Dose Of Valproic Acid Research Articles

Inter-ictal fatigue and antiepileptic drugs in patients with epilepsy.

Fatigue is a frequently reported symptom in patients with epilepsy (PWE) while the pathophysiology, causes and effects on the disease are not yet fully understood. Fatigue may occur as a side effect of antiepileptic drugs (AEDs); however, it varies greatly depending on both the characteristics of the patients and the AEDs used. The aim of this study was to investigate the relation between fatigue, clinical features and AEDs and doses used in monotherapy in PWE. Ninety consecutive patients with the diagnosis of epilepsy, treated as monotherapy were included in the study. Demographic data, seizure type and frequency, AEDs and their doses were recorded. Fatigue severity scale (FSS) was used in the evaluation of fatigue. Cases of fatigue were defined by a FSS score ≥ 4. The mean age of the patients (57 females, 33 males) was 33 ± 12.7years and the mean disease duration was 11.7 ± 9.1years. Used as monotherapy, AEDs included carbamazepine (n = 29, 32.2%), valproic acid (n = 28, 31.1%), levetiracetam (n = 23, 25.6%) and lamotrigine (n = 10, 11.1%). Fatigue was reported by 52.2% of patients (FSS score ≥ 4). It was found that patients with fatigue had more seizures in the last year than those without (p = 0.031). There was no relation between fatigue and AEDs. The doses of carbamazepine and levetiracetam were significantly correlated with the scores of FSS (p = 0.042 and p = 0.023, respectively), and there was no correlation between the doses of valproic acid and lamotrigine and the scores of FSS. The results of our study showed that; approximately half of the patients with epilepsy had fatigue. Although the relation between AEDs and fatigue was not detected, it was pointed out that AED doses may play a role in the development of fatigue.

Thrombocytopenia during intravenous valproic acid therapy in the neurological intensive care unit.

Thrombocytopenia is a common laboratory abnormality among critically ill patients under neurological intensive care unit (NCU) care. Valproic acid (VPA), a widely used antiepileptic drug, is one of the common causes of drug-induced thrombocytopenia. The purpose of this study was to estimate the incidence and risk factors of thrombocytopenia after intravenous VPA therapy among the patients admitted to NCU. We retrospectively reviewed the medical records of patients who were treated with intravenous VPA during their NCU stay between January 2014 and December 2018. We studied the frequency of thrombocytopenia and further evaluated the risk of thrombocytopenia in these patients. Among the 283 patients (181 male [64.0%], mean age: [61.0±14.9] years) who were treated with intravenous VPA, thrombocytopenia was observed in 104 patients (36.7%). Thrombocytopenia was associated with several risk factors, including lower baseline platelet counts (<200×109 /L); aetiologies other than intracranial or subarachnoid haemorrhage; longer use of VPA (more than 3days); higher daily dose of VPA (more than 1000mg/d); concurrent use of VPA with other antiepileptic drugs; infection; and the use of mechanical ventilation. Multivariate analysis found several independent risk factors of thrombocytopenia with intravenous VPA therapy, including lower baseline platelet counts, aetiologies other than intracranial or subarachnoid haemorrhage, use of VPA for more than 3days and infection. Thrombocytopenia is common in NCU patients. Because several clinical and laboratory factors are associated with thrombocytopenia, careful use of VPA should be considered in patients with these risk factors.

Platelet counts in epileptic children receiving valproic acid

Background Epileptic seizures are a transient occurrence resulting from abnormal, excessive, or synchronous neural activity in the brain. Epilepsy requires long-term treatment, increasingly larger doses, and combination therapy. Anti-epileptic drugs (AEDs), especially valproic acid (VPA), are the main treatment of choice. Thrombocytopenia is the most common adverse event from AEDs.&#x0D; Objective To evaluate platelet counts in epileptic children receiving valproic acid monotherapy vs. polytherapy.&#x0D; Methods This analytic, observational, retrospective cohort study was conducted in children with epilepsy below 18 years of age and treated in Dr. Moewardi Hospital, Surakarta, Central Java. Subjects had received VPA treatment for at least 6 months, either as monotherapy or polytherapy. There were 40 subjects in each group (VPA monotherapy vs. VPA polytherapy). The exclusion criteria were patients who had thrombocytopenia and did not take valproic acid regularly. The data was taken from laboratory and the outcome assessed was decreasing of platelet count.&#x0D; Results Administration of VPA as monotherapy vs. polytherapy was not significantly associated with incidence of thrombocytopenia. However, duration of VPA use &gt; 2 years was associated with significantly greater proportion of thrombocytopenia, with OR 33.0 (95%CI 4.157 to 261.962; P=0.001) compared to VPA use &lt; 2 years. Similarly, VPA dose of &gt;30 mg/kg/day was significantly associated with greater proportion of thrombocytopenia, with OR 4.081 (95%CI 1.337 to 12.458; P=0.013) compared to &lt;30 mg/kg/day dosage.&#x0D; Conclusion Incidence of thrombocytopenia is not significantly different between VPA as a monotherapy and polytherapy. However, higher VPA dose and longer VPA duration are associated with higher proportion of thrombocytopenia.

