Dose Of Valproic Acid Research Articles

Exposure to valproic acid (VPA) reproduces hdac1 loss of function phenotypes in zebrafish.

Histone deacetylases are enzymes that remove acetyl groups from histone tails and are understood to act as repressors of transcriptional activity. Hdac1 has been previously shown to function in eye, pectoral fin, heart, liver, and pharyngeal skeletal development. We show that high doses of Valproic Acid (VPA) reproduce the hdac1 phenotype. We identify tbx5 genes as potential targets of Hdac1 in eye, pectoral fin, and heart development. Using timed exposures, we show that skeletal structures in the pharyngeal arches are impacted by VPA between 24-36 hours post-fertilization, indicating a role for Hdac1 during post-migration patterning, differentiation, or proliferation of cranial neural crest cells.

PTPRC, KDM5C, GABBR1 and HDAC1 are the Major Targets of Valproic Acid in Regulation of its Anticonvulsant Pharmacological Effects

Background: Valproic acid (VPA) is a small molecule which is the 3rd most prescribed drug among anticonvulsant therapeutics. Understanding of the pharmacology of VPA targets will help optimally rationalise the therapeutic effects and also minimise the undesired outcomes. Hence this study analysed the human specific targets of VPA and assessed the affinity of VPA to these targets to interpret potential safe therapeutic range for VPA. Materials and Methods: The targets of VPA were identified from the SwissTargetPrediction server and STITCH database and analysed for their affinity with VPA using Autodock vina 1.2.0. The volume of distribution (Vd, L) and the dose of VPA reported in the DrugBank database was used for estimation of the plasma and CSF concentration. The plasma and CSF Concentration Affinity (CA) ratio of VPA against each of the high affinity targets was assessed at variable Vd (0.1 to 0.4 L/kg) to identify the therapeutic safety window of VPA. Results: The plasma/CSF concentration of VPA range from 170 to 7000 μM and 17 to 700 μM respectively. The plasma concentration achieved was within the safety limits (170 to 700 μM) at higher Vd (>10 L), while at lower Vd (<10L), the plasma or CSF concentration achieved was of concern at VPA dose of >1000 mg/day. The plasma concentration at very low Vd (< 2L) was of concern even at dose of 500 mg/day. The affinity of VPA against all its human specific targets ranged from 2.9 to 52.1 mM. The CA ratio of VPA against its high affinity target was observed to be greater than 0.8, indicating potentially significant modulation of these targets. The following four targets showed CA ratio of over 1: PTPRC, KDM5C, GABBR1 and HDAC1, indicating their preferential targeting by VPA. CES1 and SLC22A12 are high affinity targets of VPA which can contribute to its undesired pharmacological effects (CNS oedema and hepatotoxicity). Conclusion: This study offers a novel insight into the anticonvulsant and undesired pharmacology of VPA by specifically identifying the targets involved and recommends an evidence-based approach to personalise dose titration of VPA to achieve optimal therapeutic benefits.

Valproic acid-induced hyperammonemia in neuropsychiatric disorders: a 2-year clinical survey.

Valproic acid (VPA)-induced hyperammonemia (HA) is a rare adverse effect reported even at therapeutic VPA levels. The present study aimed to investigate the characteristics of VPA-induced HA and its association with the total dose, duration, and level of VPA. This study also investigated whether the use of VPA in combination with other medications has any effect on elevating serum ammonia levels. A total of 316 patients with a history of VPA prescribed for underlying neuropsychiatric disorders were found eligible for the study. Data including demographic information, medical history and diagnosis, VPA dosage, VPA treatment duration, VPA level, and ammonia serum level were extracted and reviewed from our hospital records. The history of other neuropsychiatric medications was also included. Among 316 patients receiving VPA, HA was observed in 54 (17%) patients, and 15 patients were symptomatic among them. There was no significant difference in demographics between symptomatic and asymptomatic HA groups except for the number of co-administrated medications (p = 0.044). Besides, VPA duration and dose did not show a significant difference between the two groups. Additionally, the VPA level was significantly higher in patients who used risperidone in addition to VPA (p = 0.019). Eventually, VPA level showed a significant association with ammonia level (p = 0.025) and symptomatic HA (p = 0.033) after adjusting for possible confounders. VPA level showed a significant association with ammonia level and symptomatic HA. Moreover, co-administrated medications such as risperidone might have an impact on the serum level of VPA. Further studies are recommended to confirm these findings.

