Role Of Valproate Research Articles

Treating post-dengue mania: Is role of valproate and quetiapine related to histone deacetylase inhibition?

Treating post-dengue mania: Is role of valproate and quetiapine related to histone deacetylase inhibition?

Valproate for acute mania.

Valproate for acute mania.

Role of valproate in hyperammonemic encephalopathy in women in a tertiary psychiatric clini

Objective: In patients with acute mental status change with elevated serum ammonia levels, when there is conco-mitant use of valproate, carbamazepine or any other susceptible agent, hyperammonemic encephalopathy is a possible phenomenon. Our aim was to describe this underreported phenomenon in detail and find possible risk factors associated with valproate induced hyperammonemic encephalopathy. Methods: We analyzed retrospective records of two years for female inpatients in the psychiatric ward for women in our hospital. Spearman’s rho correlation analysis was used for assessing the relation between serum ammonia and valproate levels. During the two years’ period, 961 patients were treated in the inpatient clinic. Because of a suspicion of hyperammonemic encephalopathy, serum ammonia levels of 37 patients were analyzed, revealing a total of 34 patients with high ammonia levels, warranting a diagnosis of hyperammonemic encephalopathy. Results: In 28 of these patients hyperammonemic encephalopathy was associated with valproate use. The time interval between initiation of valproate treatment and hyperammonemia was 11±7 days. For these patients, initiation dose of valproate was 883.93±249.83 mg/day (median: 1000 mg/day), daily valproate dose was 914.90±202.87 (median: 928.25) mg and during encephalopathy; valproate blood level was 82.36±25.80 ng/mL (median: 87.50 ng/mL). Serum ammonia level was positively correlated with the initiation dose of valproate ((28)=0.472, p=0.011) and valproate blood levels during hyperammonemia ((28)=0.522, p=0.004). Polypharmacy and long-term intramuscular treatment were also prevalent in patients with hyperammonemic encephalopathy. Discussion: Early suspicion of hyperammonemic encephalopathy in patients taking valproate may improve the outcome of this under recognized problem.

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity.

Upregulation of sodium channel SCN3A expression in epileptic tissues is known to contribute to enhancing neuronal excitability and the development of epilepsy. Therefore, certain strategies to reduce SCN3A expression may be helpful for seizure control. Here, we reveal a novel role of valproate (VPA) in the epigenetic downregulation of Scn3a expression. We found that VPA, instead of carbamazepine (CBZ) and lamotrigine (LTG), could significantly downregulate Scn3a expression in mouse Neuro-2a cells. Luciferase assays and CpG methylation analyses showed that VPA induced the methylation at the -39C site in Scn3a promoter which decreased the promoter activity. We further showed that VPA downregulated the expression of methyl-CpG-binding domain protein 2 (MBD2) at the posttranscriptional level and knockdown of MBD2 increased Scn3a expression. In addition, we found that VPA induced the expression of fat mass and obesity-associated (FTO) protein and FTO knockdown abolished the repressive effects of VPA on MBD2 and Nav1.3 expressions. Furthermore, VPA, instead of other two anticonvulsant drugs, induced the expressions of Scn3a and Mbd2 and reduced Fto expression in the hippocampus of VPA-treated seizure mice. Taken together, this study suggests an epigenetic pathway for the VPA-induced downregulation of Scn3a expression, which provides a possible role of this pathway in the anticonvulsant action of VPA.