Peripheral Oxidative Stress Markers in Patients with Bipolar Disorder during Euthymia and in Siblings.

Oxidative stress is increased during the acute phases of bipolar disorder (BD). Our aim here was to analyze oxidative stress biomarkers in patients with BD during euthymia and their siblings. A cross-sectional study was performed in euthymic patients with BD-I (n=48), unaffected siblings (n=23) and genetically unrelated healthy controls (n=21). Protein carbonyl content (PCC), total antioxidant capacity (TRAP), lipid peroxidation (TBARS) and uric acid were measured as biomarkers of oxidative stress in blood. The antioxidant capacity (TRAP) was lower (p<0.001) in patients with BD compared to their siblings and controls, whereas no differences were observed in PCC, TBARS or uric acid. In patients, the concentrations of TRAP and TBARS were positively associated with the dose of valproic acid (p<0.05 and p<0.001, respectively). The concentrations of these biomarkers were not significantly associated with any of socio-demographic and clinical variables. A selective reduction in antioxidant capacity is present in BD during euthymia state, whereas other markers of oxidative stress are unaltered during euthymia. Siblings did not show any alterations in oxidative stress biomarkers. Oxidative stress might represent a state-dependent marker in BD. The association between treatment with valproic acid and oxidative stress markers in euthymia deserves further studies.

Prenatal exposure to valproic acid is associated with altered neurocognitive function and neurogenesis in the dentate gyrus of male offspring rats

In pregnant women with epilepsy, it is imperative to balance the safety of the mother and the potential teratogenicity of anticonvulsants, which could cause impairments such as intellectual disability and cleft lip. In this study, we examined behavioral and hippocampal neurogenesis alterations in male offspring of rats exposed to valproic acid (VPA) during pregnancy. Pregnant Wistar rats received daily intraperitoneal injections of VPA (100 mg/kg/day or 200 mg/kg/day) from embryonic day 12.5 until birth. At postnatal day 29, animals received an injection of bromodeoxyuridine (BrdU). At postnatal day 30, animals underwent the open field (OF), elevated plus-maze, and Y-maze tests. After behavioral testing, animals were decapitated, and their brains were dissected for immunohistochemistry. Of the offspring of the VPA200 mothers, 66.6% showed a malformation. In the OF test, these animals showed locomotor hyperactivity. In the elevated plus-maze, offspring of VPA-treated mothers spent significantly more time in the open arms, irrespective of the treatment dose. The number of BrdU-positive cells in the dentate gyrus of the offspring of VPA-treated mothers increased significantly in a dose-dependent manner compared with the control. A significant positive correlation between spontaneous locomotor activity in the OF and BrdU-positive cell counts was observed across groups. In conclusion, VPA administration during pregnancy results in malformations and attention-deficit/hyperactivity disorder-like behavioral abnormalities in the offspring. An increase in cell proliferation in the hippocampus may underlie the behavioral changes observed. Repeated use of high doses of VPA during pregnancy may increase the risk of neurodevelopmental abnormalities dose dependently and should be carefully considered.

Dose optimization of valproic acid in a lethal model of traumatic brain injury, hemorrhage, and multiple trauma in swine.

