how rTMS works remains unclear, which restrict the clinical application of magnetic stimulation in the autism treatment. In this study, we investigated the effect of low-frequency rTMS on the autistic-like symptoms and explored if this neuroprotective effect was associated with synaptic plasticity and neuroinflammation in the hippocampus. A rat model of autism was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats and male offspring were treated with 1 Hz rTMS daily for two weeks continuously. Behavior tests were performed to identify behavioral abnormality. Synaptic plasticity was measured by in vivo electrophysiological recording and Golgi-Cox staining. Synapse and inflammation associated proteins were detected by immunofluorescence and Western blot analyses. Results showed prenatal VPA-exposed rats exhibited autistic-like and anxiety-like behaviors, and cognitive impairment. Synaptic plasticity deficits and the abnormality expression of synapse-associated proteins were found in the hippocampus of prenatal VPA-exposed rats. Prenatal VPA exposure increased the level of inflammation cytokines and promoted the excessive activation of microglia. rTMS significantly alleviated the prenatal VPA-induced abnormalities including behavioral and synaptic plasticity deficits, and excessive neuroinflammation. TMS maybe a potential strategy for autism therapy via rescuing synaptic plasticity and inhibiting neuroinflammation.

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.

Fluvoxamine Ameliorates the Damage to the Neuro-Behavioral Status of Rats Caused by the Administration of Valproic Acid by Preventing Cognitive Memory Deficits and Decreased Hippocampal Cellular Proliferation.

Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as it inhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.

Evaluation of CYP2C19 Genetic Variant and Its Lack of Association with Valproic Acid Plasma Concentrations Among Zhuang and Han Schizophrenia Patients in Guangxi.

Purpose: To investigate the CYP2C19 genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between CYP2C19 genetic variants and standardized blood levels of Valproic Acid (VPA) in schizophrenic patients, and evaluate the effects of age, gender, and Body Mass Index (BMI) on standardized VPA blood concentrations. Patients and Methods: Between February and December 2022, 192 Zhuang and Han schizophrenia patients treated with VPA were studied. Steady-state VPA concentrations were determined using homogeneous enzyme immunoassays, and CYP2C19 *1, *2, and *3 loci via q-PCR. CYP2C19 genotype distributions between Zhuang and Han groups in Nanning were compared using chi-square tests and contrasted with other ethnicities. Non-parametric tests analyzed VPA variations, identifying critical factors through multivariate stepwise regression. Results: The study identified five CYP2C19 genotypes at the *2 and *3 loci, with the *3/*3 genotype absent in both cohorts. The CYP2C19 distribution in Guangxi Zhuang and Han mirrors, yet diverges significantly from Hui and Kazakh groups. Among 192 subjects, VPA blood levels remained consistent across metabolic types and ages 18-60 but varied significantly by gender. Multivariate analysis revealed gender and BMI as significant factors, overshadowing CYP2C19 genotype and age. Conclusion: In Guangxi, CYP2C19 genetic variants in Zhuang and Han schizophrenia patients demonstrate statistically indistinguishable allelic and metabolic distributions. Gender and BMI can influence standardized VPA blood concentrations in schizophrenia patients. However, in our study cohort, the CYP2C19 genotype and age are not the primary determinants of standardized VPA blood levels.

Valproic Acid Causes Redox-Regulated Post-Translational Protein Modifications That Are Dependent upon P19 Cellular Differentiation States.

Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted. We hypothesize that VPA causes redox-sensitive post-translational protein modifications that are dependent upon cellular differentiation states. Undifferentiated P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, prior to VPA exposure. Undifferentiated cells treated with VPA alone exhibited an oxidized glutathione redox couple and increased overall protein oxidation, whereas differentiated neurons were protected from protein oxidation via increased S-glutathionylation. Pretreatment with D3T prevented the effects of VPA exposure in undifferentiated cells. Taken together, our findings support redox-sensitive post-translational protein alterations in undifferentiated cells as a mechanism of VPA-induced developmental toxicity and propose NRF2 activation as a means to preserve proper neurogenesis.

