Dose Of Valproic Acid Research Articles

Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5–1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 – β) = 0.8486 at type I level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy.

Unraveling the Cytoprotective Effects of Valproic Acid: A Transcriptomics Meta-Analysis of Transfusion Strategies for Hemorrhagic Shock and Traumatic Brain Injury

Introduction: Traumatic brain injury (TBI) results in widespread impairment of hemostasis, fibrinolysis, coagulation, endothelial function, and immune function. While damage control resuscitation (DCR) is a well-established treatment strategy for life-threatening hemorrhage, alternative treatment strategies should be applied to patients with concurrent TBI. Commonly used resuscitation fluids such as crystalloids or colloids have several disadvantages and may even be harmful when administered in large quantities. In contrast, pharmacologic agents, such as the histone deacetylase inhibitor valproic acid (VPA), have shown promising results in animal studies of TBI and hemorrhagic shock (HS). We previously showed that VPA not only decreases platelet hyper-activation and improves clot dynamics in in-vitro experiments, but also decreases transfusion requirements and improves survival in a porcine DCR model. In those animal models, VPA was administered in conjunction with fluid resuscitation such as fresh frozen plasma (FFP) or hextend (HEX). However, we wondered whether VPA itself induces cytoprotective properties that may underlie the restoration of hemostasis, endothelial function, and immune function that we observed in our models. This meta-analysis used computational biology to identify changes in the brain transcriptome due to VPA treatment that occurred independent of the chosen transfusion fluid.Methods: Swine underwent TBI+HS, kept in shock for 2 hours, and resuscitated with normal saline (control), FFP, FFP+VPA, HEX, or HEX+VPA (n=5/group; all VPA doses 300 mg/kg). After 6 hours of observation, brain RNA was isolated and gene expression was analyzed using a microarray. Gene expression data were normalized to a normal saline control group. Transcriptomic data were imported into iPathwayGuide to identify significantly enriched genes and Gene Ontology (GO) terms. Genes were considered to be differentially expressed if they exhibited a log-fold change (logFC) > 1.0 (fold change > 2) and a p-value < 0.05. The differences in gene expression where then summarized in a Venn-diagram. GO terms identified the Biological Processes with the greatest modulation based on both significance and number of DE genes. GO term P-values were corrected using Elim-pruning.Results: A total of 673 differentially expressed genes were identified. The FFP+VPA group exhibited 206 uniquely expressed genes and the HEX+VPA group 121. We found a total of 113 genes that were expressed in both the FFP+VPA and HEX+VPA groups, but not in the FFP and HEX only groups (Figure). Table 1 summarizes the 10 most up- and down-regulated genes that are only expressed in VPA groups (i.e. FFP+VPA and HEX+VPA). Unregulated genes specifically associated with VPA were involved in promotion of cell division, neurogenesis, cytoskeleton, and ion-channels, while down-regulated genes were involved in metalloproteins, neurodegenerative diseases, and cell cycle arrest. Significantly modulated Biological Processes identified by GO terms include: erythrocyte maturation, macrophage activation, microglial cell proliferation, signal transduction by P53, fibrinolysis and plasminogen activation, fibroblast migration, and neurogenesis.Conclusion: Overall, this meta-analysis suggests that VPA altered the expression of approximately 1/6 th of all genes that were differentially expressed in our cohort. These genes are involved in a variety of biological processes such as cell division, neurogenesis, coagulation, cytoskeleton, and inflammation. These results suggest that VPA treatment may promote an environment that favors the restoration of hemostasis, production of new neurons, removal of damaged cells, and attenuation of inflammation. Such findings suggest that VPA treatment alone may be a promising therapeutic for the treatment of life-threatening hemorrhage and TBI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A single dose of valproic acid improves neurologic recovery and decreases brain lesion size in swine subjected to an isolated traumatic brain injury.

We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. Physiologic parameters and laboratory values were similar in both groups. Valproic acid-treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.