Trauma is a leading cause of death, and traumatic brain injury is one of the hallmark injuries of current military conflicts. Valproic acid (VPA) administration in high doses (300-400 mg/kg) improves survival in lethal trauma models, but effectiveness of lower doses on survival is unknown. This information is essential for properly designing the upcoming clinical trials. We, therefore, performed the current study to determine the lowest dose at which VPA administration improves survival in a model of lethal injuries. Swine were subjected to traumatic brain injury (10-mm cortical impact), 40% blood volume hemorrhage, and multiple trauma (femur fracture, rectus crush, and Grade V liver laceration). After 1 hour of shock, animals were randomized (n = 6/group) to four groups: normal saline (NS) resuscitation; or NS with VPA doses of 150 mg/kg (VPA 150) or 100 mg/kg (VPA 100) administered over 3 hours or 100 mg/kg over 2 hours (VPA 100 over 2 hours). Three hours after shock, packed red blood cells were given, and animals were monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. Without resuscitation, all of the injured animals died within 5 hours. Similar survival rates were observed in the NS (17%) and VPA 100 (0%) resuscitation groups. Survival rates in the 100-mg/kg VPA groups were significantly (p < 0.05) better when it was given over 2 hours (67%) compared to 3 hours (0%). 83% of the animals in the VPA 150 group survived, which was significantly higher than the NS and VPA 100 over 3 hours groups (p < 0.05). A single dose of VPA (150 mg/kg) significantly improves survival in an otherwise lethal model of multiple injuries. This is a much lower dose than previously shown to have a survival benefit and matches the dose that is tolerated by healthy human subjects with minimal adverse effects. Therapeutic, level V.

Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism.

Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Valproic acid effect on neural tube defects is not prevented by concomitant folic acid supplementation: Early chick embryo model pilot study

BackgroundNeural tube defect is one of the most prevalent congenital malformations and it involves a variety of malformations ranging from anencephaly to spina bifida. Folic acid supplementation during pregnancy is known to reduce risk of neural tube defects. Antiepileptic drugs have been associated with neural tube defects, one of which is valproic acid. Protective effect of folic acid on congenital malformations in patients using valproic acid or other antiepileptic medicines during pregnancy has not clearly been delineated uniformly in previous clinical series. In this experimental animal study of early chick embryo model, we would like to determine if there is any dose-response relationship between VA and NTDs and if there is any protective effect of FA on this relationship in early chick embryo period. MethodsOne hundred twenty-two fertile leghorn type chicken eggs were used in this study. Six groups, each of which composed of 20 fertilized eggs, were categorized as: group A-control, group B- folic acid, group C-low-dose valproic acid, group D-high-dose valproic acid, group E-low-dose valproic acid + folic acid, group F-high-dose valproic acid + folic acid. Eggs were hatched for 24 h and injected with destined solutions and hatched till 72th hour. ResultsNo neural tube defect was observed in group A and B. High dose valproic acid led to significantly higher number of embryos with neural tube defects compared to low-dose valproic acid (p = 0.018). This significant difference was also present between low-dose and high dose valproic acid combined with folic acid (p = 0.031). When effect of folic acid was evaluated no significant difference observed between groups. ConclusionsEven though number of embryos with neural tube defects decreased with concomitant folic acid administration, this difference could not reach a statistical level. More experimental animal and large-scaled prospective clinical studies are in need to detect folic acid mechanism in inhibiting antiepileptic drugs, if any present.

Association of valproic acid and 2-propyl-4-pentenoic acid concentrations with adverse reaction in 254 Chinese patients with epilepsy.

To investigate the correlation of the concentrations of valproic acid (VPA) and 2-propyl-4-pentenoic acid (4-ene-VPA) with their adverse reactions, and to guide the clinical safety and rational use of VPA. Methods: We collected 254 epilepsy outpatients who took long-term use of sodium valproate oral solution single or combined with other antiepileptic drugs from Xiangya Hospital. The plasma concentrations of VPA and 4-ene-VPA in patients were determined by gas chromatography-mass spectrometry (GC-MS). The double variable correlation analysis was performed to analyze the effect of plasma 4-ene-VPA and VPA concentrations on adverse reactions. Results: The correlations between the PLT level and the dosage of VPA (P<0.01 and P<0.05, respectively), and the RBC level and the concentration of VPA (All P<0.01) were significant negatively. The concentrations of 4-ene-VPA, VPA, ALT, and AST in the polytherapy group were much higher than those in the monotherapy group (All P<0.05). In the monotherapy group, the ALT and AST levels in patients younger than or equal to 2 years old were significantly higher than those over 2 years old (P<0.001). In the polytherapy group, the levels of AST, WBC, and PLT in patients younger than or equal to 2 years old were higher than those over 2 years old (P<0.05). The levels of AST did not show positive correlation with the concentrations of 4-ene-VPA and VPA (r=0.031, r=0.035, all P>0.05), and the levels of ALT also did not show positive correlation with the concentrations of 4-ene-VPA and VPA (r=-0.064, r=-0.089, all P>0.05). Conclusion: VPA may affect blood routine indexes. Age and combination therapy with the non-enzyme-induced anti-epileptic drugs are risk factors for VPA-related liver dysfunctions and renal impairment. The determination of VPA and 4-ene VPA is not a suitable tool for early warning of the VPA-induced liver dysfunction.