Serum concentrations of valproic acid in people with epilepsy: Clinical implication

Context: Therapeutic drug monitoring (TDM) allows personalizing the dose of valproic acid in patients with epilepsy to optimize drug therapy, minimize adverse effects and detect interactions. Aims: To determine valproic acid concentrations in serum samples from people with epilepsy and to analyze its clinical implications. Methods: Cloned donor enzyme immunoassay; descriptive, cross-sectional, non-randomized, convenience recruitment study of 57 voluntary patients with epilepsy (n = 39 male, 68.42%; n = 18 female, 31.58%) aged between 19 and 62 years. After three months of treatment with valproic acid, a single blood sample was collected from each volunteer at a minimal concentration. Results: Serum drug concentrations 51.30-100.10 mg/L (SD 5.94) and level/dose 2.17-5.31 (SD 1.14) were observed. Association was shown between the dose ratio/dose of valproic acid (R2 = 0.8693; p<0.05) and the Mann-Whitney U test (p<0.05). Valproic acid monotherapy and association with carbamazepine and phenytoin are not different between treatment groups (Mann-Whitney U test: p = 0.391 > α = 0.05). Conclusions: Serum valproic acid concentrations are within the therapeutic range, and there is a significant inverse linear correlation between dose ratio/dose, which must be considered to personalize the dose and optimize the pharmacotherapeutic result.

Granulocyte Colony-Stimulating Factor Improved Core Symptoms of Autism Spectrum Disorder via Modulating Glutamatergic Receptors in the Prefrontal Cortex and Hippocampus of Rat Brains.

Chronic neuroinflammation-induced anomalous glutamate receptor activation has been identified as one of the important factors in the pathogenesis of autism spectrum disorder (ASD). Thus, the current study was designed to elucidate the neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth factor, an anti-inflammatory, and a neuroprotectant to decipher the underlying mechanism(s) in the valproic acid (VPA)-induced experimental model of ASD. Experimentally, the ASD rat model was induced by a single dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant female rats. After birth, pups were treated with vehicle, normal saline 0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70 μg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups were subjected to various developmental and behavior tests from birth. The rats were sacrificed on PND 55, and their brain was excised and processed for biochemical parameters (oxidative stress, inflammatory markers, BDNF), histological examination (H&E, Nissl staining), NMDA, and AMPA receptor expression by immunohistochemistry, western blot, and real-time polymerase chain reaction evaluation. Also, the possible interaction of the G-CSF with NMDA and AMPA receptors was evaluated using the in-silico method. The results of the study showed that in VPA-exposed rats, postnatal treatment of G-CSF rescued all the behavioral abnormalities, oxidative stress, and inflammatory parameters in a dose-dependent manner while risperidone did not show any significant results. The in-silico analysis showed the direct interaction of G-CSF with NMDA and AMPA receptors. The upregulated expression of NMDA and AMPA both in the prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby validating its anti-inflammatory and excitoprotective properties. Thus, G-CSF demonstrated neuroprotection against the core symptoms of autism in the VPA-induced rodent model, making it a potential candidate for the treatment of ASD.

Blood Levels of Ammonia and Carnitine in Patients Treated with Valproic Acid: A Meta-analysis.

ObjectiveLong-term valproic acid (VPA) administration is associated with adverse metabolic effects, including hyperammonemia and hypocarnitinemia. However, the pathogeneses of these adverse events remain unclear, and not enough reviews have been performed. The aim of this study was to conduct a meta-analysis of studies examining blood levels of ammonia and carnitine in patients treated with VPA.MethodsWe conducted database searches (PubMed, Web of Science) to identify studies examining blood levels of ammonia and carnitine in patients treated with VPA. A meta-analysis was performed to conduct pre- and post-VPA treatment comparisons, cross-sectional comparisons between groups with and without VPA use, and estimations of the standardized correlations between blood levels of ammonia, carnitine, and VPA.ResultsAccording to the cross-sectional comparisons, the blood ammonia level in the VPA group was significantly higher than that in the non-VPA group. Compared to that in the non-VPA group, the blood carnitine level in the VPA group was significantly lower. In the meta-analysis of correlation coefficients, the blood VPA level was moderately correlated with blood ammonia and blood free carnitine levels in the random effects model. Furthermore, the blood ammonia level was moderately correlated with the blood free carnitine level.ConclusionAlthough the correlation between ammonia and free carnitine levels in blood was significant, the moderate strength of the correlation does not allow clinicians to infer free carnitine levels from the results of ammonia levels. Clinicians should measure both blood ammonia and free carnitine levels, especially in patients receiving high dosages of VPA.

Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota-Gut-Brain Axis Modulation in a Valproic Acid Mouse Model.

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota–gut–brain axis.

Pharmacokinetic interactions between clozapine and valproic acid in patients with treatment-resistant schizophrenia: Does UGT polymorphism affect these drug interactions?

The combination of valproic acid (VPA) and clozapine (CLZ) is regularly prescribed for augmentation therapy in treatment resistant schizophrenia. The VPA has been shown to reduce norclozapine (NCLZ) plasma levels, but the mechanism of this interaction remains unknown. The aim of this study is to examine the differences between patients treated with CLZ and patients treated with CLZ plus VPA. For it, various factors have been evaluated. The study was based on plasma samples from CLZ and CLZ plus VPA treated patients (n = 61) subjected to routine therapeutic drug monitoring considering clinical data, smoking status, daily dose of CLZ and VPA, concomitant medications, albumin, and renal and hepatic function. Genotyping of polymorphisms of CYP1A2, CYP3A4/5, CYP2C19, ABCB1, UGT2B10 and CYP2C19 were performed by real time PCR. CYP2D6 were genotyped using competitive allele-specific PCR and by a long PCR based method. Plasma CLZ and NCLZ concentrations were measured by Liquid Chromatography-Tandem masses (LC-MS/MS) and plasma VPA by Ultraviolet–Visible (UV–vis) spectrophotometric immunoassay. The patients presented adequate CLZ levels in relation to the dose. However, NCLZ levels were excessively low and the CLZ/NCLZ ratio very high. Patients with UGT2B10 GT (rs61750900) genotype showed lower NCLZ plasma levels and C/D NCLZ, and higher CLZ/NCLZ ratio versus patients with UGT2B10 GG genotype. VPA, smoking, the presence of UGT2B10 GT genotype and having low albumin levels indicate that the CLZ/NCLZ ratio is affected, mostly coinciding with decreased NCLZ levels and possibly with an increased risk of neutropenia.

The impact of ibuprofen on valproic acid plasma concentration in pediatric patients

The combination of valproic acid (VPA) and ibuprofen is common in children with epilepsy. Three case reports investigated that ibuprofen might decrease plasma concentration of VPA, however, no cohort study was published to evaluate the interaction of ibuprofen on VPA plasma concentration in pediatric patients. Data from patients with measured VPA trough concentrations (C0) were retrospectively collected in a Chinese teaching and tertiary Children’s Hospital from January 2017 to June 2019. The samples measured within 6 weeks of the last ibuprofen administration were considered as ibuprofen combination samples. Patients with paired samples before and after ibuprofen administration were additionally analyzed. The effects of ibuprofen on the VPA trough concentration to dose (C0/D) ratio were investigated. The proportion of samples with achieved target concentrations of VPA (50–100 mg/L) and the corresponding required dosage were compared. Moreover, subgroup analysis according to the interval between the last ibuprofen dosage and C0 measurement was performed. A total of 616 samples from 434 patients, of whom 16 had paired samples, were included. VPA C0/D decreased when ibuprofen was administered by 7.5% and 30.6% of the total samples and paired samples, respectively. The interaction was significant within 1 week of the last ibuprofen dose. No significant differences were observed in the proportion of target concentration achieved and VPA dose requirement when ibuprofen was combined. A moderate effect of ibuprofen on VPA C0/D was observed within 1 week of ibuprofen administration; the target concentration and required doses of VPA were comparable.

