-
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jul 2020Due to the narrow therapeutic window of valproic acid (VPA), grievous adverse reactions such as hepatotoxicity, nephrotoxicity may occur in patients with epilepsy for a...
OBJECTIVES
Due to the narrow therapeutic window of valproic acid (VPA), grievous adverse reactions such as hepatotoxicity, nephrotoxicity may occur in patients with epilepsy for a long time. This study aimed to explore the effect of VPA concentration on biochemical and routine blood test related to liver, renal, and hematology in epileptic outpatients treated with VPA alone or combined with other antiepileptic drugs.
METHODS
A total of 3 194 Chinese epileptic outpatients from Xiangya Hospital, were analyzed in a crude analysis after stratifying through dosage regimens. The plasma VPA concentration was detected by gas chromatography method and then standardized through dosage and body weight. Ten biochemical indexes related to liver, renal, and hematology were evaluated.
RESULTS
Of all patients, blood urea nitrogen (BUN), serum creatinine (SCr) level, and erythrocyte count (RBC) showed positive correlations with standardized VPA concentration (=0.494, =0.157, =0.596, respectively), while platelet specific volume (PCT) and blood platelet (PLT) showed negative correlations with standardized VPA concentration (=-5.500, =-0.086, respectively). After stratifying through dosage regimens, significantly positive associations between SCr and standardized VPA concentration were found in the juvenile patients from the monotherapy group and combination therapy group (=1.800, =0.352, respectively). In addition, PLT and leukocyte count (WBC) in the juvenile patients from the combination therapy group were negatively correlated with standardized VPA concentration (=-1.463, =-0.079, respectively), while RBC showed a positive association with standardized VPA concentration in the juvenile patients from the monotherapy group (=0.068).
CONCLUSIONS
SCr level is significantly associated with plasma VPA concentration. Drug combination and age are important factors leading to hematological disorders. The finding provides potential theoretical guidance for the rational and safe clinical use of VPA.
Topics: Adolescent; Anticonvulsants; Combined Modality Therapy; Drug Therapy, Combination; Epilepsy; Humans; Outpatients; Valproic Acid
PubMed: 32879081
DOI: 10.11817/j.issn.1672-7347.2020.190360 -
Der Nervenarzt May 2023Until now the long-term consequences of the medical treatment for bipolar disorder have barely been examined, especially the consequences with respect to cognitive... (Review)
Review
BACKGROUND
Until now the long-term consequences of the medical treatment for bipolar disorder have barely been examined, especially the consequences with respect to cognitive impairment and dementia. Some studies show signs that some treatment options have a better effect on the brain than others. This review summarizes the current state of research.
OBJECTIVE
The effects of long-term consequences of lithium, valproic acid, carbamazepine and antipsychotic agents on the development of dementia or cognitive impairments in patients with bipolar disorder were investigated.
METHODS
A systematic literature search was carried out in the PubMed data base from May to July 2022.
RESULTS
The majority of studies showed that lithium has a neuroprotective effect and can lower the risk of developing dementia, whereas an increased risk was found in patients taking valproic acid. There are only very few studies that deal with antipsychotic medication and the long-term consequences concerning dementia.
CONCLUSION
Lithium should be recommended for the long-term treatment of bipolar disorder. Valproic acid should not or carefully be used as it can affect the risk of developing dementia. With respect to antipsychotics there is no recommendation as more studies are needed to evaluate the long-term consequences.
Topics: Humans; Antipsychotic Agents; Bipolar Disorder; Valproic Acid; Lithium; Carbamazepine; Benzodiazepines; Dementia; Cognition; Antimanic Agents
PubMed: 36922444
DOI: 10.1007/s00115-023-01454-y -
Asian Journal of Psychiatry Jul 2023Mood stabilizers are psychotropic drugs mainly used to treat bipolar disorder in the acute phase or for maintenance therapy to prevent relapse. In clinical practice,...