Using high-resolution Twin-Ion Metabolite Extraction (HiTIME) mass spectrometry with stable isotope labelling to investigate the metabolism of valproic acid in vivo

Valproic acid (VPA) is a medication that is widely used in the treatment of epilepsy and bipolar disorder, despite a known potential for liver damage in some patients and a specific risk of teratogenic effects if taken by pregnant women. Here the metabolism of VPA has been investigated in male adult Sprague-Dawley rats using the twin-ion method and HiTIME (High-resolution Twin-Ion Metabolite Extraction) analysis under acute dosing. VPA and 13C4-VPA were administered to rats via intra venous infusion and then blood extracts were analysed by liquid chromatography mass spectrometry (LC-MS). Following HiTIME analysis, 13 high-scoring data regions were identified that were not present in control samples and corresponded to VPA together with 12 known VPA metabolites. Tandem mass spectrometry was performed on selected VPA metabolites. Increasing the dose of VPA resulted in an increase in the proportion of phase II metabolites formed at the expense of oxidative phase I products. A twin ion corresponding to a putative VPA-ascorbate adduct was observed and confirmed via independent synthesis. The origin of twin-ion artefacts detected in LC-MS is also discussed as well as proposed methods to reduce their formation.

Outcomes of low-dose valproic acid treatment in patients with juvenile myoclonic epilepsy

PurposeThere are conflicting data regarding the drug dose that is sufficient to achieve seizure control as well as the parameters of seizure remission in juvenile myoclonic epilepsy (JME). The present study aimed to identify factors that contribute to seizure control in JME and to evaluate factors associated with JME remission and the efficacy of low-dose valproic acid (VPA) therapy. MethodsThis retrospective, cross-sectional study included a total of 215 patients (121 female and 94 male; mean age: 28.03 ± 8.43 [14–59] years) diagnosed with JME. The patients were divided into remission and refractory groups. Remission was defined as a seizure-free (myoclonic, absence, and/or generalized tonic–clonic) period of at least 2 years. Patients in whom remission was achieved with VPA monotherapy were further divided into two groups according to the use of low-dose VPA therapy (VPA ≤ 750 mg/day and >750 mg/day). Potential contributing factors were evaluated in terms of the relationship between the dose and the remission parameters. ResultsRemission was achieved with VPA monotherapy in 116 patients (87.9%) in the remission group; the VPA dose was ≤750 mg in 77.6% of the patients. The dose of VPA was higher in patients with absence seizure who achieved remission (p = 0.026). Remission was achieved with a lower dose of VPA in females than in males (p = 0.004). ConclusionsLow-dose VPA can be used to achieve remission in JME. However, identification at follow-up visits of the factors that may affect remission may change the planned effective dose of VPA.

Estimation of apparent clearance of valproic acid in adult Saudi patients.

Background Valproic acid is one of several antiepileptic medications requiring therapeutic drug monitoring due to its complex and wide pharmacokinetic interindividual variability. Objective The objective of this study was to determine the population pharmacokinetics of valproic acid in adult Saudi patients and to identify factors that explain its pharmacokinetic variability. Setting Tertiary referral teaching hospital, Riyadh, Saudi Arabia. Method A retrospective chart review was performed at King Saud University Medical City of patients who received oral valproic acid. The population pharmacokinetic models were developed using Monolix 4.4. After development of the base model, we investigated several covariates including age, sex, weight, total daily dose, and cotherapy with carbamazepine and phenytoin. Main outcome measures the pharmacokinetic parameters of valproic acid and the variables that contributing towards its inter-individual variability. Results The analysis included a total of 54 valproic acid plasma concentrations from 54 patients (42.5% male). The data were sufficiently described by a one-compartment model with linear absorption and elimination processes. Average parameter estimates for valproic acid apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.14 L/h and 37.7 L (fixed), respectively. The inter-individual variability (coefficients of variation) in CL/F was 12%. The most significant covariates for valproic acid CL/F were age, body weight, total daily dose, and cotherapy with carbamazepine and phenytoin. Conclusion This model showed significant inter-individual variability between subjects. Our findings showed that patient age, body weight, total daily dose, and cotherapy with carbamazepine and phenytoin are the most significant covariates of valproic acid clearance. Collectively, healthcare providers should take these factors in consideration for optimal valproic acid dosage regimen.

Twenty-eight-day repeated oral doses of sodium valproic acid increases neural stem cells and suppresses differentiation of granule cell lineages in adult hippocampal neurogenesis of postpubertal rats

Developmental exposure to valproic acid (VPA), a model compound for experimental autism, has shown to primarily target GABAergic interneuron subpopulations in hippocampal neurogenesis of rat offspring. The VPA-exposed animals had revealed late effects on granule cell lineages, involving progenitor cell proliferation and synaptic plasticity. To investigate the possibility whether hippocampal neurogenesis in postpubertal rats in a protocol of 28-day repeated exposure is affected in relation with the property of a developmental neurotoxicant by developmental exposure, VPA was orally administered to 5-week-old male rats at 0, 200, 800 and 900 mg/kg body weight/day for 28 days. At 900 mg/kg, GFAP+ cells increased in number, but DCX+ cells decreased in number in the granule cell lineages. Moreover, CHRNB2+ cells and NeuN+ postmitotic neurons decreased in number in the hilus of the dentate gyrus. Transcript level examined at 900 mg/kg in the dentate gyrus was increased with Kit, but decreased with Dpsyl3, Btg2, Pvalb and Chrnb2. These results suggest that VPA increased type-1 stem cells in relation to the activation of SCF-KIT signaling and suppression of BTG2-mediated antiproliferative effect on stem cells. VPA also decreased type-3 progenitor cells and immature granule cells probably in relation with PVALB+ interneuron hypofunction and reduced CHRNB2+ interneuron subpopulation in the hilus, as well as with suppression of BTG2-mediated terminal differentiation of progenitor cells. Thus, the disruption pattern of VPA by postpubertal exposure was different from developmental exposure. However, disruption itself can be detected, suggesting availability of hippocampal neurogenesis in detecting developmental neurotoxicants in a 28-day toxicity study.

Effects of valproic acid on histone deacetylase inhibition in vitro and in glioblastoma patient samples.

BackgroundThe antiepileptic drug valproic acid (VPA) inhibits histone deacetylase in glioblastoma cells in vitro, which influences several oncogenic pathways and decreases glioma cell proliferation. The clinical relevance of these observations remains unclear, as VPA does not seem to affect glioblastoma patient survival. In this study, we analyzed whether the in vitro effects of VPA treatment on histone acetylation are also observed in tumor tissues of glioblastoma patients.MethodsThe in vitro effects of VPA treatment on histone acetylation were assessed with immunofluorescence and western blotting. On tissue microarrays and in fresh-frozen glioblastoma tissues we investigated the histone acetylation patterns of patients who were either treated with VPA or did not receive antiepileptic drugs at the time of their surgery. We also performed mRNA expression-based and gene set enrichment analyses on these tissues.ResultsVPA increased the expression levels of acetylated histones H3 and H4 in vitro, in agreement with previous reports. In tumor samples obtained from glioblastoma patients, however, VPA treatment affected neither gene (set) expression nor histone acetylation.ConclusionsThe in vitro effects of VPA on histone acetylation status in glioblastoma cells could not be confirmed in clinical tumor samples of glioblastoma patients using antiepileptic doses of VPA, which reflects the lack of effect of VPA on the clinical outcome of glioblastoma patients.

Nauclea latifolia stem-bark extract protects the prefrontal cortex from valproic acid - induced oxidative stress in rats: Effect on B-cell lymphoma and neuron specific enolase protein expression

Nauclea latifolia stem-bark (NLS) is widely utilized for broad spectrum pathologies. The study evaluated the protective effects of NLS extract supplemented along with valproic acid on oxidative stress markers, and neuron specific enolase (NSE) and B cell lymphoma 2 (bcl-2) protein expressions in prefrontal cortex of rats. The NLS extract was administered in three doses (50, 100, 200mg/kg) after pre-treatment of the experimental animals with high dose valproic acid (VPA) (500 mg/kg) orally daily by subacute exposure for 28 days. The rats were sacrificed and the prefrontal cortex (PFC) of the brain abstracted and homogenized in ice for biochemical assays to estimate the levels oxidative stress markers; histopathological examination to reveal the histomorphorgical changes and immunohistochemistry to examine effect on NSE andbcl-2protein expressions. The findings revealed significant (P < 0.05 – 0.001) elevation of oxidative stress induced by VPA. The NLS extract supplementation mediate significant elevation of the levels of reduced glutathione (P< 0.05 – 0.01), antioxidant enzymes [glutathione peroxidase (P< 0.001), superoxide dismutase (P < 0.001), catalase (P< 0.05 – 0.01) and glutathione-s-transferase (P < 0.05 – 0.01)] and significant decline of lipid peroxidation marker, malondialdehyde, (NLS group vs diseases control group (P < 0.001). The NLS extract studied down-regulated NSE at the prefrontal cortex preventing neuronal damage but no effect on bcl-2 protein expression. We conclude that NLS extract has potential to mitigate VPA induced neurotoxicity by obliterating oxidative stress and down regulating NSE expression, effects demonstrating probable therapeutic role in neurodegenerative diseases.

Nauclea latifolia (Rubiaceae) Stem-bark Hydromethanolic Extract Abrogates a Histone Deacetylase Inhibitor - Induced Multifocal Toxicity in Albino Rats

Objective: Nauclea latifolia (Rubiaceae) stem-bark enjoys wide patronage in ethnomedicine due to multiplicity of usage. Acute and subacute hematological and biochemical toxicity studies are available in literature but none underpins its ameliorative effect with a histone deacetylase inhibitor (HDAC), valproic acid (VPA) which mediates multifocal toxicity in different histological milieu.&#x0D; Methods: Subacute exposure of experimental albino rats with a high dose of valproic acid (500 mg/kg) was executed orally one hour before post-treatment with Nauclea latifolia stem-bark (NLS) extract in three doses (50, 100, 200 mg/kg) and with another group of rats with reference drug, vinpocetine, 25 mg/kg daily for 28 consecutive days after which hematological and biochemical analyses were executed. The liver, kidney and lungs were abstracted for histopathological evaluation.&#x0D; Results: The HDAC inhibitor, Valproic acids induced multifocal biochemical insults on liver function enzymes, lipid profiles, electrolytes and kidney function which were dose- dependently and significantly (P &lt; 0.05 – 0.001) abrogated by the varying doses of administered NLS extract. On the histology the NLS extract effects corroborated the biochemical study in the liver and kidney. The NLS did not demonstrate significant toxicological impingement on the hematology and did not alter VPA-induced histomorphological injury in the lungs cytoarchitecture. The reference drug, vinpocetine was unresponsive to VPA-induced alteration in all the tissues investigated in the administered posology.&#x0D; Conclusion: The NLS extract was effective in abrogating toxicological insults in the liver and kidney but not in the lungs. Further studies are required to understand the mechanism of pharmacological effects of NLS extract and the differential in tissue response.

A Factorial Analysis of Drug and Bleeding Effects in Toxicokinetic Studies.

The ICH revised the S3A guidance allowing blood to be microsampled for toxicokinetic analysis from the main study cohorts of rats in general toxicology studies. The resulting changes in the hemogram have been examined in healthy animals but the ability to read through the data when there are toxicological changes has not been thoroughly examined in the literature. To address this, a toxicology study in Sprague Dawley rats was conducted where animals received repeated doses of saline or valproic acid by IP injection daily for 7 days. Animals in both treatment groups were unbled, serially bled (6 bleeds/animal at 0.1 ml/bleed) or compositely bled (2 bleeds/animal at 0.6 ml/bleed) on days 1 and 7 for TK analysis. No statistically significant changes in the clinical pathology were observed for either the serial bleed or composite bleed animals when compared with their respective unbled control; however, a 4%-7% decrease in erythrocyte counts following serial bleeding and a 5%-19% decrease following composite bleeding was observed. When all the clinical pathology and organ weight data were equivalence tested, both the serial bleed and composite bleed results were equivalent to their unbled controls except for the erythroid parameters in the composite bleed group. Toxicokinetic analysis of the blood samples resulted in comparable concentration-time curves, regardless of the method of blood collection. Under these study conditions, the results show blood microsamples can be collected from the core or recovery cohort of animals in a toxicology study without impacting the toxicological interpretation in rats.

Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes. Fifteen Yorkshire swine (40-45 kg) were subjected to lethal (50% estimated total blood volume) hemorrhagic shock (HS) and randomized to three groups: (1) HS, (2) HS-DCR, (3) HS-DCR-VPA (150 mg/kg over 3 hours) (n = 5/cohort). In groups assigned to receive DCR, Tactical Combat Casualty Care guidelines were applied (1 hour into the shock period), targeting a systolic blood pressure of 80 mm Hg. At 72 hours, surviving animals were given transfusion of packed red blood cells, simulating evacuation to higher echelons of care. Survival rates, physiologic parameters, resuscitative fluid requirements, and laboratory profiles were used to compare the clinical outcomes. This model was 100% lethal in the untreated animals. DCR improved survival to 20%, although this was not statistically significant. The addition of VPA to DCR significantly improved survival to 80% (p < 0.01). The VPA-treated animals also had significantly (p < 0.05) higher systolic blood pressures, lower fluid resuscitation requirements, higher hemoglobin levels, and lower creatinine and potassium levels. VPA administration improves survival, decreases resuscitation requirements, and improves hemodynamic and laboratory parameters when added to prolonged DCR in a lethal hemorrhage model.

HDAC2 Inhibitor Valproic Acid Increases Radiation Sensitivity of Drug-Resistant Melanoma Cells.

Resistance to anticancer drugs limits the effectiveness of chemotherapy in cancers. Melanoma cell lines B16F10C and A375C (parental) and B16F10R and A375R (drug-resistant sublines) were used to test radiation sensitization potential of valproic acid (VPA), an inhibitor of Histone deacetylase2 (HDAC2) and LDN193189 (BMP inhibitor). Inhibitors of other signaling pathways were tested for cross-resistance with the resistant cell lines. Cells were pretreated with low concentrations of VPA/ LDN193189 and exposed to 2 Gy radiation for radiation sensitization experiments. Assays-3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), live/dead, clonogenic, and melanin estimation were performed to test the effects of radiation sensitization. Interactions of VPA and HDAC2 were studied in silico. Dose-dependent growth inhibition was observed with all tested drugs. Radiation sensitization of melanoma cells with low dose of VPA induced synergistic cell death, decreased clonogenicity, and decreased melanin content. In silico docking showed two stable interactions between Arg39 of HDAC2 and VPA. In conclusion, pretreatment with low doses of VPA has a potential for sensitizing melanoma cells to low doses of radiation. The binding of VPA to HDAC2 reverses the drug resistance in melanoma and induces the cell death. Sensitization effects of VPA can be used for targeting drug-resistant cancers.

Effects of levetiracetam and valproic acid treatment on liver function tests, plasma free carnitine and lipid peroxidation in childhood epilepsies

Background and aimsThe relationship between anti-epileptic usage and oxidative damage has not yet been clearly understood. In our study, we investigated oxidative stress parameters, carnitine levels, liver function tests (LFT) and their relationship in epileptic children treated with valproic acid or levetiracetam. MethodLFTs, serum free carnitine and oxidative damage markers and their relations with each other were determined in patients who are on valproic acid or levetiracetam treatment at least for 6 months. 25 patients on therapeutic doses of valproic acid, 26 patients on therapeutic doses of levetiracetam and 26 healthy volunteers as controls were included. LFTs, ammonia, carnitine, lipid peroxidation biomarker malondialdehyde (MDA) and a sensitive marker of DNA damage, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were measured. Results of patients are compared to healthy controls. The data is evaluated with IBM SPSS Statistics 22.0. ResultsAmmonia and MDA levels were elevated in patients using levetiracetam; 8-OHdG levels were elevated in both patient groups. Carnitine levels were significantly low in patients under valproic acid therapy, however they were not found to be correlated with MDA, 8-OHdG or LFTs. MDA showed positive correlation with ammonia and 8-OHdG in the levetiracetam group. ConclusionWe did not observe hepatotoxicity in patients under therapeutic doses of valproic acid. However, epileptic children under therapeutic doses of levetiracetam showed significantly elevated levels of MDA and 8-OHdG, which is supportive for oxidative damage under levetiracetam therapy. This result was observed for the first time in childhood epilepsies and further studies are needed to understand its mechanism.