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To examine whether "outer-directed irritability," a mood construct from the adult literature, characterizes a subgroup of disruptive behavior disordered children and adolescents previously shown to improve on divalproex, a mood stabilizer.
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder, commonly characterized by altered social behavior, communication, biochemistry and pathological conditions. One percent of the worldwide population suffers from autism and males suffer more than females. NMDA receptors have the important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. This study has been designed to investigate the role of memantine, a NMDA receptor modulator, in prenatal valproic acid-induced autism in rats. Animals with prenatal valproic acid have shown the reduction in social interaction (three-chamber social behavior apparatus), spontaneous alternation (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, prenatal valproic acid-treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood-brain barrier permeability. Treatment with memantine has significantly attenuated prenatal valproic acid-induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, memantine has also attenuated the prenatal valproic acid-induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood-brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behavior, biochemistry and blood-brain barrier impairment in animals, which were significantly attenuated by memantine. NMDA receptor modulators like memantine should be explored further for the therapeutic benefits in autism.
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Valproic acid (VPA) is a well-known anti-epileptic and mood stabilizing drug. A growing number of reports demonstrate that VPA is neuroprotective against various insults. Despite intensive efforts to develop new therapeutics for stroke over the past two decades, all treatments have thus far failed to show clinical effect because of treatment-limiting side effects of the drugs. Therefore, a safety-validated drug like VPA would be an attractive candidate if it has neuroprotective effects against ischemic insults. The present study was undertaken to examine whether pre- and post-insult treatments with VPA protect against brain infarct and neurological deficits in mouse transient (tMCAO) and permanent middle cerebral artery occlusion (pMCAO) models. In the tMCAO (2 hr MCAO and 22 hr reperfusion) model, intraperitoneal injection of VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly reduced the infarct size and the neurological deficit. VPA treatment immediately after reperfusion significantly reduced the infarct size. The administration of VPA at 4 hr after reperfusion failed to reduce the infarct size and the neurological deficit. In the pMCAO model, treatment with VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly attenuated the infarct size, but did not affect the neurological deficit. Western blot analysis of acetylated H3 and H4 protein levels in extracts from the ischemic cortical area showed that treatment with VPA increased the expression of acetylated H3 and H4 at 2 hrs after MCAO. These results demonstrated that treatment with VPA prior to ischemia attenuated ischemic brain damage in both mice tMCAO and pMCAO models and treatment with VPA immediately after reperfusion reduced the infarct area in the tMCAO model. VPA could therefore be evaluated for clinical use in stroke patients.
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HDAC-I substances with favourable in vivo profiles, valproate (VPA) and ITF2357, were investigated on HCC cell lines and primary human hepatocytes (PHH). Histone acetylation and apoptosis-modulating proteins were investigated by western-blotting, proliferation by sulforhodamin B binding, toxicity by enzyme release, apoptosis by FACS analysis.
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LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain.
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We performed a phase I trial combining 5-aza-2'-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5-15 mg/m(2)) IV for 10 days in combination with VPA (10-20 mg/kg/day) PO on days 5-21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression.
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Acetylcholinesterase inhibitors may have beneficial effects on aggressive behaviour in the course of Alzheimer's Disease, similar to that seen with the use of valproic acid and antipsychotics.
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Valproic acid is often used in psychiatry to treat schizophrenia and other conditions outside of indication ("off-label"). However, its effectiveness has not been sufficiently demonstrated and its use is not exempt of adverse effects. This study's main objective is to determine the frequency of use of valproic acid in approved indications and the "off-label" use in psychiatric patients.
We prospectively examined the effects of valproic acid on the endocrine system and metabolic variables in epileptic children. Patients with newly diagnosed idiopathic epilepsy were included in the study. Laboratory and clinical variables were assessed before and after 6 and 12 months of treatment. In total, 30 patients (mean age, 8.6 +/- 4.4 years S.D.) were investigated. Body mass index and body mass index standard deviation scores of patients increased significantly during treatment. Although there was no statistical significance regarding fasting glucose, serum insulin, triglyceride, and high-density lipoprotein cholesterol levels and the insulin resistance index, a statistically significant increase in total and low-density lipoprotein cholesterol levels had occurred after 12 months of valproic acid treatment. At the end of the study period, four patients were obese, and six patients were overweight. There was a significant correlation between serum levels of valproic acid and body mass index at month 6 of treatment. There was no significant change in androgen hormone levels during treatment in the prepubertal group. Body mass index and body mass index standard deviation scores increased during the first 6 months of valproic acid treatment. Patients treated with valproic acid should be regularly followed for obesity.
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Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulin-like growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased (P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period.