Neurosyphilis as a cause for neuropsychiatric symptoms: a case report

IntroductionSyphilis is a sexually transmitted infection which in its late phase can cause all kinds of neuropsychiatric symptoms. A case report of a 79-year-old male with a manic episode probably due to lues is presented.ObjectivesA case of a patient with neurosyphilis is presented followed by a theoretical review on the topic.MethodsA case is presented with a bibliographic review.ResultsA 79-year-old male was hospitalized with symptoms of disorientation, inattention, and difficulty for abstract thought. His speech was verbose, incoherent with megalomaniac ideas. He presented affective symptoms such as hyperthymia, emotional lability and intermittent crying. He also had nomination problems and recent memory mistakes. He also suffered from insomnia. He presented as his medical history HIV infection under control and syphilis treated in December 2020 with a negative RPR test in June 2021. During his hospitalization he was treated with increasing doses of olanzapine and valproic acid. Irritability improved with this treatment.ConclusionsNeurosyphilis may be presented as any kind of neuropsychiatric disorder. Laboratory tests are required as there is no conclusive imaging test. Penicillin and symptomatic management are the proper treatment. Neuropsychiatric disorders in elderly population must consider infectious diseases and previous pathologies as differential diagnosis.DisclosureNo significant relationships.

Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature.

We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.

Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder

ABSTRACT Background This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance. Methods Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting). Results Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting. Conclusion In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.

Different Effects of Valproic Acid on SLC12A2, SLC12A5 and SLC5A8 Gene Expression in Pediatric Glioblastoma Cells as an Approach to Personalised Therapy.

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene expressions in pediatric PBT24 (boy’s) and SF8628 (girl’s) glioblastoma cells. The SLC12A2, SLC12A5 and SLC5A8 RNA expressions were determined by the RT-PCR method. The SLC12A2 and SLC5A8 expressions did not differ between the PBT24 and SF8628 controls. The SLC12A5 expression in the PBT24 control was significantly higher than in the SF8628 control. VPA treatment significantly increased the expression of SLC12A2 in PBT24 but did not affect SF8628 cells. VPA increased the SLC12A5 expression in PBT24 and SF8628 cells. The SLC12A5 expression of the PBT24-treated cells was significantly higher than in corresponding SF8628 groups. Both VPA doses increased the SLC5A8 expression in PBT24 and SF8628 cells, but the expression was significantly higher in the PBT24-treated, compared to the respective SF8628 groups. The SLC5A8 expression in PBT24-treated cells was 10-fold higher than in SF8628 cells. The distinct effects of VPA on the expression of SLC12A2, SLC12A5 and SLC5A8 in PBT24 and SF8628 glioblastoma cells suggest differences in tumor cell biology that may be gender-related.

Autism-like symptoms by exposure to air pollution and valproic acid-induced in male rats.

Exposure to air pollution during prenatal or neonatal periods is associated with autism spectrum disorder (ASD) according to epidemiology studies. Furthermore, prenatal exposure to valproic acid (VPA) has also been found to be associated with an increased prevalence of ASD. To assess the association between simultaneous exposure to VPA and air pollutants, seven exposure groups of rats were included in current study (PM2.5 and gaseous pollutants exposed - high dose of VPA (PGE-high); PM2.5 and gaseous pollutants exposed - low dose of VPA (PGE-low); gaseous pollutants only exposed - high dose of VPA (GE-high); gaseous pollutants only exposed - low dose of VPA (GE-low); clean air exposed - high dose of VPA (CAE-high); clean air exposed - low dose of VPA (CAE-low) and clean air exposed (CAE)). The pollution-exposed rats were exposed to air pollutants from embryonic day (E0) to postnatal day 42 (PND42). In all the induced groups, decreased oxidative stress biomarkers, decreased oxytocin receptor (OXTR) levels, and increased the expression of interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α) were found. The volumes of the cerebellum, hippocampus, striatum, and prefrontal decreased in all induced groups in comparison to CAE. Additionally, increased numerical density of glial cells and decreased of numerical density of neurons were found in all induced groups. Results show that simultaneous exposure to air pollution and VPA can cause ASD-related behavioral deficits and air pollution reinforced the mechanism of inducing ASD ̉s in VPA-induced rat model of autism.