In Vitro Determination of Valproic Acid and Cisplatin Combination Antitumor Effect on Neuroblastoma Tumors Viability

Neuroblastoma (SH-SY5Y) is one of the most common solid tumors in children, with aggressive and resistant features. Valproic acid (VPA) is a histone deacetylase inhibitor (HDAC) and is thought to have antitumoral activity. The aim of the current study is the evaluation of valproic acid and cisplatin (CSP) combination antitumor effects on SH-SY5Y. For this aim, the different doses of cisplatin (5, 10, and 15 μg/ml), VPA (5mM), and CSP (5, 10 and 15 μg/ml) + VPA (5 mM) were applied on SH-SY5Y tumor cell culture for 24 hours. For evaluation of cell viability, apoptosis, antioxidant and oxidant status, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT), Anexin-V-FITC apoptosis, Total Antioxidant Capacity (TAC) and Total Oxidant Status (TOS) tests were done 24 hours after drug administration. According to our results, the combination of 15 μg/ml cisplatin and 5 mM VPA reduced cell viability and increased apoptosis status, compared with the negative control group (P<0.05). Our studies showed valproic acid increased the cisplatin effect and reduced the viability of tumor cells. The combination of VPA + CSP is more effective than only using cisplatin. In the light of these data, it is thought that the efficacy of VPA + CSP combined therapy should be investigated more comprehensively with in vivo studies.

Investigation of the risk of valproic acid-induced tremor: clinical, neuroimaging, and genetic factors.

Investigation of associated risk factors of valproic acid (VPA)-induced tremor helped in increasing tolerance and optimizing treatment scheme individually. To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations. Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. One hundred andeighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p = 0.014), family history of tremor (OR = 7.595, p = 0.003), treatment duration (> 24months; OR = 3.294, p = 0.002), and daily dosage (> 1,000mg/d; OR = 19.801, p = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER (p = 0.030) and carbamazepine combination (p = 0.040) reduced the incidence of tremor. One hundred andseventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values (p > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p = 0.001), reduced cerebellar hemisphere thickness (p = 0.025), and right cerebellar hemisphere longitudinal diameter (p = 0.047). Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000mg and treatment duration > 24months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor.

Social Deficits and Repetitive Behaviors Are Improved by Early Postnatal Low-Dose VPA Intervention in a Novel shank3-Deficient Zebrafish Model.

Mutations of the SHANK3 gene are found in some autism spectrum disorder (ASD) patients, and animal models harboring SHANK3 mutations exhibit a variety of ASD-like behaviors, presenting a unique opportunity to explore the underlying neuropathological mechanisms and potential pharmacological treatments. The histone deacetylase (HDAC) valproic acid (VPA) has demonstrated neuroprotective and neuroregenerative properties, suggesting possible therapeutic utility for ASD. Therefore, SHANK3-associated ASD-like symptoms present a convenient model to evaluate the potential benefits, therapeutic window, and optimal dose of VPA. We constructed a novel shank3-deficient (shank3ab–/–) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including of core ASD-like behaviors, as well as molecular analyses of synaptic proteins expression levels. Furthermore, different VPA doses and treatment durations were examined for effects on ASD-like phenotypes. Compared to wild types (WTs), shank3ab–/– zebrafish exhibited greater developmental mortality, more frequent abnormal tail bending, pervasive developmental delay, impaired social preference, repetitive swimming behaviors, and generally reduced locomotor activity. The expression levels of synaptic proteins were also dramatically reduced in shank3ab–/– zebrafish. These ASD-like behaviors were attenuated by low-dose (5 μM) VPA administered from 4 to 8 days post-fertilization (dpf), and the effects persisted to adulthood. In addition, the observed underexpression of grm5, encoding glutamate metabotropic receptor 5, was significantly improved in VPA-treated shank3ab–/– zebrafish. We report for the first time that low-dose VPA administered after neural tube closure has lasting beneficial effects on the social deficits and repetitive behavioral patterns in shank3-deficient ASD model zebrafish. These findings provide a promising strategy for ASD clinical drug development.

Association of Therapeutic Dose of Valproic Acid and Plasma Glycine Levels in Epileptic Patients.

To determine the frequency of hyperglycinemia in epileptic patients taking valproic acid (VPA); and the correlation between therapeutic dose of valproic acid and plasma glycine levels in epileptic patients. Observational, cross-sectional study. Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology Rawalpindi, in collaboration with Combined Military Hospital, Rawalpindi, from August 2020 to January 2021. Plasma glycine levels were analysed on ion exchange chromatography (IEC)-based instrument, Biochrome 30+ of epileptic patients undergoing treatment with anti-epileptic agents. Therapeutic doses of valproic acid were taken as serum trough levels of valproic acid and analysed on chemiluminescence-based Abbott Architect Plus i1000 SR. Mann-Whitney U-test was applied to compare plasma glycine levels in epileptic patients on valproic acid and those on multiple anti-epileptic agents. Spearman's correlation was used to correlate plasma glycine levels in epileptic patients with trough levels of valproic acid, duration of treatment and frequency of fits/year. A total of 77 participants, upto 15 years of age, were enrolled. Plasma glycine levels were significantly raised (p <0.001) in those epileptics who were on valproic acid (monodrug therapy), in comparison with those on multiple anti-epileptic agents. There were significant positive correlations between glycine levels and trough valproic acid levels (r = 0.830), duration of treatment (r = 0.525) and frequency of seizures (r = 0.326). Epileptic patients treated with valproic acid (VPA) had raised plasma glycine levels, that increased with therapeutic dose of valproic acid and duration of treatment and was associated with increased frequency of fits in those patients. Key Words: Epilepsy, Seizure, Glycine, Valproic acid.

Chronic intake of valproic acid decreases total cholesterol level in adult population

Background: Valproic acid (VA) serve as the antimigraine, anti-mental disturbances agent and antiepileptic medicine. After using VA, metabolic rearrangements seen in patients that include alteration in lipoproteins levels; however, this topic is still under discussion and disputable. Aim: To discuss the effects of VA after using for long duration on total levels of cholesterol in adult. Methods: About Eighty candidates participated and they were divided into two groups namely, case group (40 candidates) and control groups40 candidates). All the candidates were asked for collection of venous blood sample in order to determine total cholesterol serum level among them via aid of enzymatic cholesterol oxidase phenol 4-aminoantipyrine peroxidase. By the aid of the logistic regression analysis, the relationship of the long-term VA treatment and the level of total cholesterol was obtained. With respect to our analysis, there is a co relation between total levels of cholesterol and long term usage of VA (P=0.003). Results: There were no noteworthy link for age, sex, body BMI, height medication usage, smoking, diabetes mellitus and VA dosage , except combination of anti-epileptic drugs Conclusion: In a net shell, by using VA for long duration, the total level of cholesterol in adults reduces. Keywords: Lipid profile, side effects, total cholesterol, valproic acid

Synergetic Potential of Combination Probiotic Complex with Phytopharmaceuticals in Valproic Acid Induced Autism: Prenatal Model

Background: Autism spectrum disorder (ASD) is a developing neuronal disorder with hindered social correspondence and repetitive behaviors. Hereditary and ecological factors have been related to this problem, including the introduction of valproic acid during pregnancy. Dysbiosis is the most common comorbid condition in autism, numerous probiotic strains have been known to forestall social impairments in autism. Method: Prenatal autism model was done on 12th embryonic day of pregnancy in Wistar rats with the valproic acid dose 400 mg/kg, i.p. Those offspring exhibiting autistic symptoms were selected for study and were treated with polyphenols, probiotics and their combination for the study period of postnatal day (PND) 08-50. Results: Prenatal model showed significant autistic and dysbiotic symptoms in the animals. With the probiotic and polyphenols treatment combination it was understood that bio-activation of polyphenols are crucial in the correction of neurochemical abnormality, oxidative stress, behavioral deficits and neuroprotection. Probiotic complex with acetyl-l-carnitine combination was also essential for the growth of gut bacteria, functionality of brain. Through this combination study behavioral and biochemical alterations were recovered. Conclusion: Establishing a good ecosystem in the gut with good probiotics and polyphenols-like compounds is essential, gut targeted brain functionality is a remarkable way to challenge autistic disorder, advice on this combination may be helpful in the right way of accessing the gut-brain-axis and useful in amending of autism.

Case of refractory delirious mania responsive to lithium.

Delirious mania is an uncommon condition that is challenging to diagnose and treat. More often seen in patients with a history of bipolar disorder, it frequently presents with prominent catatonic features and overlaps with other diseases in the catatonic spectrum, such as neuroleptic malignant syndrome, serotonin syndrome and malignant catatonia. We present a case of delirious mania refractory to high doses of lorazepam, several antipsychotics and valproic acid, which responded dramatically to therapy with lithium after 26 days of minimal improvement with the other medications. The pathophysiology of delirious mania is reviewed, and the unique actions of lithium are discussed, highlighting possible reasons as to why lithium might offer advantages in the treatment of this disease.

Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (p < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.

Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia.

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery. Next, we investigated the number and morphological characteristic of peri-infarct microglia at different time points and elucidated the mechanism of microglial response by VPA treatment. Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 min, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 min after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 h after reperfusion, and neurological symptoms were evaluated. VPA didn’t significantly reduce infarct volume but did ameliorate neurological deficit at least partially compared with vehicle. Meanwhile, VPA reduced dMCAo-induced elevation of IL-6 at 24 h post-stroke and significantly decreased the number of CD11b-positive microglia within peri-infarct cortex at 7 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions, smaller soma size and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 and 7 days, suggesting that VPA has core effects on microglial morphology. The modulation of microglia morphology caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Furthermore, qPCR analysis of CD11b-positive cells at 3 days post-stroke suggested that VPA could partially enhance M2 subset polarization of microglia in peri-infarct cortex. Analysis of VPA-induced changes to gene expressions at 3 days post-stroke implies that these alternations of the biomarkers and microglial responses are implicated in the upregulation of wound healing, collagen trimmer, and extracellular matrix genes within peri-infarct cortex. Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the morphological characteristics and transcriptional profiles of microglia and extracellular matrix remodeling, which could contribute to the improved recovery.

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma

Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury. We analyzed data from two separate experiments where swine were subjected to lethal insults. Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation).Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration).Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n=5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy. VPA treatment significantly (P < 0.05) improved survival inboth models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%).Model 1(Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P=0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P=0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P=0.02).Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment. A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

Valproic acid use in fertile women with genetic generalized epilepsies.

In genetic generalized epilepsies (GGE), valproic acid (VPA) is the most efficacious compound. However, due to teratogenicity and increased risk for impaired cognitive development after intrauterine exposure, its use in women of fertile age is strictly regulated but sometimes unavoidable. All patients with GGE treated at the outpatient clinic of a tertiary epilepsy center with at least one visit between January 2015 and April 2020 were included in this retrospective study. The rate of women aged 18 to 49years taking VPA was compared to that of men of the same age group and to women > 49years. Furthermore, in each group, clinical variables associated with VPA use were sought. Twenty-eight out of 125 women of fertile age (22%) were treated with VPA, compared to 28 out of 56 men ≤ 49years (50%; p=.002) and to 22 out of 40 female patients > 49years (55%; p<.001). VPA dose was lower in fertile women compared to men, with no difference in seizure freedom rates. In women ≤ 49years, multivariate analysis demonstrated age as the only variable independently associated with VPA use (OR 1.095; 95% CI 1.036-1.159). In the other two groups, no associated variables were identified. Despite warnings with respect to teratogenicity and impaired cognitive development with VPA, from 2015 to 2020, almost every fourth women of fertile age with GGE received this compound. Inevitably lower VPA doses in these women seem sufficient for favorable seizure freedom rates.

Hyperammonemia in Patients With Status Epilepticus Treated With or Without Valproic Acid.

Hyperammonemia is a common side effect of valproic acid (VPA) and can occur after generalized seizures, but the clinical significance is unclear. The aim of this study was to better understand the clinical practice and utility of ammonia testing in status epilepticus (SE) treated with or without VPA. Charts of adult patients with SE from St. Mary's Hospital Intensive Care Units (ICUs) (Mayo Clinic, Rochester, MN) from 2011 to 2016 were reviewed. Clinical factors were compared between patients who had ammonia checked versus those who did not, and those with normal ammonia versus hyperammonemia (>50 µg/dL). Charts were reviewed to determine if hyperammonemia changed clinical management and if it was felt to be symptomatic. There were 304 patients identified: 94 received VPA, 142 had ammonia checked and receiving VPA was associated with ammonia testing (P<0.001). Hyperammonemia was identified in 32 and associated with younger age, being in a non-neurological intensive care unit, and liver disease, but was not statistically associated with VPA. Only one patient had valproate-induced hyperammonemic encephalopathy; however, many patients received treatment for hyperammonemia such as lactulose, levocarnitine, or VPA dose reductions. This study demonstrated variability in ammonia testing and management changes in SE but does not support the routine monitoring of ammonia levels and showed that hyperammonemic encephalopathy was rare in this clinical setting.

Valproic Acid Administration in Management of Status Epilepticus Causing Reye’s Syndrome

AbstractIntroduction Valproic acid is commonly used to treat seizures in children. Regular use of valproic acid is known to cause hepatic dysfunction, and in extremely rare cases, it is known to have caused Reye’s syndrome. There are very few reports of Reye’s syndrome caused by valproic acid use.Methods A 2-year asymptomatic girl underwent modified Blalock–Taussig shunt surgery for correction of tetralogy of Fallot. Postoperatively the girl developed status epilepticus, which did not subside with initial use of intravenous midazolam and phenytoin sodium. She eventually responded to two doses of intravenous valproic acid administered 10 minutes apart. She developed depressed sensorium and was put on mechanical ventilation. The following day’s laboratory investigations revealed raised levels of serum ammonia, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) with normal serum bilirubin. Thus, a diagnosis of Reye’s syndrome was established. The patient succumbed to disease 2 days later.Discussion Reye’s syndrome is a rare and a fulminant illness seen typically in children following a viral illness and/or use of salicylates or other medications. There are rare reports of Reye’s syndrome following use of medications like valproic acid. This patient had a noninflammatory encephalopathy with hepatic dysfunction following two doses of valproic acid.Conclusion There are very few reports on Reye’s syndrome in the literature as it is a rare condition and diagnosis is difficult. Knowledge of the presentation of Reye’s syndrome is essential for treatment and management. When using drugs like valproic acid in children, liver enzymes and serum ammonia levels should be monitored.