Acyl glucuronides are reactive metabolites of carboxylate drugs, able to undergo a number of reactions in vitro and in vivo, including isomerization via intramolecular rearrangement and covalent adduct formation with proteins. The intrinsic reactivity of a particular acyl glucuronide depends upon the chemical makeup of the drug moiety. The least reactive acyl glucuronide yet reported is valproic acid acyl glucuronide (VPA-G), which is the major metabolite of the antiepileptic agent valproic acid (VPA). In this study, we showed that both VPA-G and its rearrangement isomers (iso-VPA-G) interacted with bovine brain microtubular protein (MTP, comprised of 85% tubulin and 15% microtubule associated proteins [MAPs]). MTP was incubated with VPA, VPA-G and iso-VPA-G for 2 h at room temperature and pH 7.5 at various concentrations up to 4 mM. VPA-G and iso-VPA-G caused dose-dependent inhibition of assembly of MTP into microtubules, with 50% inhibition (IC(50)) values of 1.0 and 0.2 mM respectively, suggesting that iso-VPA-G has five times more inhibitory potential than VPA-G. VPA itself did not inhibit microtubule formation except at very high concentrations (> or =2 mM). Dialysis to remove unbound VPA-G and iso-VPA-G (prior to the assembly assay) diminished inhibition while not removing it. Comparison of covalent binding of VPA-G and iso-VPA-G (using [14C]-labelled species) showed that adduct formation was much greater for iso-VPA-G. When [14C]-iso-VPA-G was reacted with MTP in the presence of sodium cyanide (to stabilize glycation adducts), subsequent separation into tubulin and MAPs fractions by ion exchange chromatography revealed that 78 and 22% of the covalent binding occurred with the MAPs and tubulin fractions respectively. These experiments support the notion of both covalent and reversible binding playing parts in the inhibition of microtubule formation from MTP (though the acyl glucuronide of VPA is less important than its rearrangement isomers in this regard), and that both tubulin and (perhaps more importantly) MAPs form adducts with acyl glucuronides.
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Valproic acid is a well-tolerated anticonvulsant that has been identified recently as a histone deacetylase inhibitor. To evaluate the antitumor efficacy and mechanisms of action of valproic acid in medulloblastoma and supratentorial primitive neuroectodermal tumor (sPNET), which are among the most common malignant brain tumors in children with poor prognosis, two medulloblastoma (DAOY and D283-MED) and one sPNET (PFSK) cell lines were treated with valproic acid and evaluated with a panel of in vitro and in vivo assays. Our results showed that valproic acid, at clinically safe concentrations (0.6 and 1 mmol/L), induced potent growth inhibition, cell cycle arrest, apoptosis, senescence, and differentiation and suppressed colony-forming efficiency and tumorigenicity in a time- and dose-dependent manner. The medulloblastoma cell lines were more responsive than the sPNET cell line and can be induced to irreversible suppression of proliferation and significantly reduced tumorigenicity by 0.6 and 1 mmol/L valproic acid. Daily i.p. injection of valproic acid (400 mg/kg) for 28 days significantly inhibited the in vivo growth of DAOY and D283-MED s.c. xenografts in severe combined immunodeficient mice. With Western hybridization and real-time reverse transcription-PCR, we further showed that the antitumor activities of valproic acid correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, and suppression of TP53, CDK4, and CMYC expression. In conclusion, valproic acid possesses potent in vitro and in vivo antimedulloblastoma activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, valproic acid may represent a novel therapeutic option in medulloblastoma treatment.
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In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.
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Thirty-two children were diagnosed and prospectively followed up for at least 3 years at our unit between 1991 and 2007. Twenty-seven children were included in the prospective treatment study with valproate (VPA) and 17 with VPA combined with ethosuximide (ESM). Treatment response of disappearance of electrical status epilepticus during sleep (SES) was documented with overnight EEG recordings. Neuropsychological follow up for at least 5 years was available in 18 patients.
Naturalistic, prospective, national and multicenter study, in which 21 Spanish neurologists took part. Patients with partial or generalized epilepsy from 18 to 50 years, who were under monotherapy with lamotrigine or valproic acid and clinically stables, were included. Two visits were carried out, one basal visit and a 6, month follow-up visit. Sociodemographic, clinical (ti-me since diagnosis, previous treatment, current treatment and perceived adverse events) and social variables (QOLIE-31, QOLIE-10) were collected.
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Thirty children with epilepsy on AEDs (13.3±2.3 years, 14 male) and 30 controls (13.9±2.9 years, 14 male) were recruited. Fasting tHcy, folate, pyridoxal-5-phosphate (PLP), vitamin B12, glucose and lipids were measured. Vascular function and structure were assessed using FMD (brachial artery) and IMT (carotid/aortic arteries).
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To report on severe acid-base disturbance in a child with symptomatic epilepsy treated with sulthiame.
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Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation.
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To assess the knowledge of pediatric residents regarding principles of management of seizures and epilepsy.
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Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers-anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders.
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We present a case of a mixed ingestion of valproic acid, gabapentin, mexilitine, and ethanol with central nervous system depression that was reversed by naloxone. This report represents the fourth case demonstrating the antidotal efficacy of naloxone in reversing central nervous system depression associated with acute valproic acid overdose. Increasing clinical experience will more fully elucidate indications for, and optimal dosing of, naloxone in valproic acid toxic states.
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Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg(-1)) was administered by gavage and VitE (50 mg kg(-1)) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA.
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This condition resembles that described in 1995 by Ricci et al. In must be differentiated from other myoclonic epilepsies of infancy, reflex epilepsies and hyperekplexia. It could be the earliest from of idiopathic generalized epilepsy.
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To examine if, during conversion from conventional divalproex to once-daily divalproex extended-release (ER) tablets, plasma valproic acid (VPA) concentrations in the first 48 hours after conversion are maintained within the accepted therapeutic range (50-100 mg/L).
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Postanoxic myoclonus is a rare manifestation after an anoxic event, with fewer than 150 cases reported in the literature. The condition is characterized by myoclonic jerks, which are worse on action than at rest, and postural lapses, ataxia, and dysarthria. The disability caused by postanoxic myoclonus can be profound, and treatment in the rehabilitation setting is exceptionally challenging. We present 2 patients who suffered from postanoxic myoclonus after an anoxic event, both of whom were successfully treated with a combination of levetiracetam, valproic acid, and clonazepam. These cases act as a framework for discussing the management of postanoxic myoclonus in the clinical setting.