Neuroprotective effect of the standardised extract of Bacopa monnieri (BacoMind) in valproic acid model of autism spectrum disorder in rats

Ethnopharmacological relevanceBacopa monnieri (BM) is commonly employed in the Indian traditional system of medicines, i.e. Ayurveda as a memory booster, antioxidant, anti-inflammatory, antipyretic, analgesic, sedative and anti-epileptic for decades. Aim of the studyTo evaluate the neuroprotective effect of Bacopa monnieri (BM) in experimental model of autism spectrum disorder (ASD) in Wistar rats and explore its mechanism of action. Materials and methodsBacoMind, was evaluated for its neuroprotective effect in valproic acid (VPA) model of ASD. For in-vivo study, the pregnant female Wistar rats were divided in two groups; normal control (NC) and VPA group who received single dose of normal saline (0.9%) or 600 mg/kg dose of VPA respectively on gestation day (G.D) 12.5. After the birth, all pups were segregated according to the sex. All the male pups from the dams were divided into six groups: Group 1 (NC, treated with only 0.9% normal saline, group 2 (VPA, treated 600 mg/kg on G.D12.5 and normal saline from post natal day (PND) 23 to 43), group 3 (risperidone 2.5 mg/kg, PND 23 to 43) and groups 4, 5 and 6 (BM 20, 40, 80 mg/kg, PND 23 to 43). All experimental groups were subjected to batteries of behavior parameters (three chamber sociability test, Morris Water Maze, elevated plus maze, open field and rota rod test), biochemical parameters such as oxidative stress (GSH, SOD, Catalase, MDA), inflammatory cytokines (Il-1β, IL-6, IL-10, TNF-α), histopathological examination (cresyl violet staining) of hippocampus (HC) and prefrontal cortex (PFC) regions. Further, the mRNA as well as protein expression of AMPA receptor was evaluated using RT-PCR and western blot respectively to study the mechanism of neuroprotective effect of BM. The in-silico analysis followed evaluating the binding profile of different constituents of BacoMind with AMPA receptor. ResultsThe results of the in-vivo study indicated BM at 80 mg/kg ameliorated abnormal behavioral paradigms such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination exhibited by the VPA model of ASD in rats. Furthermore, BM was found to have a significant anti-oxidant (increasing GSH, SOD, and catalase and decreasing MDA levels) and anti-inflammatory properties (decreasing IL-1β, 6, TNF- α). The histopathological score was also found to be significantly improved by BM in a dose dependent manner in both HC and PFC. In addition to this, the up-regulated mRNA as well as protein expression of AMPA receptor was significantly reduced by 80 mg/kg dose of BM in both HC and PFC. Further, the in-silico analysis of different constituents of BacoMind with AMPA receptor demonstrated that luteolin and apigenin showed good binding to both the competitive antagonist binding site, non-competitive antagonist binding site and allosteric modulator site while Bacosaponin C showed good binding to the non-competitive antagonist binding site. ConclusionThe present study concluded that BM can be a potential candidate for ameliorating the ASD symptoms in rats and acts via modulating the up-regulated AMPA receptor expression.

Transcranial photobiomodulation add-on therapy to valproic acid for pentylenetetrazole-induced seizures in peripubertal rats

BackgroundConvulsive status epilepticus (CSE) prevention is critical for pediatric patients with epilepsy. Immediate intervention before CSE reduce severity. Despite its wide usage as an anticonvulsant, valproic acid (VPA) results in harmful side effects such as dose-dependent hepatotoxicity. Hence, reducing VPA dosage to minimize side effects while maintaining its efficacy is necessary, and transcranial photobiomodulation (tPBM) add-on therapy could facilitate this. We recently demonstrated for the first time that tPBM at a wavelength of 808 nm attenuated CSE in peripubertal rats. However, the effects of VPA with the add-on therapy of tPBM prior to seizures have not yet been explored. This study investigated whether adding tPBM to VPA exerts synergistic effect for CSE prevention in peripubertal rats.MethodsA gallium-aluminum-arsenide laser (wavelength of 808 nm with an exposure duration of 100 s and irradiance of 1.333 W/cm2 at the target) was applied transcranially 30 min after VPA injection in Sprague Dawley rats. All the rats received 90 mg/kg of pentylenetetrazole (PTZ). Except for the saline (n = 3), tPBM + saline (n = 3), and PTZ group (n = 6), all the rats received a PTZ injection 30 min after VPA injection. The rats received add-on tPBM with PTZ immediately after tPBM. In the VPA + PTZ group, the rats received low-dose (100 mg/kg, n = 6), medium-dose (200 mg/kg, n = 6), and high-dose (400 mg/kg, n = 7) VPA. In the VPA + tPBM + PTZ group, the rats received low (100 mg/kg, n = 5), medium (200 mg/kg, n = 6), and high (400 mg/kg, n = 3) doses of VPA. Seizures were evaluated according to the revised Racine’s scale in a non-blinded manner.ResultsAdding tPBM to low-dose VPA reduced the incidence of severe status epilepticus and significantly delayed the latency to stage 2 seizures. However, adding tPBM to high-dose VPA increased the maximum seizure stage, prolonged the duration of stage 4–7 seizures, and shortened the latency to stage 6 seizures.ConclusionsAdding tPBM to low-dose VPA exerted a synergistic prevention effect on PTZ-induced seizures, whereas adding tPBM to high-dose VPA offset the attenuation effect.

Does Valproate Treatment in Childhood Epilepsy Affect Nutritional Status and Biochemical Parameters?

Objective: Valproic acid is widely prescribed for the treatment of various neurological and neuropsychiatric disorders. This study aimed to determine the effect of valproic acid therapy, which is thought to have weight gain effect on nutritional status and some biochemical factors in children with epilepsy. Material and Methods: The study included 30 children and adolescents who received valproic acid monotherapy because of the diagnosis of epilepsy. Selected biochemical parameters before and 12 months after treatment were recorded retrospectively from the patient files. Valproic acid doses ranged from 11-40 mg/kg/day and plasma levels were maintained within the therapeutic limits throughout the study. The anthropometric measurements of the patients were recorded in the WHO Anthro program for children aged 1-5 years and the WHO Anthro-Plus program for children aged 5-18 years. Results: The epilepsy age of the patients was determined as 48.85±38.16 months; and they have been receiving valproic acid therapy at a dose of 25.00±10.75 mg/kg/day for 18.95±6.02 months. While no difference was found in terms of hunger VAS scores before and after treatment, VAS scores of appetite increased and satiety decreased (p<0.05). BMI-SDs, fasting insulin, HDL cholesterol and triglyceride levels increased after treatment (p<0.05). Conclusion: For this reason, it was thought that it is important to include a dietitian in multidisiplinary team for growth and weight monitoring in children receiving VPA therapy.

Association of Valproic Acid Use With Post-Myocardial Infarction Heart Failure Development: A Meta-Analysis of Two Retrospective Case-Control Studies.

Despite advances in treatments, myocardial infarction (MI) remains a significant cause of morbidity and mortality worldwide. Our team has previously shown that valproic acid (VPA) is cardio-protective when administered to rats post-MI. The aim of this study was to investigate the association of VPA use with post-MI heart failure (HF) development in humans. This study was a random effects meta-analysis of two retrospective case-control studies collected from electronic health record (Michigan Medicine) and claims data (OptumInsight). Cases with an active prescription for VPA at the time of their MI were matched 1:4 to controls not taking VPA at the time of their MI by multiple demographic and clinical characteristics. The primary outcome, time-to-HF development, was analyzed using the Fine-Gray competing risks model of any VPA prescription versus no VPA prescription. An exploratory analysis was conducted to evaluate the association of different VPA doses (≥1000 mg/day vs <1000 mg/day vs 0 mg/day VPA). In total, the datasets included 1313 patients (249 cases and 1064 controls). In the meta-analysis, any dose of VPA during an MI tended to be protective against incident HF post-MI (HR = 0.87; 95% CI = 0.72-1.01). However, when stratified by dose, high-dose VPA (≥1000 mg/day) significantly associated with 30% reduction in risk for HF post-MI (HR = 0.70; 95% CI = 0.49-0.91), whereas low-dose VPA (<1000 mg/day) did not (HR = 0.95; 95% CI = 0.78-1.13). VPA doses ≥1000 mg/day may provide post-MI cardio-protection resulting in a reduced incidence of HF.

Case series of HaNDL syndrome responding to valproic acid

Objective: We report a case series of patients diagnosed with the syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) responding to high dose Valproic acid. Background: HaNDL syndrome is an infrequent entity, presenting with neurological impairment episodes and severe headache. A treatment to prevent the attacks has not been proposed yet. Results: We describe 6 patients with a definite diagnosis of HaNDL, responding to Valproic acid 1000–1500 mg/day. Conclusion: Although HaNDL’s self-limiting nature, episodes may cause important disability and can last up to 3 months. Valproic acid may be a good choice to prevent attacks due to its effect on cortical depression and fast titration.

Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder.

To develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population. A total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model. A one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70kg administered VPA 1000mg/day were 0.18h-1, 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model. A qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients.