Valproate Acid Research Articles

Blocking salt-inducible kinases with YKL-06-061 prevents PTZ-induced seizures in mice.

Epilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in salt-inducible kinases (SIKs) have been identified in epileptic encephalopathy, it is not known whether blocking SIKs can prevent pentylenetetrazole (PTZ)-induced seizures. We first determined the time course of SIKs (including SIK 1, 2, and 3) in the hippocampus of PTZ treated mice. And then, we evaluated the effects of anti-epilepsy drug valproate acid (VPA) on the expression of SIK 1, 2, and 3 in the hippocampus of PTZ treated mice. Next, we investigated the effect of different dose of SIKs inhibitor YKL-06-061 on the epileptic seizures and neuronal activation by determining the expression of immediate early genes (IEGs) in the PTZ treated mice. We found that PTZ selectively induced enhanced expression of SIK1 in the hippocampus, which was blocked by VPA treatment. Notably, YKL-06-061 decreased seizure activity and prevented neuronal overactivity, as indicated by the reduced expression of IEGs in the hippocampus and prefrontal cortex. Our findings provide the first evidence that SIK1 affects gene regulation in neuronal hyperactivity, which is involved in seizure behavior. Targeting SIK1 through the development of selective inhibitors may lead to disease-modifying therapies that reduce epilepsy progression.

Zebrafish EEG predicts the efficacy of antiepileptic drugs.

Background: Pharmacological evaluation of antiepileptic drugs (AEDs) using mammalian animals takes long time and is expensive. The zebrafish is a species commonly used to study brain functions, neurological diseases, and drug toxicity, and attracts more attention as an alternative animal model to substitute or supplement mammalian animals in drug development. Electroencephalogram (EEG) is a key indicator for diagnosing brain diseases such as epilepsy, by directly measuring the brain activity. We propose a novel method for pharmacological evaluation of AEDs based on EEG from adult zebrafish, which allows researchers to select more clinically valuable drugs at the early stage of AED screening. Methods: To evaluate the efficacy of AEDs, zebrafish EEG signals were measured after administering six AEDs (valproate acid, gabapentin, ethosuximide, oxcarbazepine, tiagabine, and topiramate) at various doses to pentylenetetrazol (PTZ)-induced seizure models. The change in seizure activity was investigated according to doses. The antiepileptic effect was determined by observing a significant decrease in at least one out of three indicators of the number, total duration, and mean duration of ictal events. Results: Using EEG signals from adult zebrafish, antiepileptic effects were observed with all six AEDs. Among them, antiepileptic effects depending on dose were confirmed with valproate acid, gabapentin, ethosuximide, and tiagabine. Moreover, the 50% effective doses (ED50) of valproate acid and tiagabine were determined based on zebrafish EEG for the first time, indicating that the quantitative inter-species comparison of the AED efficacy is possible between zebrafish and mammals such as rodents. Significance: The results show that zebrafish can be used to effectively and quantitatively evaluate the efficacy of AEDs based on EEG, the same method to evaluate antiepileptic effects in mammals, suggesting that the proposed method can contribute in reducing the cost and duration of search for AEDs and thus accelerate the drug development cycles.

Two cases of childhood absence epilepsy who showed seizure disappearance after ethosuximide drug eruption

BackgroundRecent studies suggest potential roles of immune response in the pathophysiology of epilepsy. Anti-seizure medications (ASMs) are known to have side effects of drug eruption caused by immune responses. A few reports in adults have demonstrated disappearance of seizures after an ASM drug eruption episode. In this paper, we described 2 cases of childhood absence epilepsy (CAE) who showed seizure disappearance after ethosuximide (ESM) drug eruption, suggesting the possibility that the epilepsy disappears due to immune responses to ASM.Case presentationCase 1 was an 8-year-old girl diagnosed with CAE. She was treated with valproate acid (VPA) initially, and then ESM was administered as an additional treatment. Her epileptic seizure disappeared 4 days after initiation of ESM. However, drug eruption appeared 1 week after the administration of ESM. Even after discontinuation of ESM administration, she maintains no seizure after the drug eruption. Case 2 was a 5-year-old boy diagnosed as CAE. He was treated with VPA initially, and ESM was administered additionally. Drug eruption appeared 1 month after the administration of ESM. Even after ESM was terminated, he maintained seizure freedom after the appearance of eruption.ConclusionsEpileptic seizures may have been suppressed due to the immune responses caused by ASM eruption. Further studies are needed to elucidate the pathophysiologic effects of drug eruption on epilepsy through immune responses.

