Dose Of Sodium Valproate Research Articles

Facial dysmorphism and Limb abnormalities of Fetal Valproate Syndrome.

A neonate born to nonconsanguineous parents was evaluated for dysmorphic features. The neonate was born at term by normal vaginal delivery. The mother has had epilepsy for 12 years and has been on sodium valproate (700 mg/day) since conception and throughout pregnancy. Examination revealed facial dysmorphism, including triangular forehead, sparse arched eyebrows, telecanthus, flat nasal bridge, long thin upper vermilion border, smooth philtrum, and low-set ears. The limb anomalies observed were arachnodactyly, wrist and elbow contractures, clinodactyly, hypoplastic toenails, and overlapping toes. The other dysmorphisms noted were widely spaced nipples and hypospadias. Ultrasonogram (USG) cranium showed bilateral choroid plexus cysts, and USG abdomen revealed bilateral mild hydronephrosis. 2D-Echocardiography revealed a small patent ductus arteriosus (PDA). A diagnosis of fetal valproate syndrome (FVS) was considered, and other differentials, including fetal alcohol syndrome and genetic conditions, were ruled out by a clinical geneticist review. The index neonate is currently on multidisciplinary follow-up. The index neonate had common features of FVS as described in the literature, in addition to wrist and elbow contractures. Apart from the anomalies, there is a significant risk for neurocognitive delay and neurodevelopmental disorders. Postnatally, these babies need multidisciplinary care and neurodevelopmental follow-up. Valproate use for treating epilepsy in pregnant women and women of childbearing age may be restricted, and alternative choices of ASMs with better safety profiles should be preferred. Facial dysmorphism and limb anomalies in fetal valproate syndrome may occur irrespective of the dose of sodium valproate. Fetal valproate syndrome may present with wrist and elbow contractures.

Dermatoprotective effect of Moringa oleifera leaf extract on sodium valproate-induced skin damage in rats

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.

<i>Sinapis alba</i> ln Status Epilepticus: A Preclinical Study

In this study, the anti-convulsant effect of Sinapis alba seed oil and its combination with sodium valproate was evaluated in Wistar albino rats using the lithium-pilocarpine Status Epilepticus (SE) model. The experimental groups included: Group I - normal control; Group II - disease control; Group III - Sinapis alba seed oil; Group IV - sodium valproate; Group V - Sinapis alba seed oil + ½ dose sodium valproate. Antioxidant markers and Brain-Derived Neurotrophic Factor (BDNF) levels were measured from the brain samples. The pathological changes were also determined using Cresyl violet staining. Sinapis alba oil did not prevent rats from developing status epilepticus but reduced the intensity and frequency of occurrence. Oil administration increased antioxidant levels and decreased lipid peroxide levels as well. The combination of oil and sodium valproate showed a synergistic effect in the status epilepticus model. The study results show that Sinapis alba can be used as an adjuvant in status epilepticus along with other antiepileptic drugs.

DETERMINATION OF THE LEVEL OF VALPROIC ACID IN THE BLOOD AGAINST THE BACKGROUND OF THE COMBINED USE OF VALPROATES WITH ERTAPENEM IN PEDIATRIC PRACTICE

The article presents a clinical case of the combined use of valproic acid and an antibacterial drug from the carbapenem group – ertapenem in a 15-year-old girl with epilepsy in a pediatric hospital. Therapeutic drug monitoring with an assessment of the level of valproic acid in blood plasma against the background of joint use with carbapenem (ertapenem) allowed to revise and adjust the prescribed antibacterial therapy, and later allowed to adjust the daily dose of sodium valproate in a child with epilepsy. The change of the antibacterial drug was accompanied by an increase in the level of valpro-ic acid in the blood plasma. The transition from intravenous administration of valproic acid to enteral administration of the drug was accompanied by a decrease in the concentration of valproic acid in blood plasma. The authors of the article presented data confirming the need for therapeutic drug moni-toring in children receiving valproic acid and beta-lactam antibiotic from the carbapenem group - ertapenem, based on the known mechanisms of famacokinetic interaction, as well as in patients whose management tactics are planned to change the dosage form of valproic acid.

Therapeutic Potency of Camellia sinensis Extract on Neurochemical and Oxidative Changes Correlates to Autistic Disorder in Rat Pups Model

Background: Prenatal exposure to valproate is capable of inducing experimental autism in rat pups. This study aimed to investigate the role of Camellia sinensis green tea extract (GTE) in ameliorating the neurochemical changes induced by autism. Methods: Pregnant rats were treated with a single intraperitoneal dose of sodium valproate (600 mg/kg) on the 12.5th gestational day. The treatment with GTE (300 mg/kg) orally in autistic rat pups at postnatal day 15 for 20 days. Result: Induction of autism resulted in a significant decrease in the cerebellum and cortical 5-HT, DA, NE, GABA, glycine and taurine and a decrease in brain cholesterol and antioxidants enzymes (GSH, SOD and CAT) at P less than 0.05. However, it showed a significant increase in MAO, AChE, glutamate, aspartate, serine and lipid peroxidation in addition to elevation in inflammatory biomarkers in brain tissue. Treatment with GTE extract showed significant decrease in AChE and MAO in addition to reduction in the excitatory amino acid GABA in brain tissue which in accordance resulted in marked elevation in cerebellar and cortical monoamine contents. Furthermore, administration of GTE improved the antioxidant defence system in cerebellum and cerebral cortex by activating the level of GSH, SOD and CAT. These results are accompanied by marked reduction in oxidative stress biomarker (NO and MDA) and lowering in the level of TNF-α and IL-6. In conclusion, it could be stated that GTE exerts an ameliorative effect on autistic rat pups possibly due to antioxidant and anti-inflammatory effects and could be effective in the management of autism.

P01 An unusual case of pregnancy associated osteoporosis presenting with bilateral neck of femur fractures

P01 An unusual case of pregnancy associated osteoporosis presenting with bilateral neck of femur fractures

Antioxidant, Antiinflammatory, and Antiapoptotic Effects of Rutin in Spleen Toxicity Induced by Sodium Valproate in Rats

Aim: Long-term exposure to sodium valproate, an antiepileptic drug, causes toxic effects in tissues, especially by increasing oxidative stress and inflammation. Rutin is a flavanoid with antioxidant, anti-inflammatory and antiapoptotic effects found naturally in many plants. In this study, we aimed to investigate the effects of rutin, a natural antioxidant, on sodium valproate-induced spleen tissue damage. 
 Materials and Methods: 35 male rats were divided into 5 groups as control, sodium valproate, rutin, sodium valproate+Rutin 50 and sodium valproate+Rutin 100 groups. For 14 days, 500 mg/kg dose of sodium valproate and 50 or 100 mg/kg of rutin were administered by oral gavage. On day 15, spleen tissues were removed and biochemical methods, oxidative stress, inflammation and apoptotic parameters were analyzed and histologic analysis was performed.
 Results: The levels of sodium valproate-induced oxidative stress, inflammation and apoptosis parameters increased in spleen tissues compared to the control group (p

Genetic generalized epilepsy: factors associated with drug resistance polytherapy

BackgroundDifferent studies investigating generalized genetic epilepsy (GGE) have shown that achieving 5 years of remission, early seizure remission, and needing antiseizure medication (ASM) monotherapy may predict favorable long-term outcomes.ResultsThis is a retrospective analytical cohort study. Records of patients with GGE diagnoses at a large epilepsy center in Cairo served as the data source. 630 patients (297 male patients (47.1%) and 333 female (52.9%)) were included, their median onset age was 13 years. The follow-up period of this study was at least 4 years. 418 patients (66.1%) were early remitters, 160 patients (25.4%) were late remitters, and 52 patients (8.3%) were intractable. In addition, 367 patients (58.3%) needed a single ASM to achieve a maximum remission period (monotherapy group), while 263 patients (41.7%) needed ASM polytherapy. Stepwise regression analysis revealed that absence seizures, clusters of seizures, seizure frequency before treatment, and dose of sodium valproate (VPA) until the first remission were independent predictors for polytherapy. Moreover, absence seizures, seizure frequency before treatment, VPA dose, and catamenial seizures in females were independent predictors of intractability.ConclusionThe majority of GGE have a favorable outcome, some clinical features could predict the need for polytherapy and failure of remission on treatment.

Co-administration of Zingiber officinale Extract and Sodium Valproate Ameliorates Seizure Severity, Cognitive Deficit, and Neuronal Cell Loss in Pentylenetetrazole-kindled Mice

Preparations of Zingiber officinale are used in Nigerian folk medicine to manage colds, pain, arthritis, nausea, and epilepsy. The ameliorative effects of co-administering aqueous Zingiber officinale extract (GE) and sodium valproate (SDV) on pentylenetetrazole-kindled mice were evaluated regarding cognitive deficits, neuronal cell loss, and seizure severity. GFAP was also quantified. Male mice were pretreated with GE (50 mg/kg), SDV (100 and 200 mg/kg), and GE + SDV before kindling. After kindling, the mice underwent a learning performance test. The animals received a challenge dose of pentylenetetrazole one week after kindling. The brains were excised one day after the challenge test and were processed for GFAP immunohistochemistry and histopathology. GE alone did not affect PTZ-kindled seizures. However, treatment with GE and SDV significantly improved learning performance and protected against neuronal cell loss in pentylenetetrazole-kindled mice. The level of astrocyte activation was reduced in the kindled group pretreated with the extract. The results obtained suggested that co-administration of GE and a low dose of SDV significantly ameliorated learning deficits and protected against neuronal cell loss, astrogliosis, and neuroinflammation, suggesting that GE might be a beneficial co-medication in the management of epilepsy.

Efficacy of levetiracetam, lamotrigine and sodium valproate on seizure attacks and EEG disorders in patients with juvenile myoclonic epilepsy: A double blind randomized clinical trial.

Background:Juvenile myoclonic epilepsy (JME) is one of the most important types of generalized idiopathic epilepsy. Patients generally respond quickly and perfectly to standard antiepileptic drugs but lifelong medication is necessary. Sodium valproate is the drug of choice in most references but it has some adverse reactions and some patients cannot tolerate the complications. Because of the need for life long treatment in this young aged group particularly child bearing women, we aimed to analyze the efficacy of these drugs to determine which has better efficacy with lower adverse effects.Methods:In this double-blind clinical trial 102 patients suffering from juvenile myoclonic epilepsy were randomly divided to three groups and treated with valproate, levetiracetam or lamotrigine and followed for 12 months at specified intervals.Results:Patients' mean age was 22.8 years and 28.4% of them were males and 71.6% were females. Effective terminal dose of sodium valproate, levetiracetam and lamotrigine were 1000, 1000 and 250mg, respectively. The rate of failure in controlling seizures and myoclonic jerks in lamotrigine group was meaningfully more than levetiracetam and sodium valproate (P=0.037).The general side effects of sodium valproate were much more; but there was not any significant difference between their effects on electroencephalogram (EEG) findings (P=0.81).Conclusion: Levetiracetam and sodium valproate have similar efficacy. But in the group of lamotrigine, rate of failure, myoclonus and drug adverse reactions were meaningfully more than sodium valproate and levetiracetam. According to our study, lamotrigine could not be a suitable treatment option for JME patients as a mono therapy. Levetiracetam can be a good alternative to sodium valproate, especially in women of childbearing age.

The effects of regular swimming exercise during sodium valproate treatment on seizure behaviors and EEG recordings in pentylenetetrazole-kindled rats

We investigated the effects of alone/combined regular swimming exercise and sodium valproate on epileptic seizure behaviors and EEG recordings, anti-oxidative mechanism, learning, and memory in pentylenetetrazole (PTZ)–kindled rats. Forty-eight healthy rats were randomly divided into eight equal groups as control (CONT), swimming exercise (EX), sodium valproate (SV), SV+EX, PTZ, EX+PTZ, SV+PTZ and SV+EX+PTZ. The rats were forced to regular swimming exercise for 60 min every other day, 13 doses of PTZ (40 mg/kg) were given to induce epileptic seizures and 200 mg/kg SV was given for 28 days. Epileptic seizures were evaluated by visual observation and EEG recordings (total spike numbers and number of epileptiform discharges). Memory and learning skills were assessed with passive avoidance test. According to our visual seizure observations, seizure latency was prolonged only in SV+EX+PTZ (p < 0.001) group, seizure severity score decreased in SV+PTZ (p < 0.05) and SV+EX+PTZ (p < 0.001) groups and seizure frequency was reduced in SV+PTZ (p < 0,001), EX+PTZ (p < 0,001), and SV+EX+PTZ (p < 0,001) groups. Total spike numbers and number of epileptiform discharges highly increased in PTZ group, whereas they decreased in swimming exercise and/or SV treatment groups. The most effective result was seen in the combined therapy group. Memory deficit was observed in PTZ –kindling group, but it didn’t change with exercise or SV. Based on our results, regular swimming exercise had positive effects on PTZ-induced seizure frequency, and combined therapy of regular swimming exercise and SV is the most effective way to ameliorate visual seizure behaviors and decrease spike numbers and number of epileptiform discharges according to EEG recordings. Regular swimming exercise could be an alternative option to reduce the dose of SV and the side effects of SV can be avoided in clinical aspects.

Decreased fetal heart rate variability and maternal combined dose of sodium valproate and phenytoin.

A 32-year-old Japanese woman was admitted at 38 weeks' gestation with regular uterine contractions. She was diagnosed with frontal lobe epilepsy at the age of 17, and she had been treated with several anti-epileptic drugs (AEDs) since then but complied poorly due mainly to nausea and frequent seizure attacks.

An audit addressing the quality of prescribing sodium valproate in early intervention service

AimsThis Audit aims to review prescribing practice concerning Valproate in early intervention services.MethodThe audit was undertaken across four EI hubs in Birmingham. Audit standards were derived from POMH-UK (Prescribing Observatory for Mental Health) QIP. Drug cards of the entire EIS caseload in November 2020 were reviewed to identify patients on any preparation of Valproate. A total of 31 patients were identified. Electronic notes of all the patients on Valproate were reviewed to compare prescribing practices against national standards.ResultA total of 31 patients were prescribed sodium Valproate. All these patients had target symptoms documented in their notes. Reason for starting Valproate was mostly documented as agitation and aggression rather than elation in the mood. In was unclear if patients had full physical health checked before starting Valprotae as in majority (94%) valproate was commenced as an inpatient. Not all cases had detailed inpatient discharge notes making it difficult to fully understand the rationale for starting Valproate.55% of the patients were on an off-license valproate preparation. Where used off-license majority (93%)of these patients had no documentation of the rationale behind off-license use. Similarly, in most cases (93%)there was no evidence of off-license use being discussed with the patients. Most patients had received adequate monitoring in the community (74%) although there was limited documentation of screening for common side effects. Prescribers were noted to be using Semi-sodium Valproate and Sodium Valproate interchangeably despite these not being bioequivalent.ConclusionWe recommend that 1.Periodic treatment reviews should document the assessment of response and screening for side effects.2.Where used clinician should clearly discuss and document the off-license use with patients. 500 mg Semi-sodium valproate (Depakote) is approximately equivalent to 433 mg Sodium Valproate (Epilim). If switching from Semi-sodium Valproate to Sodium Valproate, a slightly higher (approximately 10%) dose of Sodium Valproate should be used.3.Unless clear evidence of affective illness is identified, the ongoing need for Valproate should be regularly reviewed by the clinicians.

Catatonia associated with seizures due to parietal cavernoma.

Catatonia associated with seizures due to parietal cavernoma.

Experimental evaluation of anticonvulsant activity of calcium channel blocker - cinnarizine alone and in combination with N-methyl-D-aspartate receptor antagonist ketamine in mice

Background: Epilepsy disease is a chronic condition of the brain affecting the global population and ranked as the world’s second most common neurological disorder, characterized by recurrent seizures. Despite enormous research advances in the treatment field of epilepsy, conventional antiepileptic drugs failed as a better treatment strategy. These limitations emphasized the necessity for exploring the drugs which make the treatment of epilepsy more effective. In our study, cinnarizine, a calcium channel blocker, and Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, are used alone and in combination to evaluate their effectiveness in treating epilepsy by controlling seizures. Aim and Objectives: The aim of the study was to evaluate the anticonvulsant activity of calcium channel blocker, using cinnarizine alone and in combination with NMDA receptor antagonist ketamine by producing pentylenetetrazol (PTZ)-induced convulsions in male albino mice. Materials and Methods: Anti-convulsant activity of calcium channel blocker, using cinnarizine alone and in combination with ketamine by producing PTZ induced convulsions in male albino mice species was studied. Institutional Animal Ethics Committee permission was acquired before the commencement of the experimental study. Thrity male albino mice (body weight – 24–40 g) were separated into five groups with the allocation of six mice in each group. Group 1 (Control group) received 0.5 ml distilled H2O, Group 2 (Standard group) received 150 mg/kg of sodium valproate dose, Group 3 (Test group 1) received 30 mg/kg of Cinnarizine, Group 4 (Test group 2) received 50 mg/kg of Ketamine, and Group 5 (Test group 3) received cinnarizine (30 mg/kg) and Ketamine (50 mg/kg) combination. After 30 min of administration of control (0.5 ml distilled water), standard drug, and test drug, male albino mice were injected, PTZ (60 mg/kg), subcutaneously and were monitored. The mean time of onset of convulsion (seconds) mean duration of convulsion, and percentage of protection readings were recorded for 1 h. Results: Group 1 (Control group) displayed 0% protection from convulsions and Group 2 (Standard group) exhibited 100% and Group 5 (Test group 3) (T3) exhibited 66.66% protection from convulsions, indicating that the combination of cinnarizine (30 mg/kg) and ketamine (50mg/kg) was effective in PTZ-induced seizures in male albino mice. Conclusion: The anticonvulsant property of cinnarizine and ketamine was less effective when used alone whereas combination was effective, supporting rational use of polytherapy in the treatment of epilepsy.

KEPPRA (Levetiracetum) VS EPIVAL (Sodium Valporate) to control generalized tonic clonic seizures.

Objective: This present study is design to assess the efficacy and frequency of side effects with a newer anti-epileptic agent levertiracetum while comparing an older anti-epileptic, Sodium Valproate, in the patients with generalized tonic colonic epilepsy. Material &amp; Methods: Patients with GTC epilepsy had been allocated in two groups, A and B, Group A was given Sodium valproate while group B was given levertiracetum. Study Design: Randomized Control Trial. Setting: Fatima Memorial Hospital, Lahore and Allied Hospital, Faisalabad. Period: December, 2017 to December, 2018. Results: Seventy five subjects were taking levertiracetum from three months out of which 56(74.7%)were seizures free, 15(20%) were seizure free on higher dose,6(8%) were with dizziness ,vertigo and 9(12%) were with somnolence. Fifty-four individuals were seizures free with normal dose of sodium valproate from last 3 months, and 16(21%) were seizures free on higher doses among which 53(70%) were with side effects of weight gain and 69(92%) were with hand tremors and this was the most prominent side effects among individuals who were taking sodium valproate. Conclusion: Generalized tonic colonic epilepsy is one of the most common forms of epilepsy and with the advent of newer anti-epileptic drugs like levertiracetum, such seizures can be controlled in with lesser side effects as compared to older antiepileptic agent Sodium Valproate.

Evaluation of the Protective Effect of Ademetionine, Cytoflavin, and Dihydroquercetetine on Blood Enzymes Activity in Rats Treated with High Doses of Sodium Valproate.

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.

Evaluation of sodium valproate low dose efficacy in radicular pain management and it's relation with pharmacokinetics parameters.

BackgroundRadiculopathy due to lumbar or cervical disc disease is the most common chronic neuropathic pain in adults. The aim of present study was evaluation of low dose of sodium valproate (VPA) on radicular pain and determining VPA pharmacokinetics.Materials and MethodsIn this double blind randomized placebo control clinical study, 80 patients with established lumbar or cervical radicular pain, have been randomly allocated into two study groups: 40 have received sodium valproate 200 mg/day and Celecoxib 100 mg/day and acetaminophen 500 mg PRN as rescue medication, and second group has received placebo, Celecoxib and acetaminophen. Quantitative assessment of pain was done by visual analogue scale (VAS) prior to perform the intervention and after ten days (treatment duration). Blood sample has been taken for determining mean through concentration after five half-lives. Evaluation of plasma concentration of VPA and that of efficacy on pain score relationship by comparing VAS before and after the therapy was done.ResultsGroup A and B have demonstrated significant alleviation in mean VAS score; −21.97 ± 25.41, −14.39 ± 23.03 respectively (P < 0.001). The mean plasma concentration of VPA in group A was: 26.9 ± 13.5 mg/L. Moreover, no significant correlation was seen between pain score with age, gender, and weight (p > 0.05).ConclusionLow dose of sodium valproate especially together with NSAIDs demonstrated good efficacy in lumbar and cervical radicular pain management.

A Case of Macrophagic Activation Syndrome in a Child with Epilepsy Treated with an Excessive Dose of Sodium Valproate

Macrophagic Activation Syndrome (MAS) is a rare disorder and is thought to result from non-malignant activation and proliferation of macrophages and T-cells. It can be of primary or secondary origin and its prognosis is often poor. Authors report a case of a three-year-old boy admitted in the intensive care unit for MAS secondary to an overdose of sodium valproate to remind practitioners to think about it in the presence of a febrile pancytopenia.

Interaction of Sodium Valproate With Low-Frequency Electrical Stimulation During Kindlingn.

Introduction:The interaction between antiepileptic drugs and brain electrical stimulation is a potential therapy to control seizures in patients with pharmacoresistance to drugs. So, the present study aimed to design to determine the effect of a subeffective dose of sodium valproate combined with low-frequency electrical stimulation during kindling.Methods:One tripolar electrode was implanted stereotactically in the CA1 hippocampus of male Wistar rats. One week after surgery, the rats were kindled by electrical stimulation of hippocampus in a rapid manner (12 stimulations/day) for 6 days with sodium valproate alone or combined with low-frequency electrical stimulation (four packages contained 200 monophasic square wave pulses of 0.1-ms duration at 1 Hz, immediately after kindling stimulations). The duration of afterdischarge, maximum latency to stages 4 and 5, and the maximum duration of these stages were recorded by electromadule during kindling.Results:Application of sodium valproate with low-frequency electrical stimulation caused a reduction in cumulative afterdischarge duration. The maximum latency to the onset of stage 5 seizure increased after sodium valproate application alone, without having a significant effect on the fourth stage. Our findings showed reductions in the seizures duration and increasing in the latency times of both stages after the application of sodium valproate with low-frequency electrical stimulation.Conclusion:It seems that usage of sodium valproate with low-frequency electrical stimulation during kindling was more effective to suppress the epileptic activity than its administration alone and may have a critical role on the antiepileptic effects of sodium valproate.