Histological changes in female mice kidneys as a result of Valproic acid drug treatment

Valproic acid is a broad spectrum anti- convulsant drug, established as a long – term treatment for epilepsy and has toxic effect on kidney tissues. This study aimed to investigate the histological changes that may occur in the kidney in association with prolonged administration and overdose treatment of valproic acid. 35 albino mice were used, they were divided into four groups, group(I) included 5 animals and served as control group, group(II) included 10 animals and given progressive doses of valproic acid for ten weeks, starting with (15mg/kg/day) as minimum recommended dose and ending with (60mg/kg/day) as maximum recommended dose, group(III) included 10 animals and received an overdose (120mg/kg/day) for one week, group(IV) included 10 animals and treated exactly as group(II) then the animals were left for recovery for three weeks. The animals were sacrificed at the end of each period and the kidney tissue was excised. The drug induced many histological changes in kidney tissues, including inflammatory cellular infiltration, cell necrosis, cloudy swelling, hydropic degeneration, hemorrhage areas, oedema, and collagen deposition. The study concluded that valproic acid has multiple toxic effects on kidney tissues as far as the histological studies concerned and the effects were dependent on the dose and on the duration of treatment. Incomplete recovery was recorded after discontinuation of the drug.

Prenatal valproate exposure and adverse neurodevelopmental outcomes: Does sex matter?

Prenatal exposure to the antiepileptic drug (AED) valproic acid (VPA) is associated with an increased risk of impaired postnatal neurodevelopment, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We aimed to evaluate the influence of sex and drug dosage on the association between prenatal VPA exposure and postnatal behavioral outcomes. The Australian Pregnancy Register of AEDs was interrogated to identify children aged 4-11years prenatally exposed to AEDs. Parents reported on their child's behavior using the Autism Spectrum Quotient-Children's Version and the National Institute for Children's Health Quality Vanderbilt Assessment Scale for ADHD. General linear mixed-effects models were used to investigate the relationship between clinicodemographic variables and psychometric scores. A total of 121 children were studied: 54 prenatally exposed to VPA (28 males, 26 females; mean dose ± SD: 644±310mg/day) and 67 exposed to other AEDs. There was a main effect of sex showing higher ASD scores in males compared to females (p=.006). An interaction between sex and VPA exposure revealed that males had higher ASD symptoms among children exposed to AEDs other than VPA (p=.01); however, this typical sex dynamic was not evident in VPA-exposed children. There was no evidence of any dose-response relationship between VPA exposure and ASD symptoms. Males had higher ADHD scores compared to females, but there was no evidence for a link between ADHD symptoms and VPA exposure. Prenatal VPA exposure seems to negate the usual male sex-related predominance in the incidence of ASD. These initial findings deepen the concept of VPA as a "behavioral teratogen" by indicating that its effect might be influenced by sex, with females appearing particularly sensitive to the effects of VPA. No association between VPA doses and adverse postnatal behavioral outcomes was detected, possibly related to the low VPA doses used in this study.

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock. Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3. Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001). In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.

Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model.

The purpose of this study was to establish a protein binding model of unbound valproic acid (VPA) based on Chinese pediatric patients with epilepsy and provide a reference for clinical medication. A total of 313 patients were included and both their total and unbound VPA concentrations (375 pairs of concentrations) were measured. NONMEM software was used for population pharmacokinetic modeling. The stepwise method was used to screen the potential covariates. Goodness-of-fit plot, bootstrap, and visual predictive check were used for model evaluation. In addition, dose recommendations for typical patients aged 0 to 16years were proposed by Monte Carlo simulations. A one-compartment model of first-order absorption and first-order elimination was used to describe the pharmacokinetic characteristics of unbound VPA, and the linear non-saturable binding equation was introduced to describe the protein binding. Body weight, age-based maturation, and co-medicated with lamotrigine could affect the CL/F of unbound and bound VPA. Model evaluation showed satisfactory robustness of the final model. The dosing regimens for children aged 0 to 16years were proposed based on the final established model. We developed a population pharmacokinetic model of unbound and bound VPA that took account of protein binding. The VPA dosing regimen in pediatric patients with epilepsy needs to be optimized by the body weight, age, and co-medications.