Efficacy and Safety of Intravenous Sodium Valproate in Convulsive Status Epilepticus in Children in Shahid Sadoughi Hospital

Efficacy and Safety of Intravenous Sodium Valproate in Convulsive Status Epilepticus in Children in Shahid Sadoughi Hospital

Potential Role for Valproate in the Treatment of High-Risk Brain Tumors of Childhood—Results from a Retrospective Observational Cohort Study

Although substantial progress has been made in pediatric brain tumor management, patients with brainstem tumors and high-grade gliomas, as well as patients less than 3 years of age with high-risk malignant tumors, have a poorer prognosis. The authors have been treating these patients with radiotherapy and standard carboplatin and vincristine chemotherapy. Since January 2007 the authors have been using valproate as anticonvulsant for prophylaxis. The authors performed a retrospective cohort analysis of pediatric patients with high-risk brain tumors treated with chemotherapy, radiotherapy, and valproate prophylaxis, comparing this group with a historical control. The 2007–2008 group was comprised of 22 patients, 15 with brainstem tumors (7 diffuse intrinsic pontine glioma [DIPG], 3 focal, the remaining infiltrating with a solid portion), 4 with diencephalic tumors (2 thalamic), and 3 with supratentorial high-grade tumors (1 glioblastoma, 1 recurrent grade III ependymoma, 1 with gliomatosis). There were 15 patients alive (68%) after a mean follow-up time of 19 months. Survival function comparison by log rank test was highly significant (P = .004) with a hazard ratio of 0.31 (0.14–0.70). Radiological response showed 3 complete responses (14%), 8 partial responses (36%), 5 stable diseases (23%), and 5 progresssive diseases (23%). The authors hypothesize that valproate may have potentiated the antiangiogenic effect of vincristine, diminished expression of resistance to carboplatin, and sensitized tumor cells to radiotherapy. The authors suggest that clinical trials of carboplatin and vincristine associated with oral continuous low-dose valproate are indicated for pediatric patients with high-risk brain tumor.

The role of valproate in metabolic disturbances in bipolar disorder patients

Background Our previous report showed that patients with bipolar disorder (BD) have higher prevalence of hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL) and obesity in Taiwan. To confirm whether the metabolic disturbances is associated with the disease itself or the medications used for treating BD, we further compared the metabolic status among the valproate (VPA) treated BD patients, drug-free BD patients and healthy controls in Taiwan. Method This cross-sectional study included 119 healthy controls and 77 BD patients diagnosed according to the DSMIV-TR criteria in a university hospital. Among the diseased group, 25 remitted BD patients were drug-free (BD-F), and 52 of them were treated with VPA (BD-VPA). Their body mass index (BMI), plasma glucose levels and plasma lipid profiles were measured. Results Plasma fasting glucose, insulin, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDL) levels were significantly different among BD-VPA, the BD-F, and the healthy control groups. Valproate treatment was associated with significant higher plasma insulin, triglyceride, and BMI levels as well as lower fasting glucose and HDL levels. However, these biochemical indexes did not differ significantly between the BD-F and the healthy control groups. Conclusion These results provide further evidence that VPA treatment for BD may increase the risk of metabolic disturbances. The risk may be reduced after discontinuing VPA medication.

Role of valproate across the ages. Treatment of epilepsy in children

In June 2005 a team of experts participated in a workshop with the objective of reaching agreement on the place of valproate use in the treatment of paediatric epilepsy patients. A general "consensus of the meeting" was that the initiation of antiepileptic drug (AED) treatment should be based on a seizure-syndromic approach in children. Participants of the meeting also agreed that valproate is currently the AED with the broadest spectrum across all types of seizures and syndromes. Its superiority has been shown over almost 40 years of clinical experience. The best results are seen in idiopathic generalized epilepsy with or without photosensitivity, idiopathic focal and symptomatic generalized tonic-clonic seizures (GTCS). Evidence supports the use of valproate, ethosuximide and lamotrigine in absence epilepsies and the use of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate and phenobarbital for primary GTCS. For new AEDs trials have been undertaken to define their therapeutic role but studies comparing their role to 'old' broad-spectrum drugs in specific syndromes are missing. Experts concluded that intravenous (i.v.) valproate is a useful agent in the treatment of non-convulsive status epilepticus (SE). There is an easy transition to oral treatment following i.v. valproate use. The discussion also concluded that, despite the lack of studies, valproate is an interesting, underutilized alternative in convulsive SE but more controlled studies are needed. The side effects of valproate use are well documented. Its effect on cognition and behaviour is more favourable than many of the other AEDs which is an important consideration in children. Overall, the clinical consensus of the meeting was that valproate's well established therapeutic properties far outweigh the negative side effects. Contraindication or withdrawal should be assessed individually.

Role of valproate across the ages. Treatment of epilepsy in the elderly

In June 2005, a team of experts participated in a workshop with the objective of reaching agreement on several important aspects of valproate in the treatment of elderly patients with epilepsy. Epilepsy in the elderly is relatively common and its incidence increases for each decade after age 60. The aetiology and manifestations of epilepsies in the elderly are complex because of comorbidity and other underlying risk factors. A consensus was reached that elderly patients who present with a seizure disorder should be referred rapidly to a specialist and that diagnosis should be improved by using a multidisciplinary team of cardiologists, neurologists and epilepsy experts (syncope, falls and seizure specialists). This is especially important to avoid mistreatment with antiepileptic drugs (AEDs). There was consensus that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults. For these reasons, in older persons AEDs should be started at low dosages, and titrated slowly according to clinical response. Some of the most troublesome side effects of AEDs in the elderly include sedation and cognitive side effects, as well as osteoporosis. Drug-drug interactions should be given special consideration. There was consensus that the pharmacokinetics of all AEDs are altered in the elderly, and that the most significant change common to all AEDs is a moderate reduction in renal and metabolic clearance. Predicting pharmacokinetic changes in the individual, however, can be very difficult because multiple factors contribute to a high inter-patient variability. There was agreement on the advantages and disadvantages of the use of valproate in the elderly, and consensus that valproate is a useful option in this population. There was no consensus, however, on whether valproate should be considered among the preferred first-line treatments in the elderly.

Role of valproate across the ages. Treatment of epilepsy in adults

A workshop was held in Göteborg in June 2005 to discuss the place of valproate in treating adult epilepsies. Consensus positions were developed on the epilepsy types for which the drug is most suitable and the use of valproate in women of child-bearing age, in men and in patients with psychiatric comorbidity. Valproate was considered to be effective across a broad variety of epilepsy syndromes and seizure types and should be considered a suitable choice for first-line monotherapy of juvenile myoclonic epilepsy and other idiopathic generalized epilepsies. The use of valproate by women of child-bearing age is associated with potential harm to the foetus. A conservative approach to treatment is recommended in these patients whereby alternative antiepileptic drugs should be proposed to women planning pregnancies wherever satisfactory seizure control can be thereby maintained. In cases where valproate is used during pregnancy, either because the pregnancy was unplanned or because alternative treatment options of equivalent efficacy are unavailable, appropriate counselling, precautionary measures and monitoring should be provided. The evidence for an impact of valproate on male reproductive health is equivocal and considerations of male fertility should not be taken into account in deciding whether to prescribe valproate to men. Valproate can be proposed safely to patients with comorbid psychiatric disease or underlying psychiatric vulnerability.

Non-dose-related side effects of valproate.

The clinical and histological findings in 88 patients in whom hepatotoxicity with valproate has been reported were reviewed. The characteristic lesion is microvesicular steatosis. Hepatotoxicity appears to be an idiosyncratic reaction and is most likely to appear within 6 months from the start of therapy, especially in young patients on comedication. The condition may be reversible if the drug is immediately withdrawn in patients who show acute gastrointestinal symptoms, drowsiness or lethargy, jaundice, or change in seizure pattern. Clinical monitoring is more important than laboratory monitoring. The outcome of pregnancies in 344 women who received valproate in the first trimester was reviewed. There were 225 normal babies and 68 abnormal babies. The role of valproate in the aetiology of neural tube defects remains uncertain, but mothers treated with valproate should receive prenatal counselling.