OBJECTIVE
Mood stabilizers are psychotropic drugs mainly used to treat bipolar disorder in the acute phase or for maintenance therapy to prevent relapse. In clinical practice, mood stabilizers are commonly prescribed for conditions other than bipolar disorder. This study investigated the distribution of mood stabilizer prescriptions for different psychiatric diagnoses and studied differences in the drugs, dosage, and plasma concentration in 10 Asian countries including Taiwan, South Korea, Malaysia, China, Thailand, India, Pakistan, Singapore, Indonesia, and Myanmar.
METHODS
Patients prescribed mood stabilizers (lithium, carbamazepine, valproic acid, or lamotrigine) for a psychiatric condition other than bipolar disorder (codes F31.0-F31.9 in the International Classification of Diseases, 10th Edition, Clinical Modification) were recruited through convenience sampling. A website-based data entry system was used for data collection.
RESULTS
In total, 1557 psychiatric patients were enrolled. Schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (F20-F29, 55.8 %) was the most common diagnosis, followed by non-bipolar mood disorders (F30, F31- F39, 25.3 %), organic mental disorder (F00-F09, 8.8 %), mental retardation (F70-F79, 5.8 %) and anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders (F40-F48, 4.4 %). The most frequently targeted symptoms (>20 %) were irritability (48 %), impulsivity (32.4 %), aggression (29.2 %), anger (20.8 %), and psychosis (24.1 %). Valproic acid was the most frequently used medication.
CONCLUSIONS
Clinicians typically prescribe mood stabilizers as empirically supported treatment to manage mood symptoms in patients with diagnoses other than bipolar disorders, though there is on official indication for these disorders. The costs and benefits of this add-on symptomatic treatment warrant further investigation.
Topics: Humans; Bipolar Disorder; Valproic Acid; Antimanic Agents; Antipsychotic Agents; Anticonvulsants; Pakistan
PubMed: 37163943
DOI: 10.1016/j.ajp.2023.103613 -
Current Neuropharmacology 2023Bipolar disorders (BDs) are a heterogeneous group of severe affective disorders generally described by the alternation of (hypo)manic, depressive, and mixed phases, with...
Bipolar disorders (BDs) are a heterogeneous group of severe affective disorders generally described by the alternation of (hypo)manic, depressive, and mixed phases, with euthymic intervals of variable duration. BDs are burdened with high psychiatric and physical comorbidity, increased suicide risk and reduced life expectancy. In addition, BDs can progress into complicated forms (e.g., mixed states, rapid/irregular cycling), which are more difficult to treat and often require personalized pharmacological combinations. Mood stabilizers, particularly Lithium and Valproic acid (VPA), still represent the cornerstones of both acute and chronic pharmacotherapies of BDs. Lithium is the gold standard in BD-I and BDII with typical features, while VPA seems more effective for atypical forms (e.g., mixed-prevalence and rapid-cycling). However, despite appropriate mood stabilization, many patients show residual symptoms, and more than a half recur within 1-2 years, highlighting the need of additional strategies. Among these, the association of atypical antipsychotics (AAPs) with mood stabilizers is recurrent in the treatment of acute phases, but it is also being growingly explored in the maintenance pharmacotherapy. These combinations are clinically more aggressive and often needed in the acute phases, whereas simplifying pharmacotherapies to mood stabilizers only is preferable in the long-term, whenever possible. When mood stabilizers are not enough for maintenance treatment, Quetiapine and, less consistently, Aripiprazole have been proposed as the most advisable adjunctive strategies, for their safety and tolerability profiles. However, in view of the increased risk of serious adverse effects, a careful patient-centered balance between costs and benefits is mandatory.
Topics: Humans; Antipsychotic Agents; Bipolar Disorder; Valproic Acid; Lithium; Antimanic Agents; Anticonvulsants; Cyclothymic Disorder
PubMed: 36825703
DOI: 10.2174/1570159X21666230224102318 -
Brain Research Bulletin Dec 2022This study aimed to explore the effect of concomitant use of Furosemide (FRS) and Valproic acid (VPA), demonstrating anti-inflammation efficacy, on epilepsy, and its...