Epigenetic regulation of GABAergic differentiation in the developing brain.

In the vertebrate brain, GABAergic cell development and neurotransmission are important for the establishment of neural circuits. Various intrinsic and extrinsic factors have been identified to affect GABAergic neurogenesis. However, little is known about the epigenetic control of GABAergic differentiation in the developing brain. Here, we report that the number of GABAergic neurons dynamically changes during the early tectal development in the Xenopus brain. The percentage of GABAergic neurons is relatively unchanged during the early stages from stage 40 to 46 but significantly decreased from stage 46 to 48 tadpoles. Interestingly, the histone acetylation of H3K9 is developmentally decreased from stage 42 to 48 (about 3.5 days). Chronic application of valproate acid (VPA), a broad-spectrum histone deacetylase (HDAC) inhibitor, at stage 46 for 48 h increases the acetylation of H3K9 and the number of GABAergic cells in the optic tectum. VPA treatment also reduces apoptotic cells. Electrophysiological recordings show that a VPA induces an increase in the frequency of mIPSCs and no changes in the amplitude. Behavioral studies reveal that VPA decreases swimming activity and visually guided avoidance behavior. These findings extend our understanding of histone modification in the GABAergic differentiation and neurotransmission during early brain development.

Autism spectrum disorders and epilepsy: dual diagnosis and therapeutic strategies (literature review)

Autism spectrum disorders (ASD) are characterized by significant genetic and clinical polymorphism, comorbidity with neurological and mental disorders. In children with ASD, hotbeds of epileptiform and specific epileptic activity are often registered on the electroencephalogram (EEG), which have a causal relationship with behavioral and emotional disorders. The presence of specific epileptic activity on the EEG, impaired social reciprocity and repetitive behavior may be manifestations of a single pathological process, that results in developmental disorder. The course of ASD can be complicated by epileptic seizures, in particular with the use of neurometabolic drugs. According to the results of some controlled studies, antiepileptic drugs (AED) have shown their effectiveness in the treatment of mental disorders in ASD, including emotional instability, irritability, inhibition of movement. AED which stimulate neurotransmission of γ-aminobutyric acid, are more effective in ASD than blockers of the glutamatergic system. Thymoisoleptic properties of some AED, in particular carbamazepine, valproate acid, lamotrigine in some controlled studies have shown efficacy in the regulation of mood disorders in both children with ASD and children with epilepsy. With the use of carbamazepine, topiramate in children with ASD, there may be impaired attention and cognitive activity; deterioration of attention may be accompanied by increased hyperactivity, impulsivity, motor deceleration. The use of AEDs should be expected to increase the frequency and severity of side effects, including cognitive impairment, motor development, which may lead to impaired general functioning and premature disability, even with seizure control. Specific data on alternative treatments for ASD with seizures such as diet (ketogenic, modified Atkins) are discussed.

Pharmacological and non-pharmacological management of spinocerebellar ataxia: A systematic review.

Spinocerebellar ataxias (SCA) comprise a rare, genetic subgroup within the degenerative ataxias and are dominantly inherited, with up to 48 recognized genetic subtypes. While an updated review on the management of degenerative ataxia is published recently, an evidence-based review focussed on the management of SCA is lacking. Here, we reviewed the pharmacological and non-pharmacological management of SCA by conducting a systematic review on Medline Ovid and Scopus. Of 29,284 studies identified, 47 studies (pharmacological: n = 25; non-pharmacological: n = 22) that predominantly involved SCA patients were included. Twenty studies had a high risk of bias based on the Cochrane's Collaboration risk of bias tool. As per the European Federation of Neurological Societies 2004 guideline for therapeutic intervention, the remaining 27 studies were of Class I (n = 4) and Class II (n = 23) evidence. Only two therapies had Level A recommendations for the management of ataxia symptoms: riluzole and immediate in-patient neurorehabilitation. Ten therapies had Level B recommendations for managing ataxia symptoms and require further investigations with better study design. These include high dose valproate acid, branched-chain amino acid, intravenous trehalose; restorative rehabilitation using cycling regimen and videogame; and cerebellar stimulations using transcranial direct current stimulation and transcranial magnetic stimulation. Lithium and coaching on psychological adjustment received Level B recommendation for depressive symptoms and quality of life, respectively. Heterogeneous study designs, different genotypes, and non-standardized clinical measures alongside short duration and small sample sizes may hamper meaningful clinical translation. Therefore, rating of recommendations only serve as points of reference.

Features of prophylactic treatment in patients with different forms of migraine, complicated by migraine status

The purpose of this study was to study the dynamics of indicators of the scale of Migraine Disability Assessment (MIDAS) in patients with different forms of migraine, which is complicated by migraine status due to the use of prophylactic treatment. 50 patients suffering from migraine, complicated by migraine status, have been examined and treated in the neurological department of the Kyiv Railway Clinical Hospital №2. The degree of pain has been assessed on a visual analog scale (VAS) and the level of disability has been assessed on MIDAS. The solution of valproate acid was used in the main group of patients for the treatment of migraine status during three days. The traditional vasoactive and dehydration therapy was used in the control group within ten days. It was proved, that the solution of preparation of valproic acid for treatment of status migrainous authentically increases degree of headache and level of disadaptation in patients during 6 months. Migraine attacks continued to lead to loss of working capacity and daily activity of patients in the control group. Treatment was safe for patients and well tolerated.Our study showed that the use of solution of valproate acid in the treatment of migraine status in patients with different forms of migraine is authentic effective and leads to decrease the degree of disadaptation in patients during 6–8 months after treatment.

Comprehensive circRNA Expression Profile and Construction of circRNAs-Related ceRNA Network in a Mouse Model of Autism.

Autism is a common disease that seriously affects the quality of life. The role of circular RNAs (circRNAs) in autism remains largely unexplored. We aimed to detect the circRNA expression profile and construct a circRNA-based competing endogenous RNA (ceRNA) network in autism. Valproate acid was used to establish an in vivo model of autism in mice. A total of 1,059 differentially expressed circRNAs (477 upregulated and 582 downregulated) in autism group was identified by RNA sequencing. The expression of novel_circ_015779 and novel_circ_035247 were detected by real-time PCR. A ceRNA network based on altered circRNAs was established, with 9,715 nodes and 150,408 edges. Module analysis was conducted followed by GO and KEGG pathway enrichment analysis. The top three modules were all correlated with autism-related pathways involving “TGF-beta signaling pathway,” “Notch signaling pathway,” “MAPK signaling pathway,” “long term depression,” “thyroid hormone signaling pathway,” etc. The present study reveals a novel circRNA involved mechanisms in the pathogenesis of autism.

Effects of Dietary Fat Profile on Gut Microbiota in Valproate Animal Model of Autism.

Autism spectrum disorder (ASD) is a developmental disability which may cause significant social, communication, and behavioral challenges. Besides certain essential symptoms, a lot of ASD individuals also suffer the comorbidity of gut microbiota dysbiosis, which possibly causes a variety of gastrointestinal (GI) difficulties. Interestingly, evidence has indicated that behavioral output may be modulated through the communication between the central nervous system and gut microbiota via the gut-brain axis. Polyunsaturated fatty acids (PUFAs) and n-3 fatty acids (n-3 PUFA) are structurally and functionally crucial components for the brain, and the state of n-3 PUFAs also affects the gut microbiota. However, how varying intake ratios of n-3/n6 PUFAs affect the gut microbiota composition in ASDs is not well-understood. Pregnant female Wistar rats with intraperitoneal administration of valproate acid (VPA) at embryonic day (E) 12.5 and their male offspring were grouped and fed three diets: a control chow (VPA group), omega-3 deficient (A group), and n-3/n6 (1:5) diet (B group). The diet of pregnant female Wistar rats with intraperitoneal administration of saline and their male offspring was a control chow (normal group). Microbial composition and species abundance were investigated accordingly by the 16S rRNA gene-based metagenomics analysis on the fecal samples. Results showed that fecal microbial abundance was decreased because of VPA administration in the period of pregnancy, and the changing pattern of gut microbiota was similar to that reported in ASD patients. Furthermore, the n-3/n6 (1:5) diet increased the fecal microbial abundance and decreased the elevated Firmicutes. In conclusion, n-3/n6 PUFAs (1:5) diet supplementation may alter gut microbiota composition in VPA-exposed rats. This study put forward a new strategy for the intervention and treatment of autism by n-3/n-6 PUFAs ratio supplementation intakes.

The Effectiveness Comparison of Valproic Acid 500 mg and Amitriptyline 15 mg in Reducing the Frequency of Headache Attack in Patients with Tension-Type Headache

Background: Tension-type headache (TTH) is the most common headache. Continuous analgesic use can develop into headache caused by drug abuse (medication overused headache); thus, the preventive therapy is necessary. Amitriptyline and valproic acid are drugs reported to reduce the frequency of headache in TTH patients. Objective: To analyze the effectiveness of valproic acid 500 mg and amitriptyline 15 mg in reducing the frequency of headache attack in patients with tension-type headache. Methods: The study applied a Double Blind Randomized Clinical Trial involving 50 TTH patients. The subjects were divided into two groups: amitriptyline 15 mg and valproate acid 500 mg. The period of drug administration was 6 weeks. The variables that were compared were the decreasing frequency of headache and the intensity of the pain. Results: There was no significant difference in the decrease of headache frequency (p = 0.730) and pain intensity (p = 0.430) between the amitriptyline group and valproate acid group. However, each drug effectively decreased the frequency of headache and pain intensity in TTH patients (p = 0.000). Conclusion: There was no significant difference between the effectiveness of valproic acid 500 mg and amitriptyline 15 mg in reducing the frequency of headache in patients with TTH.

Pola Penggunaan Obat Mood Stabilizer Pada Pasien Bipolar di Rumah Sakit Jiwa Daerah Atma Husada Mahakam

Bipolar disorder is a chronic mood disorder characterized by episodes of mania or hypomania that occur alternately or mixed with depressive episodes. This study aims to determine the characteristics of bipolar patients and patterns of drug use inpatient and outpatient bipolar patients at Atma Husada Mahakam Hospital. The type of this research is non experimental (descriptive) and done retrospectively. Data are collected from medical record. Research subjects were 84 inpatients and 137 outpatients with bipolar disorder diagnosis. Data are analyzed by describing research's objects. The results were obtained from inpatient and outpatient data showing 63% and 60% female sex, showing 26-35 years (early adulthood), not working, not married, and high school level education. The most usage pattern of drugs is a combination of 2 and 3 drugs, namely 74.99% for inpatient care and 73.71% for outpatient treatment. The drugs most commonly used are mood stabilizers (valproate acid) and atypical antipsychotics (risperidone).

2254 A Rare Case of Valproate-Induced Encephalopathy Requiring Hemofiltration

INTRODUCTION: We present a rare case of acute encephalopathy due to Valproate induced hyperammonemia required Hemofiltration (HF). CASE DESCRIPTION/METHODS: 45-year-old male was brought in by caregiver to the hospital with acute altered mental status, somnolent but arousable. PMHx of CP, Epilepsy, Left sided hemiplegia, Mental retardation, Abscess of thigh and wrist. Medications were Valproate and Phenytion. PE showed stable vitals, confused, was spitting to staff required restraints. Pupils equal, reactive to light. Neurological exam- left sided hemiplegia. Lab showed Na 140, K 4.0, HC03 30, BUN 7, Cr 1.18, Glucose 101, Osmolarity 287, ALT 24, AST 24, T Bil 1.1, Albumin 3.5, Al phos 79, Mg 2.0, lactic 1.2. WBC 6.9, hemoglobin 15.2, platelet 291, INR 1.2, Ammonia 402. Blood & urine culture and toxicology were negative. Acute hepatitis panel was non- reactive, Ceruloplasmin 32, ferritin 33.7, AMA < 20.1, Smooth muscle antibody < 1:40. Valproic acid level 125 mcg/ml (therapeutic level-50-100 mcg/ml). ECG was normal. Head CT showed no acute abnormality. Ultrasound showed fatty infiltration & Cholelithiasis. Unremarkable EGD. Lactulose & xifaxan were given for hyperammonemia, recurrent seizures occurred. RESULTS: Valproate was discontinued. L-carnitine 100 mg/kg IV loading dose was given. Received HF for 3hrs , and supportive care. Ammonia at 2hours post HF was 80. Patient’s mental status improved back to baseline over 24 hours. DISCUSSION: Acute encephalopathy due to valproate induced hyperammonemia required Hemofiltration is very rare. The incidence of valproate-induced hyperammonemia in the general population of patients taking VPA (Valproate acid) is not well established. Most cases of Valproate acid- toxicity are rather benign and resolve with supportive therapy. It is generally accepted that serum level >180 mcg/ml represents a high risk of toxicity. Our case was a first patient without chronic liver disease and valproate level was below high risk for toxicity who presented with acute encephalopathy due to valproate induced hyperammonemia and required Hemofiltration. Care of patients depends upon recognition of those at increased risk, anticipation & prevention, and appropriate response when they occur. Discontinuation of Valproate may require. L-carnitine has a significant mortality benefit in patient severe Valproate toxicity. HF is reserved for severely ill patients who have not responded to less invasive treatment.

Regional and sex-dependent alterations in Purkinje cell density in the valproate mouse model of autism.

Neuropathological and neuroimaging studies indicate a decrease in Purkinje cell (PC) density in the cerebellum of autistic patients and rodent models of autism. Autism is far more prevalent in males than females, and sex-specific properties of PCs have been reported recently. We investigated the differential sensitivity of PCs in the valproate acid (VPA) mouse model of autism by estimating the linear density of PCs immununolabelled with calbindin in the cerebellum of males and females. Whereas prenatal VPA treatment surprisingly increased PC linear density in both sexes 13 days after birth (P13), it significantly reduced the linear density of PCs in the cerebellum of 40-day-old (P40) males, but not females. In males, PC loss was more pronounced in the posterior part of the cerebellum and was significant in the VIth, VIIth, IXth and paramedian lobules. In females, PC loss was restricted to the paramedian lobule. These results suggest that this sex-specific sensitivity of PCs to VPA may contribute towards the motor disturbances and behavioural abnormalities observed in autism.

Formulation Development and Evaluation of Sodium Valproate and Valproic acid Extended Release Tablets

The objective of the present study was to formulate and develop extended release drug delivery system of antiepileptic drug Sodium valproate (VAS) and Valproic acid (VA) in the ratio of 70: 30 with extended release profile. Preliminary studies with different polymers such as HPMC K15M, PVP K90, Ethyl cellulose N50, Carbopol were performed. The results of in-vitro release data showed that HPMC K15M can sustain the drug release upto 24hr. From these studies HPMC K15M has been selected for further studies. HPMCK15M was used along with HEC 250HX to retard the drug release. VAS and VA extended release tablets were prepared by wet granulation method. The hardness of these extended release tablets was within the range between 5.63±0.42 to 6.92±0.33 kg/cm2. The drug content was within the range, 97.23±0.25 to 102.03±2.45%. The in-vitro VAS and VA release from the tablets was found sustained over 24 hours with Higuchi kinetics of drug release and release pattern followed anomalous (Non-Fickian) diffusion. The Fourier transform Infrared spectroscopy analyses indicated that there was absence of chemical interaction between the drug and the excipients. The dissolution profiles of the developed formulation and the commercial tablet formulation, Encorate, were compared using the similarity factor (f2) and difference factor (f1). The released profile of tablet containing 15% HPMC K15M and 15% HEC 250HX by weight was similar to that of Encorate® providing the values of similarity factor (f2) and difference factor (f1) of 88.20 and 3.22 respectively.

Dysregulation of bcl-2 enhanced rotenone-induced α-synuclein aggregation associated with autophagic pathways.

α-Synuclein (α-syn) aggregation has far-reaching implications in the pathogenesis of Parkinson's disease, and the levels of α-syn protein determine its neurotoxic potential. However, the intrinsic pathway of α-syn accumulation and the mode of α-syn degradation remain contentious. Following a stereotactic infusion of rotenone into the substantia nigra and the ventral tegmental area, the chronic rat model of Parkinson's disease was established successfully. In response to the rotenone, increased intracellular α-syn levels and autophagic flux monitored by LC3 II turnover were induced in dopaminergic neurons (TH-positive) of rat substantia nigra and ventral tegmental area. In the cytoplasm, increased immune response of LC3 colocalized with α-syn on the basis of rotenone-mediated neurotoxicity. The immunoreactivity for p62, an adaptor of the autophagy, was upregulated in the cytoplasm and nucleus. The enhancement of autophagy by valproate acid decreased rotenone-induced α-syn aggregation, whereas the inhibition of autophagy by 3-methyladenine increased α-syn aggregation. In addition, the expression of bcl-2 was reduced in rotenone-induced neurotoxicity, accompanied by the enhancement of autophagy. Small interfering RNA-mediated knockdown of bcl-2 expression facilitated the expression of p62 protein and autophagy. Moreover, the inhibition of bcl-2 increased rotenone-based α-syn aggregation. In short, in rotenone-based models, dowregulation of bcl-2 negatively controlled rotenone-induced autophagy and α-syn aggregation.

A nationwide multi-center questionnaire survey on the management and treatment of post-stroke seizure and epilepsy in Japan

Seizures may occur after stroke. Though the majority of clinicians are aware of this, a consensus-based treatment and management strategy for post-stroke seizures is not available because there have only been a few large-scale studies that have explored this. This study has surveyed the actual state of medical treatment for post-stroke seizure and epilepsy in Japan. We conducted a nationwide questionnaire survey of the top 500 institutions regarding the number of cerebral infarction cases between February 2015 and May 2015. The questionnaire contained 14 items regarding the number of patients, type of tests and treatments conducted, and patient response to the treatments. Surveys from 189 institutions were obtained. A history of previous stroke was reported in 41% of hospitalized patients with epilepsy. The sensitivity of diffusion-weighted MRI and electroencephalography was not sufficient to detect the abnormalities seen in epilepsy. Carbamazepine was the most chosen antiepileptic drug for secondary prophylaxis, followed by valproate acid, and levetiracetam.

Valproate acid (VPA)-induced dysmetabolic function in clinical and animal studies

BackgroundValproate acid (VPA), a commonly used antiepileptic medicine, is found to be linked to developing dysmetabolic risk. However, the proposed mechanism remains completely unknown. MethodsIn this study, we collected data from patients with epilepsy and further investigated the preclinical study in mice. ResultsAs results, the clinical data showed that VPA-used patients resulted in higher levels of blood glucose, urine acid, triglyceride (TG), and immune cells (leucocyte, neutrophil leucocyte) when compared to clinically diagnosed references, while circulating apolipoprotein A1 (Apob A1) and fatty acid binding protein 4 (FABP4) were reduced without visible drug-induced liver injury (DILI). In rodent study, short-term treatment of VPA to mice showed developing trend of metabolic dysfunction, as revealed in increased serum insulin and free fatty acid and TG, and decreased liver TG content. As shown in immunoassay, FABP4 of epididymal white adipose tissue (eWAT) was down-regulated dose-dependently. ConclusionCollectively, our present findings indicate that VPA can induce FABP4-impaired lipid dysmetabolism without DILI. More notably, FABP4 may function as a sensitive indicator for VPA-induced metabolic dysfunction.

Valproate Acid (Depakote) Induced Hyperammonemic Encephalopathy in the Pediatric Populations

Valproate acid (Depakote) (VPA) is very effective in the treatment of various illnesses including: seizure disorders, migraine headache prophylaxis, neuralgia, and bipolar disorder. The use of VPA frequently results in elevated plasma levels of ammonia. This is seen despite normal baseline liver function test results in such patients. In this case report, we describe two instances of VPA-induced hyper ammonemic encephalopathy in patients who had supra therapeutic levels of VPA. Family physicians, Child Neurologists, Child Psychiatrists and Pediatricians should be aware of this potential complication, and it is highly recommended to check ammonia levels in patients taking VPA who present with a change in mental status. With a rise in off-label use it is even more important that physicians are made aware of this potential complication. Treatment of VPA-induced hyperammonemic encephalopathy is still under investigation. As of yet, administration of L-carnitine is postulated to have a potential benefit in some cases. VPA has numerous drug interactions and toxicities, including pancreatitis, thrombocytopenia, hepatitis and hyperammonemia. Here are we list two case reports of VPA induced hyperammonemic encephalopathy both occurring in patients with no history of any underlying liver pathologies. In both two cases, both patients were under stable conditions, no comatose. In both 2 cases of patients we described, they all have normal or sub therapeutic level of VPA. Because of the wide spectrum of symptoms associated with Valproate Acid induced Hepatic Encephalopathy (VHE), clinician should be aware of hyperammonenia in differential diagnosis with other common symptoms.

Lamotrigine-induced severe cutaneous adverse reaction: Update data from 1999–2014

We systematically reviewed and analyzed published patients with Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) associated with lamotrigine therapy to identify characteristics of these reactions. We identified a total of 70 patients (42 SJS, five SJS/TEN, 23 TEN). The female to male ratio was 2.83:1 in the TEN group and 1.47:1 in the SJS group. Patients in the TEN group were younger than in the SJS group but this difference was not significant (28.35 versus 32.71years, respectively; p=0.27). The median time to onset was 25.33 versus 18.42days for SJS and TEN, respectively. The median dosage at onset was 36.46 versus 57.29mg, and final dosage 111.25 versus 97.92mg/day for SJS and TEN, respectively. The median final dosages did not significantly differ. Concomitant use of valproate acid was reported in 54.55% of the SJS patients and 50.00% of the TEN patients. Three fatal reactions were reported, of which two patients deteriorated rapidly and died within 12h of admission, indicating that this disease can develop rapidly before effective treatment. There was no significant difference between the SJS and TEN groups in any of the clinical factors examined which confirmed the opinion that SJS and TEN are part of a single disease spectrum.

ZONISAMIDE (ZONEGRAN) IN THE TREATMENT OF EPILEPSY IN ADULTS AND CHILDREN (A REVIEW AND CLINICAL CASE)

Despite the significant progress made in epileptology, resistant epilepsies constitute approximately 30 % of all forms of epilepsy. An overview of recent literature is provided on the efficacy and safety of a new antiepileptic drug zonisamide (Zonegran) in the treatment of epilepsy with emphasis on monotherapy. The mode of action, pharmacokinetic characteristics, the effectiveness and tolerance of zonisamide in resistant focal epilepsy, as well as other types of seizures and forms of epilepsy are described. Indications for use of the drug are discussed. Also a wider potential for application of zonisamide are described: in the treatment of generalized seizures, in monotherapy as well as in children and adolescents. At present, Zonegran is registered for application in children from 6 years and older, with focal seizures, in additional therapy. The authors present their own observation of high efficacy of zonisamide in adjunctive therapy in a child of 9 years with cryptogenic focal epilepsy. Onset of epileptic seizures at the age of 5 months. Since the onset of the disease the child has received a lot of antiepileptic drugs in various combinations, with no significant effect. Zonisamide (Zonegran) was introduced in therapy 4 months ago in combination with the valproate acid drug (which the child received over the years), and since the release to the full dose epileptic seizures are absent up to present. It should be noted that there was not a single remission of four-month duration since the onset of the disease. Moreover, normalization of sleep has been noted. Tolerability of the therapy is good. No side effects were noted.