Ethnic Aspects of Valproic Acid P-Oxidation.

The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review demonstrated the variability in allelic frequencies of low-functioning and non-functional single nucleotide variants in genes encoding key isoenzymes of valproic acid P-oxidation in the liver across different ethnic/racial groups. The sensitivity and specificity of pharmacogenetic testing panels for predicting the rate of metabolism of valproic acid by P-oxidation can be increased by prioritizing the inclusion of the most common risk allele characteristic of a particular population (country).

Long-Term Epigenetic Regulation of Foxo3 Expression in Neonatal Valproate-Exposed Rat Hippocampus with Sex-Related Differences.

Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes remain unclear. We used qPCR-based gene expression and epigenetics tools and Western blotting in the hippocampi of neonatal valproic acid-exposed animals at 4 weeks of age and conducted the social interaction test to detect behavioral changes. Significant alterations in gene expression were observed in males, particularly concerning mRNA expression of Foxo3, which was significantly associated with behavioral changes. Moreover, notable differences were observed in H3K27ac chromatin immunoprecipitation, quantitative PCR (ChIP-qPCR), and methylation-sensitive restriction enzyme-based qPCR targeting the Foxo3 gene promoter region. These findings provide evidence that epigenetically regulated hippocampal Foxo3 expression may influence social interaction-related behavioral changes. Furthermore, identifying sex-specific gene expression and epigenetic changes in this model may elucidate the sex disparity observed in autism spectrum disorder prevalence.

Comparison of predictive validity of two autism spectrum disorder rat models: Behavioural investigations.

The valproic acid model has been shown to reproduce ASD-like behaviours observed in patients and is now widely validated for construct, face, and predictivity as ASD model in rat. The literature agrees on using a single exposition to 500 mg/kg of VPA at gestational day 12 to induce ASD phenotype with the intraperitoneal route being the most commonly used. However, some studies validated this model with repeated exposure by using oral route. The way of administration may be of great importance in the induction of the ASD phenotype and a comparison is greatly required. We compared two ASD models, one induced by a unique IP injection of 500 mg/kg of body weight at GD12 and the other one by repeated PO administration of 500 mg/kg of body weight/day between GD11 and GD13. The behavioural phenotypes of the offspring were assessed for the core signs of ASD (impaired social behaviour, stereotypical/repetitive behaviours, sensory/communication deficits) as well as anxiety as comorbidity, at developmental and juvenile stages in both sexes. The VPA IP model induced a more literature-compliant ASD phenotype than the PO one. These results confirmed that the mode of administration as well as the window of VPA exposure are key factors in the ASD-induction phenotype. Interestingly, the effects of VPA administration were similar at the developmental stage between both sexes and then tended to differ later in life.

Reversible central respiratory events induced by valproic acid treatment: A case report.

Valproic acid holds a prominent position as the primary therapeutic option for epilepsy cases. The utilization of antiepileptic agents like valproic acid has been linked to disturbances in sleep architecture. Although scant, there exists a subset of studies that allude to the potential manifestation of sleep apnea as an adverse effect of valproic acid administration. In this context, we present a case report of a 76-year-old man with a past medical history of arterial hypertension, atrial fibrillation, and obstructive sleep apnea syndrome treated with continuous positive airway pressure since 2020. Following the commencement of valproic acid treatment for vascular epilepsy, obstructive sleep apnea evolved toward to central sleep apnea. This case exemplifies the need for a heightened awareness of the multifaceted implications of valproic acid therapy on sleep patterns.

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.

Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.

RATIONALE: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined. OBJECTIVES: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients. METHODS: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors. RESULTS: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (ß = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (ß = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction. CONCLUSIONS: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients.

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma.

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

Administration of Atosiban, an oxytocin receptor antagonist, ameliorates autistic-like behaviors in a female rat model of valproic acid-induced autism.

Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat's model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.

Involvement and regulation of the left anterior cingulate cortex in the ultrasonic communication deficits of autistic mice.

Introduction: Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC) is a core brain region for social function. Whether it contributes to the defects of social communication in ASD and whether it could be physiologically modulated to improve social communication have been poorly investigated. This study is aimed at addressing these questions. Methods: Fragile X mental retardation 1 (FMR1) mutant and valproic acid (VPA)-induced ASD mice were used. Male-female social interaction was adopted to elicit ultrasonic vocalization (USV). Immunohistochemistry was used to evaluate USV-activated neurons. Optogenetic and precise target transcranial magnetic stimulation (TMS) were utilized to modulate anterior cingulate cortex (ACC) neuronal activity. Results: In wild-type (WT) mice, USV elicited rapid expression of c-Fos in the excitatory neurons of the left but not the right ACC. Optogenetic inhibition of the left ACC neurons in WT mice effectively suppressed social-induced USV. In FMR1-/-- and VPA-induced ASD mice, significantly fewer c-Fos/CaMKII-positive neurons were observed in the left ACC following USV compared to the control. Optogenetic activation of the left ACC neurons in FMR1-/- or VPA-pretreated mice significantly increased social activity elicited by USV. Furthermore, precisely stimulating neuronal activity in the left ACC, but not the right ACC, by repeated TMS effectively rescued the USV emission in these ASD mice. Discussion: The excitatory neurons in the left ACC are responsive to socially elicited USV. Their silence mediates the deficiency of social communication in FMR1-/- and VPA-induced ASD mice. Precisely modulating the left ACC neuronal activity by repeated TMS can promote the social communication in FMR1-/- and VPA-pretreated mice.

Valproic Acid-Induced Thrombocytopenia in Treatment-Resistant GABRB3 Genetic Epilepsy: A Case Report.

Valproic acid (VPA) is utilized in the management of a variety of seizure and mood disorders. A rare side effect of this medication is dose-dependent thrombocytopenia. In this case, we report a patient with a treatment-resistant epilepsy GABRB3 genetic variant phenotype who was admitted for sepsis and found to have significant thrombocytopenia with clinical manifestations of epistaxis and easy bruising, which was found to be due to VPA use rather than secondary to other clinical pathologies. The patient's clinical condition improved with supportive treatment including fluid rehydration. Platelet counts normalized after a transfusion and holding of her valproate. She experienced breakthrough seizures despite the initiation of diazepam. The decision was made to restart VPA per Neurology consult recommendations for better seizure control. She had no breakthrough seizures reported after restarting VPA in the hospital. This case highlights the importance of monitoring antiseizure medication side effects, especially in populations at higher risk due to treatment resistance.

Human Wharton's jelly-derived mesenchymal stromal stem cells preconditioned with valproic acid promote cell migration and reduce renal inflammation in ischemia/reperfusion injury by activating the AKT/P13K and SDF1/CXCR4 pathways.

OBJECTIVE: To determine whether WJ-MSCs pretreated with VPA would enhance their migration to improve functional recovery of renal IRI in rats. METHODS: 150 Sprague-Dawley rats were distributed into 5 groups; Sham, IRI, WJ-MSC, VPA, and WJ-MSCs + VPA. 10 rats were sacrificed after 3, 5, and 7 days. Role of WJ-MSCs pretreated with VPA was evaluated by assessment of renal function, antioxidant enzymes together with renal histopathological and immunohistopathological analyses and finally by molecular studies. RESULTS: WJ-MSCs and VPA significantly improved renal function and increased antioxidants compared to IRI group. Regarding gene expression, WJ-MSCs and VPA decreased BAX and TGF-ß1, up-regulated Akt, PI3K, BCL2, SDF1α, and CXCR4 related to IRI. Additionally, WJ-MSCs pretreated with VPA improved the measured parameters more than either treatment alone. CONCLUSION: WJ-MSCs isolated from the umbilical cord and pretreated with VPA defended the kidney against IRI by more easily homing to the site of injury.

Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents.