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Valproic acid is an antiepileptic drug associated with skin-related issues like excessive hair growth, hair loss, and skin rashes. In contrast, Moringa oleifera, rich in nutrients and antioxidants, is gaining popularity worldwide for its medicinal properties. The protective properties of M. oleifera extract against skin-related side effects caused by valproic acid were investigated. Female rats were divided into control groups and experimental groups such as moringa, sodium valproate, and sodium valproate + moringa groups. A 70% ethanolic extract of moringa (0.3 g/kg/day) was given to moringa groups, and a single dose of sodium valproate (0.5 g/kg/day) was given to valproate groups for 15 days. In the skin samples, antioxidant parameters (such as glutathione, glutathione-S-transferase, superoxide dismutase, catalase, and total antioxidant capacity), as well as oxidant parameters representing oxidative stress (i.e. lipid peroxidation, sialic acid, nitric oxide, reactive oxygen species, and total oxidant capacity), were examined. Additionally, boron, hydroxyproline, sodium-potassium ATPase, and tissue factor values were determined. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was also carried out for protein analysis in the skin samples. The results showed that moringa could increase glutathione, total antioxidant capacity, sodium-potassium ATPase, and boron levels, while decreasing lipid peroxidation, sialic acid, nitric oxide, total oxidant capacity, reactive oxygen species, hydroxyproline, and tissue factor levels. These findings imply that moringa possesses the potential to mitigate dermatological side effects. [ABSTRACT FROM AUTHOR]

Our goal is to create a population pharmacokinetic (PK) model and identify the best loading dose (LD) of intravenous valproic acid for hospitalized Thai patients. Data from patients who received intravenous valproic acid and underwent measurement of serum valproic acid concentrations during hospitalization were collected retrospectively. A nonlinear mixed‐effects modeling approach was conducted to estimate the PK parameters of valproic acid. Covariates affecting the PK parameters of valproic acid were examined and ranked based on their impact on the model's performance. Monte Carlo simulations of 1000 patients were conducted to estimate the optimal LD of valproic acid. A total of 120 hospitalized patients (51.7% male) with 167 valproic acid concentrations were included in the study. A linear one‐compartment model with constant residual error was the best base model. An age‐covariate model was the best predictor of valproic acid clearance (CL). The typical values of CL and volume of distribution for valproic acid were 0.77 L/h and 14.56 L, respectively. The LD of 1000‐1200 mg intravenous was identified as the pragmatic option as an empirical regimen for hospitalized Thai patients. The recommended time to initiate maintenance dose (MD) is 4‐8 h following the LD. The population PK model and optimal LD of valproic acid in hospitalized Thai patients has been established, and it may be advisable to initiate the MD at a later time for the elderly. [ABSTRACT FROM AUTHOR]

Valproic acid (VA) is a broad-spectrum anticonvulsant agent that acts through several molecular mechanisms to control different types of seizures. The main concern of the drug is its liver toxicity. Considering the regulatory roles of the Farnesoid nuclear receptors and the nuclear transcription factor Nrf2 in modifying and neutralizing the harmful effects of oxidative damage, the present study was designed to evaluate the role of FXR-Nrf2 and some downstream target gene alterations in hepatotoxicity induced by VA. Thirty-five eight-week-old male albino mice were randomly divided into five groups, including a control group, and four groups were assigned to receive VA (300 mg/kg/day; oral) for 3, 7, 10, and 14 days. Serum levels of ALT, AST, ALP, and total and direct bilirubin (TB, DB) were measured. Liver histology and the expression of FXR, Nrf2, α-GST, SOD, and TNF-α were assessed using H&E staining and real-time RT-PCR techniques. Maximum extent of biochemical and histopathological damage was observed on the 14th day, but changes in the expression of FXR, Nrf2, α-GST, and SOD were seen at three points: a significant upregulation on the 3rd day, a remarkable downregulation on the 10th day, and a second-time upregulation on the 14th day. In conclusion, considering the observed dysregulation in FXR-Nrf2 cascade expression during VA administration, it seems that downregulation in this pathway and consequently its downstream detoxification and antioxidant genes may play a role in liver toxicity. [ABSTRACT FROM AUTHOR]

Marketed valproic acid formulations use its solid salt forms, which are hygroscopic and difficult to handle. The current study focuses on developing valproic acid nanoemulsion using the physically most stable liquid form of the drug and evaluating its anticancer potential. Valproic acid is a histone deacetylase inhibitor having anticancer potential.The valproic acid nanoemulsion was formulated using a facile and scalable homogenization process. The emulsion stabilization was achieved through viscosity-enhancing polymer polyvinylpyrrolidone K-30 and tween 80. The formulation was optimized using the Box-Behnken model of design of experiments and was evaluated for efficacy and safety in cancer and fibroblast cell lines, respectively.The optimized emulsion showed particle size below 150 nm, polydispersity index below 0.3, zeta potential near − 8.5 mV, density 0.9923 g/cm3, viscosity 2.06 poise, creaming index below 20, drug content 100.37%w/v and acceptable stability at accelerated environmental conditions. Overall, under all the studied conditions of in vitro dissolution and ex vivo permeability, drug release from emulsion was found better than the free drug and comparable to the marketed solution of sodium valproate. The cytotoxicity studies demonstrated improved IC50 values for breast and lung cancer cell lines, with selectivity for cancer cells.The valproic acid nanoemulsion was prepared using its physically stable liquid form. The combination of polymer polyvinylpyrrolidone K-30 and tween 80 demonstrated the desired stabilization of the dispersed phase of the emulsion. The formulated nanoemulsion effectively potentiated valproic acid's anticancer activity in cell culture assays. [ABSTRACT FROM AUTHOR]

Background:Autism spectrum disorder (ASD), a neurodevelopmental disease, is described by problems with social interaction and communication that arise at an early age. The only approved drugs for the treatment of ASD are risperidone and aripiprazole. Objectives:The aim of the article is to explore the potential therapeutic effects of sitagliptin on the induced offspring model of autism. Also, to evaluate the effect of sitagliptin on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Materials and Methods:We induced the disorder in mice by injecting pregnant mice with sodium valproate (600 mg/kg). Prenatal sodium valproate–exposed mice were split into four different groups, with two experimental groups taking sitagliptin (10 mg/kg and 15 mg/kg) and risperidone (1 mg/kg), and a control group receiving normal saline. Behavioral tests, including social interaction assessments were divided into three phases: habituation, familiarization, and testing, and lasted for 15 min, were conducted on postnatal day 65; also, anti-inflammatory marker assessments like TNF-α and IL-6 were conducted on postnatal day 66. Results:The study found that sitagliptin significantly improved behavioral disorders (social communication) and reduced neuro-inflammation in the brain. Sitagliptin therapy forcefully enhanced the cognitive function of ASD mice by regulating neurogenesis that could be connected with the powerful antioxidant and anti-inflammatory actions that sitagliptin possesses. Conclusion:Sitagliptin showed potent anxiolytic and anti-inflammatory properties that improved behavioral activities in the mice. These findings suggest that sitagliptin could be promising a potential treatment option for individuals with ASD.

Objective: Epilepsy affects over 1% of the global population. Polypodium vulgare L. has emerged in studies, suggesting its potential antiepileptic effect. This study evaluated the anticonvulsant efficacy of the hydroalcoholic extract of Polypodium vulgare L. in a pentylenetetrazole (PTZ)-induced epilepsy model in rats. This research aimed to determine the optimal dosage for delaying seizure onset and reducing seizure severity. This study investigated whether the active compounds offer a viable alternative for epilepsy management, mainly through their potential interaction with GABAergic mechanisms. Methods: We randomly selected four groups of 10 and 2 groups of 8 male Wistar laboratory rats. The reference and control groups received PTZ and distilled water, respectively. In contrast, experimental groups 1 and 2 received the hydroalcoholic extract of Polypodium vulgare L. at doses of 300 and 500 mg per kg of body weight. Experimental groups 3 and 4 received 150 and 300 mg per kg dose.Chemical kindling was induced in all groups via intraperitoneal injection of PTZ. Data analysis was conducted using Statistical Package for the Social Sciences version 20 software. Results: The hydroalcoholic extract of Polypodium vulgare L. exerted a pronounced mitigating effect on convulsions induced by PTZ administration, specifically at a dosage of 300 mg/kg of body weight. It effectively prolonged the time necessary for seizure onset. Conclusion: The administration of a 300 mg dose of the hydroalcoholic extract of Polypodium vulgare L. demonstrated superior efficacy compared with its 500 mg counterpart and both the 300 and 150 mg doses of sodium valproate in addressing PTZ-induced epilepsy. The results suggest that the hydroalcoholic extract of Polypodium vulgare L. has promise as an effective treatment for epilepsy.

Status epilepticus (SE) is a life-threatening neurological condition with significant mortality. Rapid management is essential to minimize the mortality and disability of SE. Two recent trials provided evidence to guide SE management in early and established stages. The Rapid Anticonvulsant Medication Prior To Arrival Trial (RAMPART, 2011) showed that intramuscular midazolam is a better alternative for early convulsive SE in prehospital settings. The Established Status Epilepticus Treatment Trial (ESETT, 2020) supported the use of sodium valproate and levetiracetam as second-line treatment for its efficacy and shorter administration time. However, there are challenges to revising the status epilepticus management in resource-limited settings, in pre-hospital, first- and second-line treatment, as well as management of refractory and super-refractory SE. These challenges included restrictions or lack of training in the administration of benzodiazepine in the prehospital setting, limited availability and accessibility of newer antiseizure medications (ASMs) in emergency departments and smaller hospitals, and low clinicians’ awareness of the latest evidence. A collaborative effort to educate, improve awareness, and make certain ASMs more readily available is recommended to achieve a better clinical outcome in SE.

Objective: Epilepsy affects over 1% of the global population. Polypodium vulgare L. has emerged in studies, suggesting its potential antiepileptic effect. This study evaluated the anticonvulsant efficacy of the hydroalcoholic extract of Polypodium vulgare L. in a pentylenetetrazole (PTZ)-induced epilepsy model in rats. This research aimed to determine the optimal dosage for delaying seizure onset and reducing seizure severity. This study investigated whether the active compounds offer a viable alternative for epilepsy management, mainly through their potential interaction with GABAergic mechanisms. Methods: We randomly selected four groups of 10 and 2 groups of 8 male Wistar laboratory rats. The reference and control groups received PTZ and distilled water, respectively. In contrast, experimental groups 1 and 2 received the hydroalcoholic extract of Polypodium vulgare L. at doses of 300 and 500 mg per kg of body weight. Experimental groups 3 and 4 received 150 and 300 mg per kg dose. Chemical kindling was induced in all groups via intraperitoneal injection of PTZ. Data analysis was conducted using Statistical Package for the Social Sciences version 20 software. Results: The hydroalcoholic extract of Polypodium vulgare L. exerted a pronounced mitigating effect on convulsions induced by PTZ administration, specifically at a dosage of 300 mg/kg of body weight. It effectively prolonged the time necessary for seizure onset. Conclusion: The administration of a 300 mg dose of the hydroalcoholic extract of Polypodium vulgare L. demonstrated superior efficacy compared with its 500 mg counterpart and both the 300 and 150 mg doses of sodium valproate in addressing PTZ-induced epilepsy. The results suggest that the hydroalcoholic extract of Polypodium vulgare L. has promise as an effective treatment for epilepsy. [ABSTRACT FROM AUTHOR]

Background: Rauvolfia vomitoria (R. vomitoria) is a plant of economic importance due to its diverse ethnomedicinal properties, including the anticonvulsant effect. In this study, we studied the antiseizure and neuroprotective potentials of R. vomitoria extracts against pentylenetetrazol (PTZ)-induced kindling. Methods: Twenty-five adult Swiss mice (25–30 g) were assigned to five groups (n = 5): control group, PTZ treatment group, and PTZ treatment after receiving oral R. vomitoria crude extract (100 mg/kg), R. vomitoria phenol extract (50 mg/kg) or sodium valproate (15 mg/kg) every 48 h for 28 days. Seizure scores, cognitive behavioral tests including novel object test, Y-maze test, and the elevated plus maze test, as well as brain neurochemicals and histomorphology studies, were performed. Results: Compared with the control group, the PTZ group showed comparable body weight and durations in closed and open arms (P > 0.05), but preference for familiar objects, significant (P < 0.05) spontaneous alternation, increased monoamine oxidase activity and nitric oxide level, and Nissl chromatolysis in the temporal lobe structures including the cortex, hippocampus, and amygdala. R. vomitoria phenol extract pretreatment significantly (P < 0.05) reduced seizures, prevented adverse cognitive behaviors, decreased the nitric oxide level, and reduced the temporal lobe Nissl chromatolysis compared with the R. vomitoria crude extract pretreatment group and the sodium valproate pretreatment groups. Conclusions: Thus, R. vomitoria phenol extract showed promising results against seizures and potential for general brain protection, suggesting that the anticonvulsant property of R. vomitoria may be attributed to its phenol constituent. More studies are needed to delineate the mechanisms of its action. [ABSTRACT FROM AUTHOR]

Objective: to investigate the effects of sodium valproate on plasma concentrations of homocysteine, folate and vitamin B12 levels in epileptic patients with long-standing tonic-clonic seizures compared to newly diagnosed epileptic patients and healthy controls.Material and methods. The study included 90 participants (mean age 36.30±12.83 years, the majority (58.89%) were males) divided into three groups: 30 non-epileptic people (control Group 1), 30 newly diagnosed epileptic patients (Group 2), and 30 patients with long-term tonic-clonic seizures epilepsy (Group 3). In Group 3, patients received sodium valproate therapy. All subjects underwent clinical and neurological examinations. Differences in plasma levels of homocysteine, folic acid and vitamin B12 in three groups were investigated after 6 months of follow-up.Results. Homocysteine level in Groups 2 and 3 was increased; for Group 2 it was significantly higher than for Groups 3 and 1 (p=0.001). Plasma folate level in Groups 2 and 3 was decreased; for Group 3 it was significantly higher than for Group 2 and lower than for Group 1 (p=0.001). Vitamin B12 level in Groups 2 and 3 was decreased, but the difference was not significant (p=0.090). In Groups 1 and 2, a significant correlation was observed between the indicators.Conclusion. Sodium valproate аdministration might disrupt the homeostatic level of homocysteine, folate and vitamin B12 and cause irregularity of their plasma contents in epileptic patients with long-standing tonic-clonic seizures.

Objective: To explore the effect of black radish (Raphanus sativus L. var niger) root extract on liver enzymes, oxidative stress, and histopathological alterations in mice with sodium valproate-induced hepatotoxicity. Methods: Thirty-two mice were divided into four groups: the control group received drinking water by gavage, the second group was administered with 100 mg/kg of sodium valproate, the third group received 300 mg/kg of black radish root extract, and the fourth group was given both sodium valproate (100 mg/kg) and black radish root extract (300 mg/kg). After 28 days, the mice were euthanized, and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), along with liver malondialdehyde (MDA), reactive oxygen species (ROS), mitochondrial parameters, tumor necrosis factor-alpha (TNF-α) gene expression, and histopathological changes were assessed. Results: Sodium valproate caused hepatic damage in mice, characterized by elevated serum levels of liver enzymes, increased MDA and ROS levels and TNF-α gene expression, as well as histopathological alterations. The black radish root extract significantly alleviated sodium valproate-caused hepatic injury by decreasing the serum levels of ALT and AST, MDA, ROS, TNF-α gene expression, as well as mitochondrial impairment, but did not have a significant effect on sodium valproate-induced histopathological changes. Conclusions: The black radish root extract demonstrates protective effects against sodium valproate-induced liver injury, possibly through mitigating oxidative stress, mitochondrial impairment, and inflammatory mediator expression.

• Exploring the mechanism of tremor induction during VPA metabolism using gene variants as an entry point. • Genotyping UGT1A6 may help guide therapeutic decisions. • UGT1A6 A541G genotype can be used as one of the predictors to have VPA associated tremors. Individual susceptibility to sodium valproate (VPA)-induced tremors may be due to genetic polymorphisms in the gene encoding the uridine diphosphate glucuronosyltransferase (UGT) enzyme, which affec the drug's clinical efficacy and cause toxic side effects. This study aimed to investigate the association between UGT1A6 polymorphisms and VPA-induced tremors in patients with epilepsy. In total, 128 patients with epilepsy were enrolled. Patients with epilepsy who received VPA were divided into tremor and non-tremor groups. Polymerase chain reaction-restriction fragment length polymorphism was used to investigate the genotype of UGT1A6 polymorphisms. Carriers of the UGT1A6 A541G mutant genotype conferred a higher risk of tremor than wild-type carriers (odds ratio 2.128, P = 0.045). Logistic regression analysis showed that the A541G mutant genotype was a significant genetic risk factor for VPA-induced tremors. This suggests that individual susceptibility to VPA-induced tremors may result, at least partially, from genetic variation in UGT1A6 A541G. Patients with epilepsy carrying the UGT1A6 A541G mutant genotype may have VPA-induced tremors, and early detection of this genotype will help guide the clinical individualizsation of VPA treatment. [ABSTRACT FROM AUTHOR]

Vitamin B7(biotin) is not synthesized in our body and is retrieved from some food products like eggs, liver, pork and leafy vegetables and as well as microbes of gut. Deficiency of biotin majorly leads to loss of hair, rashes over skin, lethargy and seizures. It is noted that biotin is an anti-oxidant and negates free radical effects. Biotin is also involved in carbon dioxide metabolism and it might alter seizure threshold. Studies also suggest its effect on lipid metabolism as well. So, the primary objective of this study was to assess the efficacy of biotin in maximal electric shock (MES) induced generalized tonic-clonic seizures (GTCS) and pentylenetetrazole (PTZ) induced absence seizures. The secondary objective is to study the effect of combined treatment of biotin and sodium valproate on seizures as well as plasma lipid profile in rats. In our study 30 albino Wistar rats each were used in MES and PTZ model respectively. 30 rats were divided equally into following groups: I – distilled water (negative control) II – distilled water (positive control) III – sodium valproate (300 mg/kg) IV – biotin (10 mg/kg/day) V – biotin (10 mg/kg) + sodium valproate (150 mg/kg). We observed that the tonic hind limb extension was significantly reduced in the treatment group in MES model. Nitric oxide levels were also seen raised in combination group in MES model and all the treated groups in PTZ model. Biotin treated group showed increased high-density lipoproteins and reduced low density lipoproteins and triglycerides. Biotin had an additive effect to sodium valproate in both the models of epilepsy in rats. Further, it was also able to counteract hyperlipidemia cause by sodium valproate. [ABSTRACT FROM AUTHOR]

Abstract—Here we studied the effects of anti-epileptic substance GIZh-298 and the drug of comparison sodium valproate (NaV) on the contents of excitatory and inhibitory amino acids in the frontal cortex, hypothalamus, striatum, and hippocampus of the mouse brain in a model of generalized tonic-clonic seizures induced by maximal electroshock (MES). The levels of excitatory amino acids such as aspartate in the hypothalamus and glutamate in the hippocampus were decreased by 20.8 and 16.7%, respectively, and of inhibitory amino acids, such as glycine, GABA, and taurine were also decreased by 16–20% in average in those structures 5 min after the MES application indicating the exhaustion of aminoacidic neurotransmission. Intragastric administration of NaV at a dose of 200 mg/kg, which causes the anti-seizure effect, prevented the MES-induced decrease in the content of GABA and the GABA/glutamate ratio in the hypothalamus. NaV similarly decreased the aspartate level in the hypothalamus, striatum, and hippocampus in the intact group of mice and in mice after seizures. Intragastric administration of GIZh-298 at a dose of 60 mg/kg prevented the MES-evoked decrease in the GABA/glutamate ratio and the levels of GABA, glycine, and taurine in the hypothalamus. [ABSTRACT FROM AUTHOR]

Abstract—The study of the status of norepinephrine-, dopamine- and serotonergic neurotransmitter systems of BALB/C mice brain structures on 15 and 64 days of postnatal development (PD) in the model of autistic disturbances induced by injection of sodium valproate (SV, 400 mg/kg , s/c) to pregnant females was carried out using the HPLC/ED method. The level of both catechol- and indolamines in the brain structures of control mice at the age of 15 days was significantly lower than in adult animals at the age of 64 days. Prenatal administration of SV caused a decrease in all parameters of monoaminergic neurotransmission in the striatum of offspring at the age of 15 days but had no effect in other brain structures studied. Subsequently, the level of dopamine increased and by the 64th day of PD did not differ from the parameters of the control group. The parameters of the serotonergic system changed in a similar pattern, with the content of serotonin and the serotonin metabolite 5-OIAA in the striatum increasing gradually and reaching maximum values by the 64th day of PD. Our data allows to assume that the administration of SV to pregnant females affects the activity of the dopamine and serotonergic systems of the brain of the offspring causing a decrease in their activity in the striatum by the 15th day of PD followed by restoration to control values by the 64th day, which we previously observed in male pups. Thus, the patterns of dynamic changes in the neurochemical profile do not differ between males and females. [ABSTRACT FROM AUTHOR]

Sodium valproate (SV), as a common anti-epileptic drug, causes teratogenic effects on skeletal system by reactive oxygen species (ROS) generation. Herbal extract of Prosopis Farcta (PF), as a natural antioxidant necessary for many physiological activities, can probably ameliorate the teratogenic effects of SV during pregnancy. This study aimed to investigate the possible anti-teratogenic role of PF and Vitamin E (VE) on skeletal anomalies caused by SV in rat fetuses. Adult female rats (n=30) were categorized into 6 groups including control, SV (400 mg/kg), SV+VE (100mg/kg), and three doses of PF (50, 100, and 150 mg/kg) + SV. Each male rat mated with three adult female rats. The rats received SV, PF and VE at the 8th and 9th days of pregnancy by intraperitoneal injection. The animals were anesthetized and the laparotomy was applied at the 20th day of pregnancy. Skeletal abnormalities were analyzed using Alizarin red and Alcian blue staining. The expression of Runx2 and BMP2 genes was assessed using qPCRTM analysis in limbs bones. SV showed significant teratogenic effects including decrease in the rate of animal weight, Crown-rump length (CRL), various skeletal anomalies. The mRNA expression of Runx2 and BMP2 was also reduced in SV exposed animals. Administration of PF (especially 100mg/kg) in SV-exposed animals increased the weight of animals, CRL index, expression of Runx2 and BMP2, and reduced skeletal anomalies. The body weight, CRL index, Runx2 and BMP2 mRNA expression significantly increased, and skeletal anomalies decreased in VE group compared to the SV group. The results showed that PF could ameliorate the skeletal abnormalities and thus decreased osteogenic associated genes induced by SV in rat offsprings. [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]

Background: A myriad of therapeutic modalities for alopecia areata are available; however, none is of high level of evidence, creating an immense need for the evaluation of other treatment modalities, of which topical sodium valproate is of potential role via proposed decrease in beta-catenin breakdown, despite its well-known side effect of hair fall as an oral therapy. Objective: Evaluating the efficacy and the safety of sodium valproate (SV)-loaded nanospanlastics, in comparison to topical corticosteroids, this is the currently available gold standard topical treatment for patchy AA. Methodology: A total of 66 patients with patchy AA were randomly assigned to receive either topical mometasone furoate lotion or topical SV applied twice daily to all patches except a control patch, which was left untreated. Clinical, trichoscopic and biochemical assessments of beta-catenin tissue levels and Axin-2 gene expression were carried out at baseline and after 3 months. Results: Both therapeutic modalities were comparable. Potential efficacy was highlighted by significant improvement in the representative patch, the largest treated patch, to the control patch, the smallest untreated patch in both steroid and valproate groups (p = 0.027, 0.003 respectively). Both beta-catenin levels and Axin-2 gene expression were reduced after treatment, pointing to the inhibitory effect of dominating uncontrolled inflammatory milieu. Baseline beta-catenin was found to significantly negatively correlate with improvement in the representative patch in patients with baseline level above 0.42 ng/ml (p = − 0.042). Conclusion: Both topical SV and steroids are of comparable modest efficacy. Thus, further evaluation of SV is due in combination with intralesional steroids and other anti-inflammatory treatment modalities, together with developing individualized approaches based on baseline beta-catenin level. ClinicalTrials.gov Identifier: NCT05017454, . [ABSTRACT FROM AUTHOR]

This study assessed the inhibitory effect of sodium valproate (VPA) on apoptosis of cardiomyocytes in lethally scalded rats. The model of a 50% total body surface area (TBSA) third-degree full-thickness scald was produced, 48 male SD rats were randomly divided into three groups (n = 16), the sham group and the scald group were given an intraperitoneal injection of 0.25ml of saline, the scald +VPA group was given an intraperitoneal injection of VPA (300 mg/kg) after scalded, Each group was subdivided into two subgroups (n=8) according to the two observation time points of 3h and 6h after scald. Apoptotic cardiomyocytes were observed, and myocardial tissue levels of nitric oxide (NO), cysteine protease-3 (caspase-3) activity, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), BCL2/adenovirus E1B interacting protein 3 (BNIP3) and caspase-3 protein were measured. Compared with sham scald group, severe scald elevated CK-MB, cardiomyocyte apoptosis rate, caspase-3 activity and protein levels, NO content, and HIF-1α signalling pathway proteins; whereas VPA decreased CK-MB, cardiomyocyte apoptosis rate and inhibited HIF-1α signalling pathway protein expression. In conclusion, these results suggested that VPA inhibited early cardiomyocyte apoptosis and attenuated myocardial injury in lethally scalded rats, which may be related to the regulation of the HIF-1α signalling pathway. [ABSTRACT FROM AUTHOR]

Long-term therapy with antiseizure medications (ASMs) has been associated with metabolic consequences that lead to an increase in the risk of atherosclerosis in patients with epilepsy. This study was conducted to assess the effects of ASMs on vascular risk factors namely, serum Lipid profile and C-reactive protein (CRP) in epileptic patients and to assess the correlation between the duration of the ASMs, and carotid intima media thickness (IMT). Forty three adult patient participants who were receiving ASM monotherapy for more than 2 years and 43 control patients were enrolled in this study. All participants received measurement of common carotid artery (CCA) and IMT by B-mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index (BMI), serum lipid profile and CRP. The correlation between duration of ASM and average carotid IMT was calculated by using the Pearson's correlation coefficient method. The majority of subjects on phenytoin 8 (66.7%) were positive for CRP. There was an equal proportion of patients on carbamazepine who were equally positive 5(50%) and negative 5(50%) for CRP. There was a statistically significant association between phenytoin consumption and CRP positivity. There was positive correlation between duration of phenytoin consumption and average IMT. There was a strong positive correlation between duration of phenobarbitone consumption and average IMT and was statistically significant. Our results also suggest that long-term use of ASMs with prominent effects on the enzyme system, including Carbamazepine, phenytoin, sodium valproate or phenobarbitone may contribute to the progression of atherosclerosis in patients with epilepsy.

Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin‐binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self‐renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of sodium valproate combined with oxcarbazepine in the treatment of pediatric epilepsy and its effects on electroencephalogram, cognitive function and serum neurotrophic factors. Methods: 104 children with epilepsy from January 2019 to December 2022 were selected and divided into a monotherapy group (sodium valproate treatment) and a combination group (sodium valproate + oxcarbazepine treatment) based on different treatment methods, with 52 cases in each group. Evaluate and compare the clinical efficacy, EEG, cognitive function, serum neurofactors, and other indicators between the two groups. Results: After treatment, the frequency and duration of seizures in the combination group were lower than those in the monotherapy group (P<0.05), and the EEG showed a lower epileptiform discharge rate and total abnormality compared to the monotherapy group (P<0.05). The total effective rate of the combination group was 94.23%, higher than 71.15% in the monotherapy group (P<0.05). After treatment, the scores of VIQ, PIQ, and FIQ on the WISC-CR scale in both groups were higher than before treatment (P<0.05), while the increase in the combination group was greater than that in the monotherapy group (P<0.05). There was no difference in serum BDNF, NSE and S-100β between the two groups before treatment (P>0.05), but after treatment, the serum BDNF level in the combination group were higher than that in the monotherapy group, NSE and S-100β levels were lower than those in the monotherapy group (P<0.05). There was no difference in the total incidence of adverse reactions between the two groups (P>0.05). Conclusion: Valproate combined with oxcarbamazepine is effective in pediatric epilepsy, which can effectively relieve clinical symptoms, control abnormal brain discharge, improve cognitive function, regulate the level of serum nerve factors, and have good safety. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of different doses of valproate on serum thyroxine (TSH), prolactin ( PRL)and dopamine (DA) in patients with bipolar disorder (BPD) level of influence. Methods A total of 90 patients with BPD who received treatment in hospital from May 2020 to May 2022 were selected as the study objects. They were randomly divided into groups A, B and C, with 30 cases in all. Groups A, B and C were orally administered 10 mg/kg, 15 mg/kg and 20 mg/kg sodium valproate every day, respectively. The clinical efficacy, scores of mental diseases before and after treatment, indexes related to blood drug concentration, serum levels before and after treatment, indexes related to liver function and incidence of adverse reactions were compared among the three groups. Results There was no significant difference in the total effective rate among the three groups after treatment (P > 0.05). After treatment, the scores of the three groups were significantly improved compared with before treatment (P < 0.05). There was significant difference in the time to reach the stable state serum concentration (P < 0.05). There were no significant differences in TSH, PRL and DA levels among the three groups after treatment compared with before treatment (P > 0.05). ALT and AST levels in the three groups after treatment were increased compared with those before treatment (P < 0.05), and there were statistically significant differences in ALT and AST levels among the three groups after treatment (P < 0.05). There was significant difference in the incidence of adverse reactions among the three groups (P < 0.05). Conclusion Sodium valproate can effectively treat BPD patients and relieve the degree of mania or depression, but has no significant effect on the level of TSH, PRL and DA. Among them, small dose of sodium valproate can guarantee the therapeutic effect and have less impact on liver function, and less adverse reactions, high safety, worthy of clinical promotion. [ABSTRACT FROM AUTHOR]

We have postulated that common changes in gene expression after treatment with different therapeutic classes of psychotropic drugs contribute to their common therapeutic mechanisms of action. To test this hypothesis, we measured levels of cortical coding and non-coding RNA using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (chow only), chow containing 1.8 g lithium carbonate/kg (n = 10) or chow containing 12 g sodium valproate/kg (n = 10) for 28 days. Differences in levels of RNA were identified using JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify potential consequences of RNA. Compared to vehicle treatment, levels of cortical RNA for 543 and 583 coding and non-coding RNAs were different after treatment with valproate and lithium, respectively. Moreover, levels of 323 coding and non-coding RNAs were altered in a highly correlated way by treatment with valproate and lithium, changes that would impact on cholinergic, glutamatergic, serotonergic and dopaminergic neurotransmission as well as on voltage gated ion channels. Our study suggests that treating with mood stabilisers cause many common changes in levels of RNA which will impact on CNS function, particularly affecting post-synaptic muscarinic receptor functioning and the release of multiple neurotransmitters. [ABSTRACT FROM AUTHOR]

Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled‐release formulation of valproic acid, which exhibits a multi‐targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti‐inflammatory, anti‐fibrotic, and anti‐thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open‐label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS™ HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6‐min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1. [ABSTRACT FROM AUTHOR]

Background: Migraine causes patients' disability so that these patients are either absent from work and study, or even if they attend, they do not have the necessary efficiency for learning or working. Objectives of the study was to compare the effects of gabapentin (GBP) and sodium valproate (VPA) on patients with migraine headaches. Materials & Methods: In this clinical trial, patients suffering from migraine were included in the study and received preventive treatments of migraine in two groups: GBP (n=35) and VPA (n=35). In this study, headache impact test (HIT6) and Migraine Disability Assessment Scale (MIDAS) were used. the sampling method is block random and in the order of patients entering the department, they are in group A (GBP) and B (sodium VPA) and the sampling continued until the patients reached a sample size of n=70. In all patients, 6 and 12 weeks after taking the drugs, MHA was examined using HIT6 and MIDAS. the data were analyzed by SPSS 16. Results: Results showed, HIT6 score reduced from 53.68 (8.98) to 42.02 (2.61) in GBP group, and reduced from 55.57 (9.24) to 41.91 (2.17) in VAP group. MIDAS score reduced from 14.28 (1.5) to 5.97 (1.12) in GBP group and reduced from 14.85 (3.39) to 6.4 (1.11) in VAP group. Also, in the group receiving GBP, HIT6 score reduced significantly (P=0.000, F=3960.727) and MIDAS score also reduced significantly (P=0.000, F=5509.340). Also, in VAP group, a significant reduction was found in HIT6 (P=0.000, F=4855.349) and MIDAS (P=0.000, F=1332.999) Conclusions: Both GBP and VPA reduced MHA. For this reason, while suggesting the prescription of both of these drugs, it is suggested to conduct further studies in this field. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate changes in posterior segment parameters in pediatric patients with epilepsy using sodium valproate or levetiracetam monotherapy for at least 12 months. Methods: This study included 45 children with generalized epilepsy aged 6–17 years and 32 age- and gender-matched healthy subjects. The patients were assigned to three groups: Group 1 included patients using valproate monotherapy at a dose of 20–40 mg/kg/day, group 2 included patients using levetiracetam monotherapy at a dose of 20–40 mg/kg/day, and group 3 consisted of healthy controls. Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer-inner plexiform layer (mGCIPL) thicknesses were measured using spectral-domain optical coherence tomography (OCT). Results: No significant differences were noted between the groups regarding age, gender distribution, visual acuity, spherical equivalent, and intraocular pressure (p > 0.05). The average and temporal, nasal, and superior quadrants RNFL values were significantly thinner in group 1 than in group 2 (p = 0.001, p = 0.023, p = 0.011, and p = 0.001, respectively) and group 3 (p < 0.001, p = 0.032, p < 0.001, and p = 0.001, respectively). The OCT parameters were similar in groups 2 and 3 (p > 0.05). A negative correlation was observed in group 1 between only the average mGCIPL and the treatment dose (r = − 0.501). In group 2, no significant correlation was found between OCT parameters and the duration of epilepsy treatment, dose of treatment, and age at treatment onset values (p > 0.05). Conclusion: These findings support that there is an association between sodium valproate treatment and the reduction of RNFL thickness in epilepsy. Levetiracetam treatment appears to be a safe option, but care should be taken regarding ocular side effects that may occur with long-term and high-dose use of sodium valproate. [ABSTRACT FROM AUTHOR]

In the previous study, we found that the oral sodium valproate (SVP) increased the relative abundance of Akkermansia muciniphila (A. muciniphila) in rats, and plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) activities were positively correlated with A. muciniphila levels. This study aimed to further investigate the role of A. muciniphila in SVP‐induced hepatotoxicity by orally supplementing rats with the representative strain of A. muciniphila, A. muciniphila MucT. Additionally, the fresh faeces were incubated anaerobically with SVP to investigate the effect of SVP on faecal A. muciniphila in the absence of host influence. Results showed that A. muciniphila MucT ameliorated the hepatotoxicity and upregulation of A. muciniphila induced by SVP. SVP also induced a noteworthy elevation of A. muciniphila level in vitro, supporting the observation in vivo. Therefore, we speculate that A. muciniphila MucT may be a potential therapeutic strategy for SVP‐induced hepatotoxicity. In addition, the increased A. muciniphila induced by SVP may differ from A. muciniphila MucT, but further evidence is needed. These findings provide new insights into the relationships between A. muciniphila and SVP‐induced hepatotoxicity, highlighting the potential for different A. muciniphila strains to have distinct or even opposing effects on SVP‐induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Valproate is a commonly used mood stabiliser that has various adverse effects. One such adverse effect is peripheral edema. This case report highlights a case of a 25-year-old female patient who presented with severe pedal edema after starting treatment with valproate for bipolar disorder. The patient had a few other risk factors for edema which makes the diagnosis challenging. Pedal edema is a troublesome adverse effect that can significantly impact the quality of life of patients taking valproate, yet it is often neglected. This case report emphasizes the importance of recognizing and managing valproateinduced peripheral edema in clinical practice. [ABSTRACT FROM AUTHOR]

Background Epilepsy is a chronic episodic brain disorder with a high incidence and can seriously affect the quality of life of the patients. Therefore, timely treatment to control seizures is particularly important. Numerous studies have shown the effect of antiepileptic drugs on cognition, but there are few studies on the effects of different functional areas in children. Objective To explore the effects of sodium valproate (VPA) , oxcarbazepine (OXC) and levetiracetam (LEV) on the development of different functional areas in children with focal epilepsy by Griffiths Development Scales-Chinese Edition (GDS-C) . Methods A total of 83 children with focal epilepsy who attended in outpatient and ward of the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University for the first time from January 2021 to April 2022 were selected, and randomly divided into VPA group (n=27) , OXC group (n=28) and LEV group (n=28) according to the random number table method, 30 healthy children who were examined during the same period were selected as the control group. The changes of EEG interictal epileptiform activity (IEA) before and after 6 months of treatment were recorded and the clinical effect was evaluated according to seizure frequency, the GDS-C was used to evaluate the development quotient of each functional area in the children. Results The total clinical effective rates of VPA group, OXC group and LEV group were 92.6%, 89.3% and 92.9%, with no significant difference among the three groups (χ2=0.418, P=1.000) . The total EEG IEA effective rate of the VPA group, OXC group and LEV group were 88.9%, 57.1% and 89.3%, with significant differences among the three groups (χ2=11.152, P=0.004) ; the total effective rate of EEG IEA in OXC group was lower than that in VPA group and LEV group (P

Abstract Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin‐binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self‐renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.

Abstract Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled‐release formulation of valproic acid, which exhibits a multi‐targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti‐inflammatory, anti‐fibrotic, and anti‐thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open‐label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS™ HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6‐min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.

Objectives Epidemiologic studies point to an increased prevalence of migraine in children in recent decades. Migraine treatment involves acute and prophylactic therapy. Recently, such anti-epileptic drugs as Levetiracetam have been used to treat adult migraines. The present study aimed to compare the efficacy of Levetiracetam, Sodium Valproate, and Propranolol in preventing migraine headaches in children. Material & Methods In this clinical trial, children with migraine were randomly divided into three groups. Each group consisted of 13 children. Two groups were treated with Propranolol and Sodium Valproate, respectively. Another group (the case) was treated with Levetiracetam. The patients were assessed based on headache score, PedMIDAS, and headache frequency before and three months after the intervention. Finally, the data was analyzed using descriptive and analytical statistical methods. Results Levetiracetam significantly reduced the headache severity (P=0.026), frequency (P=0.024), and PedMIDAS score (P=0.001) in children with migraine. However, no significant difference was found between the three groups. The percentage of patients who experienced pain relief was detected as 69.24%, 92.31%, and 30.76% in the Propranolol, Sodium Valproate, and Levetiracetam groups, respectively. Conclusion This study concluded that Levetiracetam can be used as a migraine prophylaxis drug in children. [ABSTRACT FROM AUTHOR]

Schizophrenia is a known risk factor for coronavirus disease (COVID-19) infection and severity, and certain psychotropic drugs have been linked to increased mortality in infected patients with schizophrenia. However, little evidence exists regarding this risk. We retrospectively examined the association between mood stabilizers and the risk of pneumonia in patients with schizophrenia. This study included 99 patients with schizophrenia or schizoaffective disorder who were infected with COVID-19 in 2022 and met the inclusion criteria. After conducting propensity score matching to align patient backgrounds and concomitant medications, we assessed the impact of mood stabilizers, specifically sodium valproate, on the risk of pneumonia development. Univariate analysis revealed that patients with schizophrenia and COVID-19 who developed pneumonia were more likely to be older (64.5 [14.2] vs. 57.4 [11.5] years, p = 0.008) and using sodium valproate (44.4% vs. 16.7%, p = 0.004). Even after propensity score matching, patients who developed pneumonia were still more likely to be receiving sodium valproate than not (58.8% vs. 20.0%, p = 0.003). Sodium valproate use may be a risk factor for the development of pneumonia in patients with chronic schizophrenia who are infected with COVID-19 during long-term hospitalization. [ABSTRACT FROM AUTHOR]

In this research, carbon nitride nanocomposite coupled with Fe3O4 and CuWO4 was thermally synthesized and characterized by different techniques, including SEM, TEM, XRD, EDX, and FTIR. Due to sodium valproate's luminescence quenching of this nanocomposite, a reliable, accurate, sensitive, selective, and fast-acting sodium valproate assay was proposed. Optimization of this fluorescent sensor was carried out by the FCCD approach. In the optimum conditions, the plot of sodium valproate concentration versus nanocomposite fluorescence emission showed a linear response (R2 = 0.9918), with a range of 0–0.55 µM, the limit of detection (S/N = 3) equal to 0.85 nM and limit of qualification equal to 2.82 nM. Photocatalytic activity of g-C3N4@Fe3O4@CuWO4 (40%) nanocomposite exhibited a good potency to sodium valproate degradation. Active species of degradation including superoxide radicals, holes, and hydroxyl radicals were investigated using ammonium oxalate, benzoquinone, and 2-propanol to identify the mechanism of photodegradation action. The activity of benzoquinone in the photocatalytic process led to a reduction in the rate of analyte degradation, which indicates the prominent role of superoxide radicals compared to other species in the degradation process. The degradation rate of the analyte using the Fenton reagent was found to be around two times more than in the Fenton reagent-free process. The possible mechanism for the fluorescence sensor and photocatalytic degradation reaction was also discussed. [ABSTRACT FROM AUTHOR]

Background Neurological disorders (ND) affect the structure and function of the central nervous system, including Alzheimer's and Parkinson's diseases, epilepsy, migraine and stroke. ND has major symptoms ranging from mild to severe memory problems and physical disabilities. The present study investigated central nervous system (CNS) drug utilization trends, drug–drug interaction and morbidity patterns in ND. Methods A prospective study was carried out at a multi-specialty hospital, including neurology outpatient cases, in 2016. A study was ethically approved by the institutional ethics committee (IEC) for human research, and data were collected from patients' case records. The prescribing trend was assessed by World Health Organization (WHO) core prescribing indicators. The International Classification of Diseases (ICD) 10 was used to assess the morbidity pattern. Drug–drug interactions were analysed by a multidrug interaction checker. Results We discovered that 53.57% and 46.42% of the 280 neurology cases were female and male, respectively. Here, we showed that epilepsy was the most commonly diagnosed (31.07%) condition, followed by migraine (30.35%), Parkinsonism (Pn) (13.21%), Alzheimer's and dementia (AD) (10.71%) and myasthenia gravis (7.14%). The most commonly used CNS drugs were sodium valproates. Donepezil, fluoxatin and levodopa–carbidopa. In this study, 80% of drugs were prescribed with the most common category being antiepileptics; 16.77% and 23.21% of prescriptions observed potential drug–drug interactions. Conclusions The treatment priority for epilepsy was sodium valproate, which had a high prescription rate. For AD, donepezil was given priority, while in PN, levodopa–carbidopa was prescribed most often. In significant drug–drug interactions (DDI), pharmacodynamic mechanisms were very common, while in minor DDI, pharmacokinetic mechanisms were observed. [ABSTRACT FROM AUTHOR]

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Objective: Sodium valproate's teratogenicity has prompted increasing restrictions to its use. Our initial audit 2 years prior demonstrated continuing hazardous prescription to women of childbearing age in a New Zealand psychiatric inpatient unit, consistent with nationwide dispensing data. Method: Following a service-wide educational intervention and application of "black box" warnings, we conducted a follow-up audit of valproate prescription in the same inpatient unit by reviewing records of women admitted over a 10-month period (March 2020–January 2021). Results were compared with local and international guidelines, and against data from our initial audit. Results: Two hundred and sixty-one women of childbearing age were admitted over the sampling period, 26 of whom (10%) were prescribed valproate on discharge. Over three quarters (77%) of these patients had diagnoses other than bipolar affective disorder, valproates only approved psychiatric indication in New Zealand. Following intervention, significant improvements were observed in several key indicators of prescribing quality: pregnancy testing, documentation of contraception status, and discussion of teratogenic risk. Conclusions: Following intervention, re-audit demonstrated reduced prescription of valproate and improved management of its teratogenic risk in women of childbearing age receiving inpatient psychiatric care. These results demonstrate the value of a systematic approach to improve prescribing practice. [ABSTRACT FROM AUTHOR]