OBJECTIVES
This study aimed to explore the effect of concomitant use of Furosemide (FRS) and Valproic acid (VPA), demonstrating anti-inflammation efficacy, on epilepsy, and its underlying mechanism.
METHODS
Twenty-five adult male Wistar rats were divided into five groups including, Group 1: (Normal) rats received no drugs, Group 2: (E): rats were administered with a single dose of kainic acid (stereotaxic surgery), Group 3: (E + VPA): rats received Valproic acid (200 mg/kg/day/orally), Group 4: (E + FRS): rats received a single dose of Furosemide (100 mg/kg/I.P.) 30 min before epilepsy induction, Group 5: (E + VPA (200 mg/Kg)+FRS (100 mg/Kg, combination treatment). The treatment group received VPA for 14 days. We assessed seizures based on modified Racine΄s scores and conducted the electroencephalographic (EEG) recording. NLRP1 and NLRP3 mRNA levels, Apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), absence in melanoma2 (AIM2) protein expression levels, and apoptosis rate of the brain cells were analyzed utilizing real-time PCR, immunohistochemistry, and tunnel assay, respectively.
RESULTS
The results revealed that FRS and VPA treatment, alone or in combination, improved behavioral outcome and reduced seizure intensity in epileptic rats. The combination therapy significantly decreased the apoptosis rate NLRP1 and NLRP3 gene as well as ASC and AIM2 protein expression levels.
CONCLUSION
Combination therapy protected the brain against neuronal damages in rats, and decreased the severity of epilepsy in K.A. induced rats. Reducing inflammation and apoptosis and improving the performance of behavioral testing in the K.A. induced epilepsy model increased the likelihood of success of combination therapy compared with VPA and FRS treatment alone.
Topics: Animals; Male; Rats; Brain; Disease Models, Animal; DNA-Binding Proteins; Epilepsy; Furosemide; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Rats, Wistar; RNA, Messenger; Valproic Acid
PubMed: 36209957
DOI: 10.1016/j.brainresbull.2022.10.002 -
Neurosciences (Riyadh, Saudi Arabia) Oct 2021To evaluate the efficacy of valproic acid (VPA) in a cohort of children below 2 years of age. We also aim to review the characteristics of such patients and the role and...
OBJECTIVES
To evaluate the efficacy of valproic acid (VPA) in a cohort of children below 2 years of age. We also aim to review the characteristics of such patients and the role and safety of VPA for this age group.
METHODS
A retrospective chart review conducted at King Abdulaziz University Hospital, Jeddah, Kingdome of Saudi Arabia, for children below 2 years of age diagnosed with epilepsy and treated with valproic acid from January 2016 to January 2020.
RESULTS
The cohort for this study includes 50 children below the age of 2 years (25 males, 25 females). Aged 3 months to 23 months at commencing valproic acid. The mean age of seizure onset was 9 months and the mean age of starting valproic acid was 16 months. Thirty-two patients (64%) had more than 50% seizure improvement after valproic acid. Eleven patients (22%) were seizure-free. No statistical significance abnormalities in blood count indices and ammonia were seen during the treatment period. Two patients had dose-related lethargy that improved after decreasing their dosage. Asymptomatic mild elevation in glutamate dehydrogenase was noticed in 18% of patients.
CONCLUSION
Using valproic acid in infants and children below the age of 2 years can be considered as a safe and effective treatment option for epilepsy in this age group.
Topics: Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Humans; Infant; Male; Retrospective Studies; Seizures; Valproic Acid
PubMed: 34663708
DOI: 10.17712/nsj.2021.4.20210075 -
Brain and Behavior Jun 2023Sydenham's chorea (SC), prevalent in developing countries and occasionally affecting developed ones, poses a clinical challenge due to the lack of systematic guidelines... (Review)
Review
INTRODUCTION
Sydenham's chorea (SC), prevalent in developing countries and occasionally affecting developed ones, poses a clinical challenge due to the lack of systematic guidelines for diagnosis and treatment. Resulting from Group A Beta-Hemolytic Streptococcus infection, SC presents various symptoms. This review aims to collect and evaluate available data on SC management to propose a cohesive treatment plan.
METHODS
We searched PubMed, the Cochrane Library, Google Scholar, and ClinicalTrials.gov for literature on SC management from inception until 24th July 2022. Studies were screened by titles and abstracts. Cochrane Collaboration's Risk of Bias tool (RoB-1) assessed Randomized Controlled Trials, while the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool evaluated nonrandomized studies.
RESULTS
The review includes 11 articles assessing 579 patients. Excluding one study with 229 patients, of the remaining 550 patients, 338 (61.5%) were females. Treatments used were dopamine antagonists in 118 patients, antiepileptics in 198, corticosteroids in 134, IVIG in 7, and PE in 8 patients. Dopamine antagonists, particularly haloperidol, were the primary treatment choice, while valproic acid (VPA) was favored among antiepileptics. Prednisolone, a corticosteroid, showed promising results with weight gain as the only side-effect. Our review emphasizes the importance of immunomodulators in SC, contrasting previous literature.
CONCLUSION
Despite limitations, dopamine antagonists can serve as first-line agents in SC management, followed by antiepileptics. The role of immunomodulators warrants further investigation for conclusive recommendations.
Topics: Female; Humans; Male; Chorea; Anticonvulsants; Valproic Acid; Haloperidol; Dopamine Antagonists
PubMed: 37150977
DOI: 10.1002/brb3.3035 -
CNS Neuroscience & Therapeutics Apr 2024Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity...
INTRODUCTION
Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive.
METHODS
The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection.
RESULTS
In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes.
CONCLUSION
HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.
Topics: Animals; Rats; Cauda Equina; Ferroptosis; Inflammation; Pain; Rats, Sprague-Dawley; Reproducibility of Results; RNA; Valproic Acid; Histone Deacetylase 2
PubMed: 38105511
DOI: 10.1111/cns.14524 -
Psychopharmacology Dec 2023Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and restricted/stereotyped behavior. Prenatal exposure to...
RATIONALE
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and restricted/stereotyped behavior. Prenatal exposure to valproic acid (VPA) is associated with an increased risk of developing ASD in humans and autistic-like behaviors in rodents. Increasing evidence indicates that dysfunctions of glutamate receptors at synapses are associated with ASD. In the VPA rat model, an involvement of glutamate receptors in autism-like phenotypes has been suggested; however, few studies were carried out on metabotropic glutamate (mGlu) receptors.
OBJECTIVES
We examined the protein expression levels of group I (mGlu1 and mGlu5) and group II (mGlu2/3) mGlu receptors in rats prenatally exposed to VPA and evaluated the effect of mGlu receptor modulation on an early autism-like phenotype in these animals.
METHODS
We used western blotting analysis on synaptosomes obtained from forebrain of control and VPA rats at different ages (postnatal day P13, 35, 90) and carried out ultrasonic vocalization (USV) emission test in infant control and VPA rats.
RESULTS
The expression levels of all these receptors were significantly increased in infant VPA rats. No changes were detected in adolescent and adult rats. An acute treatment with the preferential mGlu2/3 antagonist, LY341495, attenuated the impairment in the USV emission in VPA rats. No effect was observed after a treatment with the mGlu5 selective antagonist, MTEP.
CONCLUSIONS
Our findings demonstrate that the expression of group I and group II mGlu receptors is upregulated at synapses of infant VPA rats and suggest that mGlu2/3 receptor modulation may have a therapeutic potential in ASD.
Topics: Humans; Pregnancy; Female; Rats; Animals; Adolescent; Valproic Acid; Autism Spectrum Disorder; Receptors, Metabotropic Glutamate; Social Behavior; Synapses; Prenatal Exposure Delayed Effects; Disease Models, Animal; Behavior, Animal
PubMed: 37707611
DOI: 10.1007/s00213-023-06457-w -
Biomolecules Oct 2023Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated survival benefits...
Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma-Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation.
BACKGROUND
Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated survival benefits documented in retrospective and prospective trials, when used in combination with chemo-radiotherapy (CRT).
PURPOSE
The primary goal of this study was to examine if the differential alteration in proteomic expression pre vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA as compared to standard-of-care CRT. The second goal was to explore the associations between the proteomic alterations in response to VPA/RT/TMZ correlated to patient outcomes. The third goal was to use the proteomic profile to determine the mechanism of action of VPA in this setting.
MATERIALS AND METHODS
Serum obtained pre- and post-CRT was analyzed using an aptamer-based SOMAScan proteomic assay. Twenty-nine patients received CRT plus VPA, and 53 patients received CRT alone. Clinical data were obtained via a database and chart review. Tests for differences in protein expression changes between radiation therapy (RT) with or without VPA were conducted for individual proteins using two-sided -tests, considering -values of <0.05 as significant. Adjustment for age, sex, and other clinical covariates and hierarchical clustering of significant differentially expressed proteins was carried out, and Gene Set Enrichment analyses were performed using the Hallmark gene sets. Univariate Cox proportional hazards models were used to test the individual protein expression changes for an association with survival. The lasso Cox regression method and 10-fold cross-validation were employed to test the combinations of expression changes of proteins that could predict survival. Predictiveness curves were plotted for significant proteins for VPA response (-value < 0.005) to show the survival probability vs. the protein expression percentiles.
RESULTS
A total of 124 proteins were identified pre- vs. post-CRT that were differentially expressed between the cohorts who received CRT plus VPA and those who received CRT alone. Clinical factors did not confound the results, and distinct proteomic clustering in the VPA-treated population was identified. Time-dependent ROC curves for OS and PFS for landmark times of 20 months and 6 months, respectively, revealed AUC of 0.531, 0.756, 0.774 for OS and 0.535, 0.723, 0.806 for PFS for protein expression, clinical factors, and the combination of protein expression and clinical factors, respectively, indicating that the proteome can provide additional survival risk discrimination to that already provided by the standard clinical factors with a greater impact on PFS. Several proteins of interest were identified. Alterations in GALNT14 (increased) and CCL17 (decreased) ( = 0.003 and 0.003, respectively, FDR 0.198 for both) were associated with an improvement in both OS and PFS. The pre-CRT protein expression revealed 480 proteins predictive for OS and 212 for PFS ( < 0.05), of which 112 overlapped between OS and PFS. However, FDR-adjusted values were high, with OS (the smallest p value of 0.586) and PFS (the smallest value of 0.998). The protein PLCD3 had the lowest -value ( = 0.002 and 0.0004 for OS and PFS, respectively), and its elevation prior to CRT predicted superior OS and PFS with VPA administration. Cancer hallmark genesets associated with proteomic alteration observed with the administration of VPA aligned with known signal transduction pathways of this agent in malignancy and non-malignancy settings, and GBM signaling, and included epithelial-mesenchymal transition, hedgehog signaling, Il6/JAK/STAT3, coagulation, NOTCH, apical junction, xenobiotic metabolism, and complement signaling.
CONCLUSIONS
Differential alteration in proteomic expression pre- vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA. Using pre- vs. post-data, prognostic proteins emerged in the analysis. Using pre-CRT data, potentially predictive proteins were identified. The protein signals and hallmark gene sets associated with the alteration in the proteome identified between patients who received VPA and those who did not, align with known biological mechanisms of action of VPA and may allow for the identification of novel biomarkers associated with outcomes that can help advance the study of VPA in future prospective trials.
Topics: Humans; Temozolomide; Glioblastoma; Valproic Acid; