Search

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.

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., (© 2024, The American College of Clinical Pharmacology.)

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.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: 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., Methods: 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)., Results: 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., Conclusions: 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., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

To explore the effects of antiepileptic drug sodium valproate on magnetic resonance imaging (MRI) images, neurological cognition, and JAK1/STAT3 pathway in hippocampus of rats with depression, 30 Sprague Dawley (SD) rats were included. The depression model (DM) was prepared through the chronic stress restraint test. Some model rats were injected with 10 mg/kg sodium valproate into abdominal cavity before modeling (RT group)), and healthy rats were selected as controls (healthy control (HC) group). Depth of split brain was greatly increased in DM group, and nitrogen-acetyl aspartic acid (NAA)/creatine (Cr), glutamic acid (Glu)/Cr, and choline (Cho)/Cr ratios were greatly reduced ( P < 0.05). Behavioral test results showed that sugar water preference rate, escape latency, and divergence index in DM group were greatly reduced ( P < 0.05), and cumulative immobility time, target quadrant stay time, and number of crossings in forced swimming and tail suspension were prolonged dramatically ( P < 0.05), with no difference between the two groups ( P > 0.05). Expression levels of interleukin 1β (IL-1β) and interleukin 6 (IL-6) in hippocampus of DM group were obviously increased ( P < 0.05), and expression levels of JAK1 and STAT3 were decreased visibly ( P < 0.05), with no difference between the two ( P > 0.05). In summary, anti-epileptic drug sodium valproate effectively improves hippocampal volume characteristics and memory and neurocognitive dysfunction of depression models.

Epilepsy is a common chronic neurological disease that manifests as recurrent seizures. The incidence and prevalence of epilepsy in women are slightly lower than those in men. Polycystic ovary syndrome (PCOS), a reproductive endocrine system disease, is a complication that women with epilepsy are susceptible to, and its total prevalence is 8%-13% in the female population and sometimes as high as 26% in female epilepsy patients. The rate of PCOS increased markedly in female patients who chose valproate (VPA), to 1.95 times higher than that of other drugs. In addition, patients receiving other anti-seizure medications (ASMs), such as lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ), also have reproductive endocrine abnormalities. Some scholars believe that the increase in incidence is related not only to epilepsy itself but also to ASMs. Epileptiform discharges can affect the activity of the pulse generator and then interfere with the reproductive endocrine system by breaking the balance of the hypothalamic-pituitary-ovarian (HPO) axis. ASMs may also cause PCOS-like disorders of the reproductive endocrine system through the HPO axis. Moreover, other factors such as hormone metabolism and related signalling pathways also play a role in it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zhang, Wei, Tai, Yu and Xu.)

Anti-epileptic drugs (AEDs) are the mainstay of epilepsy treatment but these may be a potential risk factor for behavioral disturbances particularly depression which requires treatment. In this study, the effect of antidepressant sertraline (SRT) in combination with AEDs sodium valproate (SV) and levetiracetam (LEV) on seizures, cognitive impairment and oxidative stress in rats was evaluated. After administration of 24th injection of pentylenetetrazole (PTZ), 77.8% rats were kindled. Administration of SRT showed no protective effect on kindling development while SV was 100% protective. With LEV 42.9% were kindled. On combining SRT with SV or LEV 25% and 20% rats were kindled. A significant increase in latency to reach platform zone in Morris water maze(MWM), and increased transfer latencies in Elevated plus maze(EPM) was observed in PTZ kindled rats as compared to normal control on day 49 and when LEV was combined with SRT. In EPM test, however none of the drug treatments had any effect on transfer latencies except LEV pretreated kindled group. In Passive avoidance (PA) test, kindling was associated with a significant decrease in retention time(p = 0.018) while LEV and SV had no effect. The PTZ kindled rats showed significantly higher malondialdehyde(MDA) levels in brain hippocampus(p = 0.0286) while both SRT and SV were associated with significantly lower MDA levels as compared to kindled control group. In case of glutathione (GSH), kindling had no significant effect. The use of sertraline for depression in persons with epilepsy on AEDs needs to be carefully evaluated and monitored due to likelihood of individual variation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the pattern of UGT1A6 and UGT2B7 gene polymorphism in pediatric epileptic patients and to compare the sodium valproate concentration in different patterns of UGT gene polymorphism., Methods: In this cross-sectional study, 99 pediatric epileptic patients aged 2-18 y receiving Sodium valproate monotherapy for the past one month were included from JusticeK S Hegde Charitable hospital, Mangalore after obtaining informed consent. Genetic polymorphism patterns were evaluated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Trough level serum valproate concentration was estimated by high-performance liquid chromatography (HPLC). Sodium valproate concentration in different UGT genotypes was compared by Analysis of Variance (ANOVA). P value <0.05 was considered significant., Results: In the present study population, the predominant mutant allele pattern was observed in UGT1A6 (T19G, A541G, A552C) gene. In UGT2B7 (A268G, C161T) showed predominant mutant allele pattern while (G211T) showed predominant wild type. Mean steady-state sodium valproate concentration was 105.40 ± 49.9 μg/ml and adjusted sodium valproate concentration was 5.5 ± 3.2 mg/kg/L. It was found that there was no statistical difference in sodium valproate concentration in different UGT1A6 and UGT2B7 gene polymorphism., Conclusion: The present study concluded that though there was a difference in pattern of gene polymorphism with concerning UGT1A6 and UGT2B7, however, it has not contributed to variation in serum concentration of sodium valproate in the present study population., (© 2021. Dr. K C Chaudhuri Foundation.)

Objective: Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH., Methods: This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction., Results: In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 μmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 μmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed., Conclusions: Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We evaluated the protective effect of ademetionine, cytoflavin, and dihydroquercetin on activity of serum enzymes in rats treated with high doses of sodium valproate for 28 days. Ademetionine and cytoflavin produced the greatest protective effect, the effect of dihydroquercetin was less pronounced. In rats treated with ademetionine, AST activity decreased as soon as on day 7 and remained at this level until the end of the experiment; ALT, alkaline phosphatase, and γ-glutamyl transferase activities decreased on days 21 and 28 of the study. Cytoflavin produced similar effects, the effect of dihydroquercetin was observed on days 21 and 28 for AST, ALT, alkaline phosphatase and on day 28 for γ-glutamyl transferase. These results substantiate the use of hepatoprotective drugs in case of long-term treatment with anticonvulsants in patients with epilepsy.

Epilepsy is one of the commonly prevailing neurological disorders. According to the reports, it is evident that about 80% of the epileptic cases have been observed in developing countries. Although there are many drugs with significant potency available in the market; still there is an issue of selectivity and toxicity. Therefore, continuous attempts have been made by the researchers to develop newer therapeutic agents against epilepsy. Many synthetic strategies have been available in the literature to synthesize various classes of anticonvulsants with promising activity. In the presented review, authors have summarized some newer synthetic routes being used for the synthesis of nitrogen-containing anticonvulsants taking a cue from the reported established anticonvulsant drugs viz. vigabatrin, sodium valproate, oxcarbazepine, felbamate, retigabine, and gabapentin. Various derivatives with the substitution for better anticonvulsant profile have been described in the figures for easy comparative study. The structure-activity relationship (SAR) of compounds with maximum potency has also been discussed. This article may serve as a boost for the researchers to modify the pre-existing synthetic routes as well as to improve potency and yield of the compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Because oral pharmacological treatment of neocortical focal epilepsy is limited due to common systemic side effects and relatively low drug concentrations reached at the epileptic foci locally, application of antiepileptic agents directly onto the neocortical focus may enhance treatment tolerability and efficacy. We describe the effects of cortically applied sodium valproate (VPA) in two patients with pharmacoresistant neocortical focal epilepsy who were selected for epilepsy surgery after a circumscribed epileptic focus had been determined by invasive presurgical evaluation using subdural electrodes. Local VPA modified epileptic activity as electrocorticographically recorded from the chronic focus in both patients. In addition, VPA induced local increase of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in cortical tissue samples, whereas the excitatory glutamate was possibly decreased. In this clinical pilot study, we could show antiepileptic effects of cortically applied VPA in humans by electrocorticographic and neurochemical parameters., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The aim of this study was to investigate the effects of sodium valproate (SV) and carbamazepine (CBZ) on neuromuscular transmission using single-fibre electromyography (SFEMG) in patients with epilepsy. We performed SFEMG during the voluntary contraction of extensor digitorum communis muscle. 30 epileptic patients taking SV, 25 epileptic patients taking CBZ, and 25 age-matched healthy volunteers were included in the study. Mean jitter values (MCD) of subjects taking SV and CBZ were compared with normal controls. MCD values of subjects taking SV and CBZ were statistically significantly higher than those of control group. Review of the correlation between disease duration and MCD values of patients showed that MCD values were increased with the prolonged use of drugs, and thus, indicated a positive relationship between these two parameters. These results suggest that both SV and CBZ reduce neuromuscular transmission in patients without a neuromuscular junction disease.

Background: We sought to explore the effects of sodium valproate combined with lamotrigine on quality of life and serum inflammatory factors in patients with poststroke secondary epilepsy., Methods: A total of 145 patients with post-stroke secondary epilepsy admitted to our hospital from January 2017 to June 2018 were collected: 76 treated with sodium valproate combined with lamotrigine (study group) and 69 patients treated with sodium valproate alone (control group). The levels of serum high-mobility group protein B1, matrix metalloproteinase 9, and interleukin 6 were detected before and after treatment, and the therapeutic efficacy and adverse reactions were compared between the 2 groups., Results: The total effective rate of the study group was higher than that of the control group. Both groups decreased in epileptiform discharges or in the number of involved leads after treatment, with the results of the study group being lower than those of the control group. The quality of life scores in both groups was increased after treatment, albeit the scores of the study group were higher than those of the control group. In terms of the levels of serum inflammatory factors, the 2 groups were reduced after treatment; the levels of the study group were lower than those of the control group. Regarding the incidence of adverse reactions, no significant difference was seen between the 2 groups., Conclusions: Sodium valproate combined with lamotrigine has better clinical efficacy and higher safety in the treatment of poststroke secondary epilepsy and is able to reduce the expression levels of serum inflammatory factors., Competing Interests: Conflict of Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Efficacy of sodium valproate in epilepsy is limited by its poor blood brain barrier penetration and side effects. Nanoparticles may offer a better drug delivery system to overcome these limitations. This study evaluated the efficacy of sodium valproate encapsulated in nanoparticles in pentylenetetrazole (PTZ) induced acute and kindling models of seizures in male Wistar rats., Methods: Poly lactic-co-glycolic acid (PLGA) based, polysorbate 80 stabilized sodium valproate loaded nanoparticles (nano sodium valproate) and rhodamine loaded nanoparticles (RLN) were formulated by double emulsion- solvent evaporation method and characterized for their size, shape, zeta potential and drug loading percentage. RLN was used to demonstrate blood brain barrier (BBB) permeability of nanoparticles. Serum drug levels were estimated using high performance liquid chromatography. The efficacy of standard sodium valproate (300 mg/kg) and nano sodium valproate (∼300, ∼150 and ∼75 mg/kg of sodium valproate) were evaluated in experimental animal models of seizures along with their effects on behavioral and oxidative stress parameters. Drugs were administered 60 min before PTZ in acute model. In the kindling model, drugs were administered every day while PTZ was administered on alternate days 60 min after drug administration. All the study drugs/compounds were administered intraperitoneally., Results: RLN were observed to be clustered in cortex which implied that the nanoparticles crossed BBB. Both standard sodium valproate and nano sodium valproate reached therapeutic serum level at 15 min and 1 h, but were undetectable in serum at 24 h. In acute PTZ (60 mg/kg) model, nano sodium valproate (∼300 mg/kg of sodium valproate) and standard sodium valproate showed protection against seizures till 6 h and 4 h, respectively. There were significant behavioral impairment and oxidative stress with standard sodium valproate in acute model as compared to nano sodium valproate at 6 h. In kindling model, induced with PTZ (30 mg/kg, every alternate day for 42 days), complete protection from seizures was observed with nano sodium valproate (∼150 mg/kg and ∼75 mg/kg of sodium valproate) and standard sodium valproate (300 mg/kg). Similarly, significant protection from behavioral impairment and oxidative stress was observed with standard sodium valproate and nano sodium valproate as compared to PTZ., Conclusion: When compared to conventional therapy, nano sodium valproate showed protection from seizures at reduced doses and for a longer duration in animal models of epilepsy. This study suggests the potential of nano sodium valproate in the treatment of epilepsy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: In November 2014, the CMDh (a regulatory body representing EU Member States) advised doctors not to prescribe sodium valproate for epilepsy or bipolar disorder in preg nant women, in women who can become pregnant, or in girls unless other treatments are ineffective or not tolerated. This study aimed to determine if this warning led to changes in prescription patterns., Design and Setting: Cohort of 5.4 million women aged between 10 and 50 years identified in electronic health care data from United Kingdom, France, and Italy (2007-2016)., Main Outcome Measures: Anti-epileptic drug (AED) prescriptions., Results: The prevalence of women receiving AED prescriptions in 2016 varied from 12.2 per 1000 to 29 per 1000 in the four regions. The incidence of prescribing any AED (excluding clonazepam, gabapentin, and pregabalin) fell each year on average by 7.5% (95% CI, 7.0%-8.0%; Emilia Romagna), 9.6% (8.3%-11.0%; France), 7.1% (6.7%-7.6%; Tuscany), and 0.4% (0.2%-1.0%; United Kingdom). The relative odds of prescribing sodium valproate rather than any other AED decreased more after 2014 compared with before the end of 2014 in France (OR = 0.77; 95% CI, 0.60-0.98), Tuscany (0.81; 0.76-0.86), Emilia Romagna (0.83; 0.76-0.90), and the United Kingdom (0.92; 0.80-1.06; not statistically significant)., Conclusions: There is evidence that the CMDh warning did lead to changes in prescription patterns of sodium valproate in women of childbearing age. There were considerable differences in prescribing practice amongst regions of Europe., (© 2019 John Wiley & Sons, Ltd.)

Endoplasmic reticulum (ER) stress has been indicated to be involved in the pathogenesis of epilepsy. Sodium valproate (VPA), one of the most commonly used antiepileptic drugs, is reported to regulate ER stress in many neurological diseases. However, the effect of VPA on ER stress in epilepsy remains unclear. The current study was performed to investigate the role of ER stress in the neuroprotection of VPA against seizure induced by pentylenetetrzole (PTZ). Our results showed that VPA treatment could inhibit the increased expressions of ER stress proteins (GRP78 and CHOP), and significantly reduce neuronal apoptosis in the PTZ-induced experimental seizure model. In addition, Salubrinal, an ER stress inhibitor, was used as a positive control, and exhibited neuroprotective effects via inhibiting excessive ER stress in the seizure model, which further supported that the inhibition in ER stress by VPA treatment could exert neuroprotection in seizures. In summary, our work demonstrated for the first time that ER stress was involved in the neuroprotective potential of VPA for seizures.

Purpose: Phenobarbital and sodium valproate are broad spectrum and inexpensive antiepileptic drugs that are used to treat convulsive epilepsy. We examined the therapeutic effects of phenobarbital and sodium valproate in patients with convulsive epilepsy in the rural northeast China, and discuss our efforts to ensure patients' compliance., Methods: Patients with convulsive epilepsy were screened by trained township health center doctors. Patients in the phenobarbital group were enrolled between January 2011 and December 2012, and followed up until December 2017. Patients in the sodium valproate group were enrolled between January 2011 and December 2017, and followed up for 1 year. Efficacy of phenobarbital or sodium valproate was assessed by the reduction in seizure frequency., Results: A total of 1200 patients were diagnosed by screening and rechecking, of which 925 patients received phenobarbital and 275 received sodium valproate. In the phenobarbital group, 528 patients were followed up for ≥60 months, and the efficacy rates of reduction of seizure frequency by at least 75% was in the fifth year. In the sodium valproate treatment group, 228 patients were followed up for 12 months, and the reduction of seizure frequency by at least 75% was 60.4%. 444 patients (37%) did not complete the study. Dizziness (27%) was a common adverse event in phenobarbital group. In the sodium valproate group, gastrointestinal complaints (27.3%) was a common adverse event., Conclusion: Phenobarbital and sodium valproate were proven to be efficacious in treating convulsive epilepsy in rural northeast China. The patients' compliance still needs to be improved., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: After a huge campaign of information on the teratogenic risk of sodium valproate (VPA) having taken place in France we aimed to evaluate the trend of its prescriptions in young epileptic girls., Method: Using the French National Health Insurance Database we searched for patients aged 0-14 years being supplied an antiepileptic drug (AED) between 2010 and 2016., Results: 113,362 children received at least one AED, 61,259 boys and 52,103 girls. Compared to 2010-2014 years, VPA was less prescribed in 2016 as first AED (29% vs 37.3% respectively). The difference between the two periods was greater for girls (-41%) than for boys (-12%)., Conclusion: The changing trend of VPA as first AED prescribed, particularly in girls, reflects published evidence in terms of safety., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Context: Migraine is the second most common headache disorder. However, prophylactic therapy remains underutilized., Aims: The objective of the study was to compare the efficacy and safety of low-dose sodium valproate and low-dose propranolol sustained release (SR) in the prophylaxis of common migraine headache., Settings and Design: The study was conducted in a tertiary care teaching institute. It was a randomized, prospective, parallel, open-label, clinical study., Subjects and Methods: The study included 60 patients with common migraine headaches (≥2 attacks/month) treated for 12 weeks. The patients were randomly divided into two treatment groups treated by sodium valproate 500 mg/day and propranolol SR 40 mg/day, respectively. The primary outcome measures were the percentage of responders (i.e., >50% decrease in mean headache frequency) at the end of 12 weeks and decrease in mean headache frequency (per 4 weeks) at the end of 12 weeks. The patients were assessed at 0, 4, 8, and 12 weeks of the study., Statistical Analysis Used: Intention-to-treat analysis was used for all the statistical analysis., Results: Fifty-five patients completed the study. At the end of the treatment, both sodium valproate and propranolol caused a significant ( P < 0.0001) reduction in frequency, severity, and duration of migraine headache. Propranolol caused significantly greater reduction in the severity of headache ( P = 0.0410) than sodium valproate. The percentage of responders was 60% in sodium valproate group and 70% in propranolol group. Drowsiness was the most common adverse effect noted in both the groups., Conclusion: Both sodium valproate and propranolol significantly reduced frequency, severity, and duration of migraine headache, but propranolol caused significantly greater reduction in the severity of headache compared to sodium valproate. Both the medications were well tolerated and did not result in discontinuation., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Indian Journal of Pharmacology.)

Background: Valproic acid (VPA) is one of the commonly used antiepileptic drug. It has various side effects which may be fatal, such as fulminant hepatitis. Nocturnal enuresis (NE) has rarely been reported as side effect of VPA. The aim of this study is to evaluate the frequency of VPA-induced NE and discuss the possible reasons., Materials and Methods: This retrospective cohort study was performed at the Department of Pediatric Neurology, Eskisehir Osmangazi University Hospital, in Eskisehir, Turkey, between April 2014 and April 2015. The patient population was generated from the epilepsy patients who were receiving VPA monotherapy. Control group population was generated from nonepileptic patients who visited our clinic for headache. Age range of the patients and the control group was determined to be 5-15 years., Results: The patients group consisted of 189 (53.7%) boys and 163 (46.3%) girls and mean age of the patients was 9.1 ± 3.02 (5-15) years. The control group consisted of 92 (51.1%) girls and 88 (48.9%) boys and mean age of the patients was 8.75 ± 3.23 (5-15) years. We found the incidence of VPA-induced NE to be 5.7%. In the control group, incidence of NE was found to be 10.7%., Conclusion: This study is one of the largest series about VPA-induced NE. NE is a side effect of VPA that is generally overlooked by clinicians and slightly less well-known too. The literature on VPA-induced NE is very inadequate, and its etiology is not clear. In our study, we did not detect renal dysfunction in the patients with VPA-induced NE; therefore, we may speculate that the NE was caused by the increased sleep depth with VPA treatment. We believe that larger prospective studies including polysomnography may be helpful to shed light on the cause of VPA-induced NE., Competing Interests: There are no conflicts of interest.

A 69-year-old man developed reduced consciousness of sudden onset. Examination and parameters were normal, except for a Glasgow Coma Scale (GCS) score of six. Brain imaging and blood tests were also normal, except for high plasma ammonia. His past medical history included epilepsy, hypertension and colitis. He was taking multiple antiepileptic medications, including sodium valproate, with no recent dose alterations. Medical intervention led to the sodium valproate being stopped and naloxone being administered. The patient's level of responsiveness and ammonia levels gradually improved. The patient was also being treated with ciprofloxacin for a urinary tract infection and a newly developed syndrome of inappropriate antidiuretic hormone secretion treated with demeclocycline. There is an association between long-term sodium valproate use and low carnitine levels, especially in the setting of polypharmacy. This in turn precipitates hyperammonaemia and encephalopathy. This case highlights the importance of an adequate drug history and the awareness of serious but uncommon adverse effects., (© Royal College of Physicians 2018. All rights reserved.)

The central neurotransmitters assume a noteworthy part in the pathophysiology of epilepsy, noradrenaline is one of them. However, its role in 6 Hz induced psychomotor seizures is not known. The present study was, therefore, designed to investigate the role of noradrenaline (NA) in 6 Hz-induced psychomotor seizures in Swiss albino mice using N-2-Chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a well-known depletor of NA. The vehicle and DSP-4 treated mice were given 6 Hz stimulation. A sham treatment was utilized as a comparator and sodium valproate (SVP) was utilized as a reference anti-epileptic medication. Behavioral changes instigated by 6 Hz stimulation were described as the increased duration of Straub's tail, stun position, twitching of vibrissae, forelimb clonus and increased rearing and grooming. DSP-4 administration further amplified the seizures and behavioral changes while pretreatment with SVP reduced the same in mice. Further, SVP pre-treatment also attenuated the ultra-structural changes observed in cortex and hippocampus of mice treated with DSP-4 and 6 Hz. Finally, the neurochemical estimation of NA in cortex and hippocampus confirmed the depletion of NA following DSP-4 and 6 Hz seizures. SVP pretreatment (but not post-treatment) protected the mice from 6 Hz seizures and attenuated the DSP-4 induced alterations of nor-adrenaline content in the mouse brain. The study indicates low brain NA content to enhance pharmacoresistant seizures in mice and demonstrates that SVP mediated protection against 6 Hz results possibly via modulation of NA content., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Women with epilepsy need to continue to take anticonvulsants during their pregnancies to prevent seizures from occurring. Since the 1980's, it has been known that the use of valproate (an anticonvulsant) in the first trimester of pregnancy is associated with an increased risk of spina bifida. Recent studies have also demonstrated increased risks of other congenital anomalies as well as a risk of cognitive impairment. Doctors in the EU are now advised not to prescribe valproate in pregnant women, in women who can become pregnant or in girls unless other treatments are ineffective or not tolerated. This study aimed to determine if there has been a reduction in the numbers of babies born with valproate syndrome in Europe from 2005 to 2014. Data from 15 European congenital anomaly registries, who are members of EUROCAT (A European network of population-based registries for the epidemiologic surveillance of congenital anomalies), identified 28 cases of valproate syndrome in 2.74 million births from 2005 to 2014. The prevalence of valproate syndrome in Europe significantly decreased from 0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14. One registry, Ile de la Reunion, had the majority of cases (17). After excluding these cases there still remained a decreasing trend even though it no longer reached statistical significance due to the small number of cases. This study emphasises the continued need for European collaboration in analysing rare exposures and rare anomalies., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Secondary osteoporosis is the major concern associated with long term intake of antiepileptic drugs (AEDs). Women are the vulnerable targets owing to post-menopausal bone loss. In the present work, we evaluated the effect of 10 weeks of treatment with AED therapy (carbamazepine, CBZ, 75 mg/kg; sodium valproate, SVP, 300 mg/kg; levetiracetam, LTM, 150 mg/kg) on bone mineral density and microarchitecture at femoral epiphysis, lumbar vertebrae and proximal tibia of normal and ovariectomised Wistar rats. In addition, we measured serum levels of vitamin D, receptor activator of nuclear factor kappa β-ligand (RANKL), procollagen type 1 amino-terminal propeptide (P1NP) and wnt inhibitors (sclerostin and DKK-1) following AED therapy. Micro-computed tomography analysis of bones revealed significant reduction in BMD at femur epiphysis and lumbar vertebrae with all the three AEDs evaluated. At proximal tibia, only CBZ showed a significant decline. The reduction in BMD was more pronounced in ovariectomised rats. AEDs also resulted in alteration of micro-CT parameters. These changes were accompanied by an increased serum RANKL with all AEDs while vitamin D levels were reduced only with CBZ treatment and P1NP levels were reduced with SVP and CBZ. Serum sclerostin levels were elevated following all AEDs in normal and ovariectomised rats except with CBZ in normal rats. However, increase in DKK-1 levels was observed with only LTM. Ovariectomy itself resulted in increased RANKL, sclerostin and DKK-1 and reduced vitamin D and P1NP levels. Significant differences were discernible between normal and ovariectomised rats treated with AEDs in all the parameters. However, while sclerostin increased further upon AEDs treatment, P1NP decreased with SVP and CBZ and serum DKK-1 levels showed a declining trend with all the three AEDs studied. We confirm adverse effects on bone following AEDs in female rats. Further, our results demonstrate for the first time that these effects are more pronounced in ovariectomised rats as compared to normal rats and that this could be related to estrogen deficiency which in turn enhances bone resorption via increased RANKL and reduces bone formation via increased sclerostin and reduced P1NP. Finally, our study demonstrated for the first time that AED treatment displayed changes in the serum levels of wnt inhibitors and hence modulation of wnt inhibitors might be partly involved in their adverse effects on bone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Renal injury is a hallmark adverse reaction to sodium valproate (SVP), and caffeic acid (CAFF) is a phenolic compound that has anti-inflammatory and antioxsidant properties. So, this investigation was assessed to evaluate the nephrotoxic potential of SVP and the defensive impact of CAFF against SVP nephrotoxicity. SVP was given at a dose of 500 mg/kg (i.p.) once daily for 2 weeks, while CAFF was given at a dose of 50 mg/kg (orally), simultaneously with SVP. Concurrent treatment with CAFF reduced urea and creatinine, lipid peroxidation (malondialdehyde), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), nuclear factor kappa B (NF-κB/p65), and transforming growth factor β (TGF-β) levels. However, with increased glutathione content, CAFF also halted the activated Notch signaling cascade. Furthermore, CAFF suppressed caspase-3 and inducible nitric oxide synthase expressions. To conclude, on the basis of the results obtained, CAFF proved to protect against SVP-induced nephrotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic properties., (© 2018 Wiley Periodicals, Inc.)

Purpose: To understand the preconception experiences of women with epilepsy who have been taking the teratogenic drug valproate., Methods: Seven women were recruited, three from a preconception clinic and four from an antenatal clinic in a region of the UK. All had taken valproate preconceptionally. Three preconception clinic encounters were observed and audio-recorded. Interviews with all women were analysed using Interpretative Phenomenological Analysis (IPA)., Results: Women experienced a "trajectory of balance". Women moved from "maintaining balance" by using valproate to control seizures, to a "shattering of harmony" at the prospect of changing medication and as a result of the physical and mental effects of changing medication, to "restoring balance" which could involve "a new self" due to dramatic changes. Women balanced their health needs with those of their baby, and took responsibility for medication decision-making. They found it difficult to see "who is looking after me" in the healthcare system, either to access preconception care, or to support them through the stress of changing medication. Their journey ended with coming to terms with a variety of experiences: choosing not to have a baby due to unsuccessful change from valproate, recognising that a child from a previous pregnancy had been harmed by valproate or that the current pregnancy might be at risk, or successful medication change in preparation for pregnancy., Conclusion: A clear and adequately funded preconception care pathway is needed from epilepsy diagnosis, including support for stress. Understanding what influences maternalisation may help understand uptake of preconception care., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Sodium valproate is a commonly used anticonvulsant. It is widely recognized that valproate can cause hyperammonemia, particularly in people with underlying liver disease. Patients with urea cycle disorders are genetically predisposed to this adverse event and can develop severe hyperammonemia if given valproate. This can occur even if liver functions tests and plasma concentration of valproate are normal, highlighting the importance of checking ammonia levels in any patient presenting with encephalopathy. Specific treatment for hyperammonemia must be implemented promptly., Case Presentation: A 22-year-old white British man with a history of epilepsy post head trauma presented with subacute encephalopathy 4 weeks after the introduction of sodium valproate. His ammonia levels were not checked until 48 hours into his presentation and were found to be elevated. He initially responded to treatment of his hyperammonemia and the raised levels were attributed to sodium valproate. However, as his ammonia levels continued to rise, further investigation led to a diagnosis of ornithine transcarbamylase deficiency., Conclusions: Ornithine transcarbamylase deficiency is the most common of the urea cycle disorders. This case highlights both the importance of checking ammonia levels early and considering the diagnosis of this X-linked disorder in patients with raised ammonia, as these have implications both for the patient's acute and further management, and for family screening.

Purpose: This study aims to evaluate the associations between genetic polymorphisms and the effect of sodium valproate (VPA) therapy in children with generalized seizures., Methods: A total of 174 children with generalized seizures on VPA therapy were enrolled. Steady-state trough plasma concentrations of VPA were analyzed. Seventy-six single nucleotide polymorphisms involved in the absorption, metabolism, transport, and target receptor of VPA were identified, and their associations with the therapeutic effect (seizure reduction) were evaluated using logistic regression adjusted by various influence factors., Results: rs7668282 (UGT2B7, T > C, OR = 2.67, 95% CI: 1.19 to 5.91, P = 0.017) was more prevalent in drug-resistant patients than drug-responsive patients. rs2242480 (CYP3A4, C > T, OR = 0.27, 95% CI: 0.095 to 0.79, P = 0.017) and rs10188577 (SCN1A, T > C, OR = 0.40, 95% CI: 0.17 to 0.94, P = 0.035) were more prevalent in drug-responsive patients compared to drug-resistant patients., Conclusion: In children with generalized seizures on VPA therapy, polymorphisms of UGT2B7, CYP3A4, and SCN1A genes were associated with seizure reduction. Larger studies are warranted to corroborate the results., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to investigate the effect of carbamazepine (CBZ) and sodium valproate (VPA) monotherapy on sexual functions, sex hormones, and semen analysis and quality in male patients with epilepsy., Methods: A total of 59 male patients with epilepsy, of which 30 were on VPA monotherapy and 29 were on CBZ monotherapy, were included in the study between January 2015 and March 2016. A control group was established with 30 healthy males. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), free testosterone (fT), estradiol (E2), sex hormone-binding globulin (SHBG) levels and bioactive testosterone (BAT)/bioactive estradiol (BAE), and BAT/LH ratio were studied in groups. All groups received semen analysis and International Index of Erectile Function Scale (IIEF-5) test for erectile dysfunction., Results: E2 and DHEAS levels were higher in VPA and CBZ groups compared to control group (P < .001, P = .014). The decrease in fT levels in the VPA group was statistically significant (P = .038). No significant difference was detected in levels of SHBG, LH, and FSH (P > .05). BAT/BAE ratios were low both in VPA and CBZ groups (P < .001; P < .001), while BAT/LH ratios were low only in CBZ group (P = .033). In semen analysis, semen volume and number of normal sperms were found to be significantly lower in patients receiving antiepileptic drugs compared to control group (P < .05). There were no differences between the groups in rates of abnormal sperm morphology. IIEF-5 scores were found to be significantly lower in VPA and CBZ groups (P < .001)., Conclusion: VPA or CBZ therapy may lead to dysregulation of sex hormones, sexual dysfunction, and alterations in semen analysis in male patients with epilepsy. This must be considered for the selection of antiepileptic drugs in young male patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To explore the risk factors for the development of sodium valproate (VPA)-induced renal tubular dysfunction for early diagnosis and treatment., Study Design: The subjects were selected from patients who were diagnosed with epilepsy and administered VPA. Blood and spot urine samples were collected and measured the concentration of VPA, the level of serum phosphorus, serum uric acid, serum free carnitine, serum cystatin-c, and urine β2-microglobulin (BMG). Patients with urine BMG/creatinine levels above 219.2 were treated as renal proximal tubular dysfunction (RTD), with all others treated as non-RTD., Results: Eighty-seven patients, 4-48 years, 53 men and 34 women, were studied. RTD group is 17 patients and non-RTD group is 70 patients. Univariate analyses revealed that the RTD patients were more likely to be bedridden, receiving enteral tube feeding, taking more anticonvulsants, and demonstrating significantly lower serum levels of free carnitine, uric acid, and phosphorus. Among them, bedridden, free serum carnitine, and phosphorus levels were associated with the development of RTD by multivariate analysis., Conclusions: Bedridden patients receiving VPA are susceptible to hypocarnitinemia, which can cause RTD and may lead to FS. Therefore, urinary BMG should be measured regularly in all patients receiving VPA to assess renal tubular function. An additional measurement of serum free carnitine level should be considered in patients who developed RTD. Supplementation of carnitine for those patients to prevent such complication deserves for further study.

Background: Status epilepticus (SE) is a neurological emergency which can be life-threatening. Several medical regimens are used in order to control it. In this study, we intended to evaluate the clinical efficacy and tolerability of sodium valproate and intravenous phenytoin (IV PHT) in the control of SE., Methods: One hundred and ten consecutive patients suffering from benzodiazepine refractory SE who were referred to the emergency ward from March 2014 to March 2015 were randomly divided into two groups. The first group received intravenous sodium valproate, 30 mg/kg as loading dose and then 4-8 mg/kg every 8 hr as maintenance regimen. The second group received IV PHT 20 mg/kg as loading dose and then 1.5 mg/kg for 8 hr as maintenance therapy. All patients were monitored for vital signs every 2 hr up to 12 hr. The patients were also followed up for 7 days regarding drug response and adverse effects., Results: The administration of sodium valproate and phenytoin respectively resulted in seizure control in 43 (78.18%) and 39 (70.90%) of the patients within 7 days of drug administration ( p  = .428). Seven-day mortality rate was similar in both groups (12.73% vs. 12.73%; p  = .612). There was no significant difference in adverse effects between two groups., Conclusion: Sodium valproate is preferred to IV PHT for treatment and control of SE due to its higher tolerability and lower hemodynamic instability.

Purpose: This study aims to describe the incidence of adverse drug reactions (ADRs) in children receiving antiepileptic drugs (AEDs) and compare ADRs to the individual drugs when given as monotherapy., Method: Paediatric patients (≤18 years old) were enrolled for this prospective observational study over a 6-month period, between September 2015 and March 2016. Adverse reactions to antiepileptic drugs (AEDs) were elicited at the time of enrolment and after 3 months using the Paediatric Epilepsy Side Effects Questionnaire., Results: A total of 1139 suspected ADRs were reported in 124 participants. Eighteen different AEDs were prescribed. Sixty-six children (53%) were receiving AED monotherapy at the time of recruitment; 34/66 (52%) of whom received new generation AEDs. Levetiracetam was the most frequently prescribed AED (62/124, 50%). When only children receiving AED monotherapy were considered, fatigue, drowsiness, weight gain, dizziness were less likely with levetiracetam (p < .01). Slow thinking and decreased concentration were less likely with levetiracetam or carbamazepine than valproic acid (p < .05). Five patients (four on polytherapy) discontinued AED treatment due to ADRs and 2 had a dose reduction., Conclusions: Levetiracetam and carbamazepine were better tolerated than sodium valproate., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: A variant in the histone deacetylase 9 ( HDAC9 ) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate., Methods: Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression., Results: A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P =0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; P =0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P =0.003)., Conclusions: These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke., (© 2017 The Authors.)

Purpose: The purpose of this study was to compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)-resistant SE., Methods: Patients with LOR-resistant SE were randomized to intravenous LCM 400mg at the rate of 60mg/kg/min or SVA 30mg/kg at the rate of 100mg/min. The SE severity score (STESS), duration of SE and its etiology, and MRI findings were noted. Primary outcome was seizure cessation for 1h, and secondary outcomes were 24h seizure remission, in-hospital death, and severe adverse events (SAE)., Results: Sixty-six patients were included, and their median age was 40 (range 18-90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One-hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs 69.7%; P=0.79). Twenty-four-hour seizure freedom was insignificantly higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%). Death (10 vs 12) and composite side effects (4 vs 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (1 patient), and SVA with liver dysfunction (6)., Conclusion: In patients with LOR-resistant SE, both LCM and SVA have comparable efficacy and safety., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sodium valproate (VP) is an important antiepileptic drug, although it can produce deleterious hepatotoxic reactions. Diallyl trisulfide (DATS) is the principle component of garlic oil that possesses antioxidant properties. This study explored the potential hepatoprotective activity of DATS against VP-induced hepatic damage and its underlying mechanisms. In addition, the study assessed the effect of DATS on VP antiepileptic activity. Rats were given DATS once daily at two different doses along with VP for 2 weeks. Results have shown the ability of DATS to counteract VP-induced hepatic damage as it decreased elevated serum transaminases (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase. Liver histopathology indicated that DATS preserved the hepatic structural integrity and protected against VP-induced hepatic steatosis and necro-inflammation injury. DATS ameliorated VP-induced oxidative stress and increased the antioxidant capacity of the liver. Immunohistochemical analysis showed activation of nuclear factor kappa-B along with high expression of cyclo-oxygenase-2 (COX-2) upon VP administration. This was accompanied by overproduction of proinflammatory mediators (TNF-α, IL-1β, IL-6). Tracing the apoptotic pathway, VP administration induced marked apoptosis using TUNEL staining. Furthermore, VP-treated animals exhibited high immunoexpression of Bax protein and increased levels of Bax and caspase-3 while level of Bcl2 was significantly decreased in hepatic tissue. However, DATS simultaneous treatment counteracted all of these molecular pathological changes. Using pentylenetetrazole (PTZ)-induced seizures model in mice, the effect of DATS on the anticonvulsant activity of VP was found to be positive, meaning that combination of DATS with VP can confer protection against VP-induced hepatic injurious effects through its antioxidant, antiinflammatory, and antiapoptotic properties without affecting VP antiepileptic activity.

Sydenham's chorea is the most common acquired cause of chorea in the third world. We report a case of recurrent chorea successfully treated with sodium valproate. Miss A.C, aged 16, with a history of recurrent angina reported an episode of choreic movements 2 years before requiring treatment with haloperidol and prevention of rheumatic fever. The patient interrupted her treatment with occurrence of a relapse a few months later. Brain MRI and transthoracic ultrasound were normal. Preventive treatment with extencilline and haloperidol was restarted without any improvement, hence the treatment with sodium valproate. The patient responded very well after 2 months of treatment, without recurrence at 3 years' follow-up. The treatment of Sydenham's chorea was based on neuroleptics. Recent studies advocate the use of other more effective and better tolerated molecules.

Purpose: Excessive weight gain associated with sodium valproate (VPA) may predispose patients with epilepsy to other health problems such as insulin resistance. We prospectively evaluated the long-term impact of VPA monotherapy compared with lamotrigine (LTG) monotherapy on anthropometric and metabolic parameters in women with epilepsy. Our primary objective is to understand the underlying mechanism responsible for VPA-induced obesity., Methods: Sixty-six female patients with newly diagnosed or untreated epilepsy were included in the study. Thirty-four patients with VPA and thirty-two patients with LTG were treated for a period of one year in our center. Anthropometric and clinical data were collected at 5 time points: before, at 6th week, 3rd month, 6th month, 9th month and 12th month (last visit). Biochemical and hormonal data were collected 2 time points: before and last visit., Results: Subjects in the VPA group had significantly higher body weight than LTG-treated subjects (64.88±3.25 vs. 58.28±2.43, P<0.001). HOMA-IR level was significantly increased (2.76 vs. 1.35, P<0.05), and adiponectin levels were significantly lower in the VPA group (3.46 vs. 6.22, P<0.05). Triglycerides levels were significantly increased (118 vs. 96, P<0.05), and HDL-C levels were significantly lower in the VPA group. Both the VPA-treated group and the LTG-treated group showed no significant difference in term of total cholesterol, LDL-C, fasting blood glucose and serum leptin levels., Conclusions: Based on the findings of this study, we proposed that VPA induced hypoadiponectinemia which correlates significantly with insulin resistance. These two factors may be responsible for weight gain, possible by stimulating appetite. Valproic acid appears to be use cautionally in obese females with epilepsy., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic malondialdehyde and tumour necrosis factor α content significantly declined with concomitant increase in hepatic heme oxygenase-1 content and glutathione concentration with SFN treatment. In conclusion, SFN can significantly ameliorate VPA-induced hepatotoxicity and liver injury primarily by direct association between antioxidant and anti-inflammatory properties.