Background: One of the metabolic processes of sodium valproate (SV) metabolism is cytochrome P450 (CYP)-mediated oxidation. Polymorphism of the genes coding CYP enzymes can cause the changes in steady state SV concentration and clinical outcome. The study's objective was to explore the CYP gene polymorphism patterns in pediatric epileptic patients and its influence on SV concentration and clinical outcome. Methods: Ninety-nine pediatric epileptics aged 2–18 years who were receiving SV monotherapy were included in this cohort study. Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP) method was adopted to examine the genetic polymorphism patterns of CYP2C9*2 and CYP3A4*1B. HPLC was used to estimate the serum valproate concentration at the trough level. SPSS 23 was used to examine the relationship between SV concentration and CYP genotypes. Analysis of variance test was utilized, and a P < 0.05 was regarded statistically significant. Results: PCR-RFLP showed homozygous pattern (GG wild type) was observed in 37.3%, whereas heterozygous in 46.6% (mutant GA) and homozygous recessive (AA) in 16.1% patients in CYP3A4*1B (G331A). Homozygous (CC-Wild) and heterozygous (CT) pattern of polymorphism was observed in 90% and 10% patients in CYP2C9*2 (C430T). The mean serum valproate concentration assayed was 105.40 ± 49.9 μg/ml. The associations between the gene polymorphism of CYP3A4*1B (G331A) and CYP2C9*2 (C375T) with SV concentration were insignificant, The SNPs were not in equilibrium. The study findings indicated that patients of homozygous (wild type) CYP2C9*2 had bad clinical outcome compared to other patterns, although statistically insignificant. Conclusions: The association of serum concentration of SV with the different alleles of CYP3A4*1B and CYP2C9*2 was insignificant. SV should be cautiously used in patients with homozygous pattern of CYP2C9*2 due to concern of recurrent seizure episodes. The study may be of great use in personalized therapy in pediatric epilepsy.

Cordyceps militaris is a valued medicinal fungus in folk medicine in East Asia. It contains two major nucleosides, cordycepin and adenosine, which have been reported to have potential antineoplastic, antioxidant, and anti-inflammatory activities. This paper aimed to study the effect of C. militaris extract on the reproductive function of a mouse model, evaluating possible toxicity, androgenic activity, and protective and rehabilitative effects against damages caused by sodium valproate (VPA). There was no death and abnormalities observed in mice. Androgen activity was also shown in young male rats by an improvement in several sexual organs. The protective effect of C. militaris extract was explained by the gain of sexual organs’ weight, testosterone concentration, and seminiferous tubule size as well as the enhancement of sperm density, alive sperm percentage, and the progressive forward movement of sperm. The pregnancy rate of female rats paired with VPA-administered male rats (500 mg/kg/day) increased proportionally with the higher dose of C. militaris extract. In the rehabilitation study, an incline in the weight of the Cowper’s gland and glans (0.112 g/kg/day) and testicle and prostate (0.336 g/kg/day) as well as an improvement of the sperm forward progressive movement was observed. The percentage of unprogressive sperm and immotile sperm has reduced. These results suggest that C. militaris is a potential supplement to reduce the negative effects of VPA and improve reproductive function, in which the two major constituents cordycepin and adenosine may play an active role.

This study aimed to carry out a comparative study of the main models of chronic epilepsy induced by pentylenetetrazole (PTZ)-kindling method and to assess the efficacy of sodium valproate, one of the main antiepileptics, on the best epilepsy-inducing kindling model. Two sets of 24 animals were divided into 4 groups of 6 animals and treated as follow: Set 1 included: group 1, control; group 2, the classic kindling PTZ group (UKEOD); group 3, PTZ kindling every other day group with challenge (CKEOD); group 4, PTZ kindling every day group, with challenge (CKED); Set 2 included: group 1, control; group 2, CKEOD group; group 3 and 4, receiving either valproate 200 mg/kg or valproate 300 mg/kg + CKEOD procedure. Results show that CKEOD group significantly reduced the number of injections necessary to reach the fully-kindled state, increased the severity of seizures and improved the stability of seizures. In addition, the CKEOD group significantly increased the level of malondialdehyde and GABA transaminase, reduced the level of reduced glutathione, catalase and GABA. Furthermore, it had no impact on plasma levels of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). Valproate 300 mg/kg significantly protected animals against kindling induced by CKEOD. The kindling model with a challenge dose administered on day 1 (CKEOD) thus allows to induce more severe, more stable chronic epilepsy and in a shorter period of time, and could thus contribute to a better understanding of epilepsy, as well as its uses in drug discovery.

Background and purpose: Curcumin is a natural polyphenolic compound in turmeric (Curcuma longa). Curcumin has potent free radical scavenger and antioxidant properties that could significantly reduce oxidative damage. Oxidative stress and mitochondrial dysfunction contribute to valproate sodium induced tissue damage. This study investigated the protective effects of curcumin against valproate sodium induced oxidative stress and mitochondrial toxicity in brain of rats. Materials and methods: Male rats were exposed to sodium valproate (500 mg/kg/day, i.p.) alone, or in combination with different doses of curcumin (25, 50, and 100 mg/kg/day, i.p.) and vitamin C (100 mg/kg/day, i.p.) for eight weeks. Then, brain tissues were separated and factors associated with oxidative stress, mitochondrial dysfunction, and histopathological changes were investigated. Results: Sodium valproate induced mitochondrial dysfunction, increased oxidative stress parameters and caused significant histopathological changes in brain tissue. Administration of curcumin attenuated the induction of oxidative damage, mitochondrial dysfunction, and histopathological changes induced by sodium valproate in brain tissue. Conclusion: Curcumin showed protective effect against sodium valproate-induced neurotoxicity which may be attributed to its antioxidant activity. So, it can be considered as an effective supplement against oxidative stress and mitochondrial dysfunction induced by sodium valproate in brain tissue.

Epilepsy is a chronic brain disorder, with anti-epileptic drugs (AEDs) providing relief from hyper-excitability of neurons, but largely failing to restrain neurodegeneration. We investigated a progressive preclinical trial in rats, whereby the test drugs; sodium valproate (SVP; 150 and 300 mg/kg), baclofen (BFN; 5 and 10 mg/kg), and thymoquinone (THQ; 40 and 80 mg/kg) were administered (i.p, once/day for 15 days) alone, and as low dose combinations, and subsequently tested for antiseizure and neuroprotective potential using electrical stimulation of neurons by Maximal electroshock (MES). The seizure stages were monitored, and hippocampal levels of m-TOR, IL-1β, IL-6 were measured. Hippocampal histopathology was also performed. Invitro and Insilco studies were run to counter-confirm the results from rodent studies. We report the synergistic effect of trio-drug combination; SVP (150 mg/kg), BFN (5 mg/kg) and THQ (40 mg/kg) against generalized seizures. The Insilco results revealed that trio-drug combination binds the Akt active site as a supramolecular complex, which could have served as a delivery system that affects the penetration and the binding to the new target. The potential energy of the ternary complex in the Akt active site after dynamics simulation was found to be −370.426 Kcal/mol, while the supramolecular ternary complex alone was −38.732 Kcal/mol, with a potential energy difference of −331.694 Kcal/mol, which favors the supramolecular ternary complex at Akt active site binding. In addition, the said combination increased cell viability by 267% and reduced morphological changes induced by Pentylenetetrazol (PTZ) in HEK-293 cells, which indicates the neuroprotective property of said combination. To conclude, we are the first to report the anti-convulsant and neuroprotective potential of the trio-drug combination.

A 63-year-old man developed reduced consciousness and dysphagia progressively. Examination and parameters were normal, except for a Glasgow Coma Scale score of seven, and his grading on the swallow water test increased from grade 1 to grade 5. Brain imaging and blood tests were unexplainable except by high plasma ammonia. His past medical history included cerebral infarction, hypertension and epilepsy induced by cerebral hyperperfusion syndrome. He was rceiving antiepileptic treatment of continuously intravenously pumped sodium valproate of 64 mg/h for 4 days, which overlapped for 12 hours with taking 500 mg sustained release tablets. Sodium valproate was stopped; testing demonstrated normal plasma concentrations of sodium valproate and elevated concentrations of ammonia. Ornithine aspartate was administrated. The patient's level of responsiveness and ammonia levels gradually improved. The patient was also being treated with ceftriaxone sodium for a hypostatic pneumonia and with desmopressin for diabetes insipidus. There is an association between sodium valproate and hyperammonaemia and encephalopathy. Immediate recognition of the serious but uncommon adverse effects is essential. To our knowledge this is the first report of ornithine aspartate being used in this disorder. [ABSTRACT FROM AUTHOR]

Background: One of the metabolic processes of sodium valproate (SV) metabolism is cytochrome P450 (CYP)-mediated oxidation. Polymorphism of the genes coding CYP enzymes can cause the changes in steady state SV concentration and clinical outcome. The study's objective was to explore the CYP gene polymorphism patterns in pediatric epileptic patients and its influence on SV concentration and clinical outcome. Methods: Ninety-nine pediatric epileptics aged 2-18 years who were receiving SV monotherapy were included in this cohort study. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method was adopted to examine the genetic polymorphism patterns of CYP2C9*2 and CYP3A4*1B. HPLC was used to estimate the serum valproate concentration at the trough level. SPSS 23 was used to examine the relationship between SV concentration and CYP genotypes. Analysis of variance test was utilized, and a P < 0.05 was regarded statistically significant. Results: PCR-RFLP showed homozygous pattern (GG wild type) was observed in 37.3%, whereas heterozygous in 46.6% (mutant GA) and homozygous recessive (AA) in 16.1% patients in CYP3A4*1B (G331A). Homozygous (CC-Wild) and heterozygous (CT) pattern of polymorphism was observed in 90% and 10% patients in CYP2C9*2 (C430T). The mean serum valproate concentration assayed was 105.40 ± 49.9 µg/ml. The associations between the gene polymorphism of CYP3A4*1B (G331A) and CYP2C9*2 (C375T) with SV concentration were insignificant, The SNPs were not in equilibrium. The study findings indicated that patients of homozygous (wild type) CYP2C9*2 had bad clinical outcome compared to other patterns, although statistically insignificant. Conclusions: The association of serum concentration of SV with the different alleles of CYP3A4*1B and CYP2C9*2 was insignificant. SV should be cautiously used in patients with homozygous pattern of CYP2C9*2 due to concern of recurrent seizure episodes. The study may be of great use in personalized therapy in pediatric epilepsy. [ABSTRACT FROM AUTHOR]

As a safe neuromodulation therapy, rTMS is applied to treat a variety of psychiatric and neurological disorders. Additionally, both aripiprazole and sodium valproate are effective in the treatment of rapid cycling bipolar disorder. This case reports a female patient with a 17-year history of bipolar disorder who developed rapidcirculation bipolar disorder 5 years prior to presentation. After combined treatment with rTMS, aripiprazole, and sodium valproate, the patient's mood remained stable and she was able to live and work normally. [ABSTRACT FROM AUTHOR]

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Background: Enuresis is an uncommon adverse effect of sodium valproate therapy that is unknown to most clinicians. This study provides an overview of the literature on enuresis associated with sodium valproate therapy, discussing the clinical manifestations and possible mechanisms of this side effect. Methods: We reported three cases of enuresis induced by sodium valproate and reviewed the published enuresis cases associated with sodium valproate therapy retrieved from databases. Case presentation and results: Three new patients with epilepsy who presented with enuresis following sodiumvalproate therapy were reported, and 55 published cases of nocturnal enuresis associated with sodium valproate were evaluated. The average age of these patients varied from 4 to 20 years. A total of 48 cases had generalized seizures, seven had focal seizures, and three had unknown seizures. In all the patients, the plasma concentration of sodium valproate was 80.76 ± 14.80µg/mL, within the therapeutic range when enuresis occurred. With discontinuation or reduction of the drug, all the patients recovered completely. Conclusion: Sodium valproate-induced enuresis is a rare and reversible side effect, occurring at a younger age, characterized by the generalized onset of seizures, and a rather high dose. The possible mechanisms include insufficient secretion of anti-diuretic hormones, sleep disorder, and hyperactivity of the parasympathetic system. Clinicians should be aware of this uncommon side effect to avoid an incorrect adjustment of the treatment direction. [ABSTRACT FROM AUTHOR]

Objective:Epilepsy, one of the most common chronic neurological diseases, is characterized by spontaneous recurrent seizures. Many studies, using various experimental epilepsy models, have shown that resveratrol reduces epileptiform activity and has neuroprotective effects. Using an epilepsy model created with penicillin, we aimed to investigate the effect of resveratrol on epileptiform activity in rats.Methods:A total of 40 Wistar albino rats were divided into 5 groups of 8. In the control group, only 2.5 μL of saline was administered intracranially (ic). In the penicillin group, 500 IU of penicillin was given intracranially with no additional procedure. In the resveratrol group, 40 mg/kg of resveratrol was administered intraperitoneally (ip) 20 minutes after penicillin was given intracranially. In the sodium valproate group, 20 minutes after penicillin ic, 300 mg/kg of sodium valproate was administered intraperitoneally. In the resveratrol + sodium valproate group, 20 minutes after penicillin ic, 40 mg/kg of resveratrol was administered intraperitoneally to the right side and 300 mg/kg of sodium valproate ip to the left side. The rats were placed in a stereotaxic device after the procedure and electrocorticogram recordings were captured for 180 minutes.Results:The number of spikes and the average amplitude of the spikes (peak-to-peak) were calculated from the electrophysiological recording data. In the resveratrol group, there was no statistically significant difference in spike frequency and amplitude values. In the resveratrol + sodium valproate group, the spike frequency values decreased significantly from the 30th minutes (P = .028 < .05) and the amplitude decreased significantly from the 60th minutes (P = .018 < .05). Conclusion:In this rat experimental epilepsy model created with penicillin, administration of resveratrol alone did not create a statistically significant difference in epileptiform activity; however, administration of resveratrol with sodium valproate significantly decreased epileptiform activity.

Yahao Gao,1,&ast; Di Jiang,2,&ast; Changshui Wang,3 Gang An,1 Li Zhu,4 Changmeng Cui3 1Clinical Medical School, Jining Medical University, Jining, Shandong, People’s Republic of China; 2Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 3Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, People’s Republic of China; 4Department of Clinical Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changmeng Cui, Department of Neurosurgery, Affiliated Hospital of Jining Medical University, 89 Guhuai Road, Jining, Shandong, 272000, People’s Republic of China, Tel +8617805378911, Email cmcuidr1989@163.comPurpose: Sodium valproate (VPA) is the most widely used broad-spectrum antiepileptic first-line drug in clinical practice and is effective against various types of epilepsy. However, VPA can induce severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity, which limits its use. Metabolomic studies of VPA-induced toxicity have focused primarily on changes in serum and urine metabolites but have not evaluated changes in major organs or tissues.Methods: Central target tissues (intestine, lung, liver, hippocampus, cerebral cortex, inner ear, spleen, kidney, heart, and serum) were analyzed using gas chromatography mass spectrometry to comprehensively evaluate VPA toxicity in mouse models.Results: Multivariate analyses, including orthogonal projections of the latent structure and Student’s t test, indicated that depending on the matrix used in the study (the intestine, lung, liver, hippocampus, cerebral cortex, inner ear, spleen, kidney, heart or serum) the number of metabolites differed, the lung being the poorest and the kidney the richest in number.Conclusion: These metabolites were closely related and were found to participate in 12 key pathways related to amino acid, fatty acid, and energy metabolism, revealing that the toxic mechanism of VPA may involve oxidative stress, inflammation, amino acid metabolism, lipid metabolism, and energy disorder.Keywords: sodium valproate, biomarker, gas chromatography mass spectrometry, metabolomics, toxicity mechanism