Purpose: Lamotrigine (LTG) is a broad-spectrum antiepileptic drug that is widely used in clinic. However, the effect of LTG on cognition and neurodegeneration during epilepsy treatment remains controversial. In this study, we compared the cognitive effects of LTG and sodium valproate in pentylenetetrazole (PTZ)-kindled animal model, and the dose dependency was tested for LTG., Methods: PTZ-kindled animals were divided into the following treatment groups: control group, treated with 3.5 mL/kg of 0.9% sodium chloride; low-dose LTG group, treated with 12.5 mg/kg of LTG; middle-dose LTG group, treated with 25 mg/kg of LTG; high-dose LTG group, treated with 50 mg/kg of LTG; VPA group, treated with 300 mg/kg of VPA. The Morris Water Maze (MWM) test commenced from the 10th day of treatment. Hippocampal cell apoptosis was determined by TUNEL staining after two weeks of treatment., Results: Compared to the vehicle-treated control group, escape latency was significantly reduced in the middle- and high-dose LTG- and VPA-treated groups on the 3rd and 4th day of the MWM test (p < .05), and spatial probe frequency was significantly improved in the middle- and high-dose LTG- and VPA-treated groups (p < .05). Furthermore, the immunohistochemical score of TUNEL positive cells significantly decreased in the hippocampal CA1 region in the middle- and high-dose LTG- and VPA-treated groups (p < .05)., Conclusion: Our data suggests that LTG may ameliorate epilepsy-induced cognitive impairment and neuronal cell apoptosis during epilepsy treatment. LTG may ameliorate cognitive impairment and neuronal cell apoptosis during epilepsy treatment., (© 2016 The Authors Synapse Published by Wiley Periodicals, Inc.)

Purpose: We report the efficacy and safety of lorazepam (LOR), phenytoin (PHT), valproate (VPA) and levetiracetam (LEV) as first and second choice antiepileptic drug (AED) in status epilepticus (SE) and their combinations in preventing refractory SE., Materials and Methods: The results of our two earlier trials on SE were compared; one evaluated VPA versus PHT (group I) and the other LOR versus LEV (group II). In group I, additional patients were recruited in addition to published data. The primary outcome was cessation of SE after first and second AEDs and secondary outcome was mortality and side effects. The efficacy of these four drugs as first and second choice was compared. The frequency of refractory seizure in groups I and II and their contributing factors were analyzed., Results: One hundred and seventeen patients were in group I and 79 in group II. The baseline characteristics of the patients were similar in LOR, LEV, VPA and PHT groups. As a first choice, LOR controlled SE in 75.1%, LEV in 76.3%, VPA in 55.4% and PHT in 44.2% patients. As a second choice, LEV was effective in 88.9%, LOR in 70%, VPA in 74.1% and PHT in 25% patients. Refractory SE was more frequent in group I than group II (29.9% versus 10.5%), however, complications and mortality were higher in group II., Conclusion: LOR and LEV combination was superior in reducing refractory SE but at the cost of higher complications and death.

Background: Epilepsy is the third most common cause of neurological disability worldwide. Despite the introduction of antiepileptic drugs (AEDs) in the past 20years, the seizures of around 30% of patients with epilepsy remain refractory to available treatment. Also, available AEDs and the disease itself have the potential to exert detrimental effects on cognitive function and therefore compromise patient wellbeing. S-adenosyl methionine has potential antiepileptic and memory-enhancing properties because of its involvement in the transmethylation reaction., Objectives: The present study was designed to evaluate the antiepileptic effect of S-adenosyl methionine and its role in memory impairment in the pentylenetetrazole (PTZ)-induced kindling model in rats., Materials and Methods: The antiepileptic effect of 2 doses of SAM (50 and 100mg/kg) was tested by evaluating seizure severity score and seizure latency in the pentylenetetrazole-induced kindling model in rats. At the end of the study, spatial memory was evaluated in an elevated plus maze (EPM) test, and animals were sacrificed for estimation of oxidative stress markers in brain tissue homogenate., Results: A higher dose of SAM (100mg/kg) exhibited an increase in seizure latency and a decrease in seizure severity score, suggesting its antiepileptic activity in the PTZ-induced kindling model. Also, the administration of SAM (50 and 100mg/kg) showed a decrease in transfer latency in the EPM test compared to the disease control group (p<0.0001). Biochemical analysis of rat brain tissue revealed significantly decreased malondialdehyde (p<0.0001) and increased glutathione (GSH) (p<0.0001) in the SAM 100-mg/kg group compared with that in the disease control group., Conclusion: The results demonstrated that S-adenosyl methionine exerts antiepileptic, memory-enhancing, and antioxidant properties in a pentylenetetrazole-induced kindling model of epilepsy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This work presents the development, validation and application of four simple and direct spectrophotometric methods for determination of sodium valproate (VP) through charge transfer complexation reactions. The first method is based on the reaction of the drug with p-chloranilic acid (p-CA) in acetone to give a purple colored product with maximum absorbance at 524nm. The second method depends on the reaction of VP with dichlone (DC) in dimethylformamide forming a reddish orange product measured at 490nm. The third method is based upon the interaction of VP and picric acid (PA) in chloroform resulting in the formation of a yellow complex measured at 415nm. The fourth method involves the formation of a yellow complex peaking at 361nm upon the reaction of the drug with iodine in chloroform. Experimental conditions affecting the color development were studied and optimized. Stoichiometry of the reactions was determined. The proposed spectrophotometric procedures were effectively validated with respect to linearity, ranges, precision, accuracy, specificity, robustness, detection and quantification limits. Calibration curves of the formed color products with p-CA, DC, PA and iodine showed good linear relationships over the concentration ranges 24-144, 40-200, 2-20 and 1-8μg/mL respectively. The proposed methods were successfully applied to the assay of sodium valproate in tablets and oral solution dosage forms with good accuracy and precision. Assay results were statistically compared to a reference pharmacopoeial HPLC method where no significant differences were observed between the proposed methods and reference method., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Epilepsy is a chronic neurological disease affecting more than 69 million people worldwide, nearly 90% of them in low and middle-income countries (LMICs). In those countries, only four major antiepileptic drugs are commonly used: phenobarbital, carbamazepine, sodium valproate and phenytoin. There are also problems with the accessibility, availability and quality of drugs. The main objective was to review the literature concerning "long" sustained-release formulations of AEDs that have the potential to reduce the number of administrations and help overcome problems of compliance, accessibility and the treatment gap. The main endpoint was a releasing of the active ingredient over more than 24h. We also assessed the feasibility and acceptability in resource-limited settings. Two drugs were found in unconventional release formulations: carbamazepine and sodium valproate; but they were not "long" sustained release because they required administration once a day. Several techniques were available, including: esterification, transdermal devices, liposomes and polymeric devices preformed or formed in situ. In situ methods for the preparation of injectable biodegradable microparticles or implants for controlled delivery seemed best suited to the objective. Furthermore, they appear to fulfil the requirements of feasibility and cost. Sodium valproate appeared as well to be a relevant candidate for a "long" sustained release formulation that would improve access to medicines for people with epilepsy in resource-limited settings. ., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Sodium valproate (VPA) is a potentially hepatotoxic antiepileptic drug. Risk of VPA-induced hepatotoxicity is increased in patients with mitochondrial diseases and especially in patients with POLG1 gene mutations. We used a HepG2 cell in vitro model to investigate the effect of VPA on mitochondrial activity. Cells were incubated in glucose medium and mitochondrial respiration-inducing medium supplemented with galactose and pyruvate. VPA treatments were carried out at concentrations of 0-2.0mM for 24-72 h. In both media, VPA caused decrease in oxygen consumption rates and mitochondrial membrane potential. VPA exposure led to depleted ATP levels in HepG2 cells incubated in galactose medium suggesting dysfunction in mitochondrial ATP production. In addition, VPA exposure for 72 h increased levels of mitochondrial reactive oxygen species (ROS), but adversely decreased protein levels of mitochondrial superoxide dismutase SOD2, suggesting oxidative stress caused by impaired elimination of mitochondrial ROS and a novel pathomechanism related to VPA toxicity. Increased cell death and decrease in cell number was detected under both metabolic conditions. However, immunoblotting did not show any changes in the protein levels of the catalytic subunit A of mitochondrial DNA polymerase γ, the mitochondrial respiratory chain complexes I, II and IV, ATP synthase, E3 subunit dihydrolipoyl dehydrogenase of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and glutathione peroxidase. Our results show that VPA inhibits mitochondrial respiration and leads to mitochondrial dysfunction, oxidative stress and increased cell death, thus suggesting an essential role of mitochondria in VPA-induced hepatotoxicity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The complexes [Pd(valp)2(imidazole)2] (1), [Pd(valp)2(pyrazine)2] (2) (valp is sodium valproate) have been synthesized and characterized using IR, (1)H NMR, (13)C{(1)H} NMR and UV-Vis spectrometry. The interaction of complexes with CT-DNA has been investigated using spectroscopic tools and viscosity measurement. In each case, the association constant (Kb) was deduced from the absorption spectral study and the number of binding sites (n) and the binding constant (K) were calculated from relevant fluorescence quenching data. As a result, a non-covalent interaction between the metal complex and DNA was suggested, which could be assigned to an intercalative binding. In addition, the interaction of 1 and 2 was ventured with bovine serum albumin (BSA) with the help of absorption and fluorescence spectroscopy measurements. Through these techniques, the apparent association constant (Kapp) and the binding constant (K) could be calculated for each complex. Evaluation of cytotoxic activity of the complexes against four different cancer cell lines proved that the complexes exhibited cytotoxic specificity and significant cancer cell inhibitory rate. Moreover, density functional theory (DFT) calculations were employed to provide more evidence about the observed data. The majority of trans isomers were supported not only by energies, but also by the similarity of its calculated IR frequencies, UV adsorptions and NMR chemical shifts to the experimental values., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: We determined the median effective dose (ED50) values for the anticonvulsants phenobarbital and sodium valproate using a modification of Lorke's method. This modification allowed appropriate statistical analysis and the use of a smaller number of mice per compound tested., Methods: The anticonvulsant activities of phenobarbital and sodium valproate were evaluated in male CD1 mice by maximal electroshock (MES) and intraperitoneal administration of pentylenetetrazole (PTZ). The anticonvulsant ED50 values were obtained through modifications of Lorke's method that involved changes in the selection of the three first doses in the initial test and the fourth dose in the second test. Furthermore, a test was added to evaluate the ED50 calculated by the modified Lorke's method, allowing statistical analysis of the data and determination of the confidence limits for ED50., Results: The ED50 for phenobarbital against MES- and PTZ-induced seizures was 16.3mg/kg and 12.7mg/kg, respectively. The sodium valproate values were 261.2mg/kg and 159.7mg/kg, respectively., Discussion: These results are similar to those found using the traditional methods of finding ED50, suggesting that the modifications made to Lorke's method generate equal results using fewer mice while increasing confidence in the statistical analysis. This adaptation of Lorke's method can be used to determine median letal dose (LD50) or ED50 for compounds with other pharmacological activities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Adverse effects on the bone are amongst the potentially adverse clinical consequences with antiepileptic drugs (AEDs). This study compared the effects of 3 AEDs (phenytoin (PHT), sodium valproate (SVP), and levetiracetam (LTM)) on the bones of a Swiss strain of albino female mice. Drugs were administered daily for 4 months at doses that produced plasma concentrations corresponding to the clinically relevant therapeutic ranges. PHT and SVP (but not LTM) significantly lowered the bone mineral density (BMD) of lumbar vertebrae (L2-L4) as evaluated by dual-energy X-ray absorptiometry (DEXA) scan. The findings were supported by histopathology of vertebral (lumbar) bone and analysis of bone turnover markers. While both PHT and SVP reduced alkaline phosphatase (ALP) and hydroxyproline (HxP) in lumbar vertebrae, and elevated tartarate-resistant acid phosphatase (TRAP) and urinary excretion of calcium, LTM did not affect any of these markers of bone turnover, indicating that the drug might be a safer option in female epileptic patients prone to bone changes.

The effects of the antiepileptic drugs sodium valproate (VPA) and levetiracetam (LEV) on reproductive endocrine function, sexual function, and spermatozoa were explored, together with their possible etiological mechanisms, in Chinese Han men with epilepsy. Following VPA treatment (n=32), luteinizing hormone and follicle-stimulating hormone levels were significantly lower than in controls (n=30). The bioactive testosterone/luteinizing hormone ratio and the prolactin level were significantly elevated in the VPA treatment group. There were no significant differences in these hormones between the LEV treatment (n=20) and control groups. The rates of sperm morphologic abnormality (head, body, and tail) were significantly higher in the VPA treatment group than the control group but did not differ significantly between the LEV treatment and control groups. The sperm motility rate was significantly lower in the VPA treatment group (grade A sperm motility rate <25%, grade A+B sperm motility rate <50%) than in controls, as well as in the LEV treatment group (grade A sperm motility rate <25%). Patients in the VPA and LEV treatment groups had lower scores on questions 1, 2 and 3 of a simplified International Index of Erectile Function Scale than controls, but no significant difference on questions 4 or 5. The total International Index of Erectile Function Scale scores were significantly lower in the VPA and LEV treatment groups. We conclude that treatment with VPA adversely affects reproductive endocrine function, sperm parameters and sexual function to varying degrees in Chinese men with epilepsy., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)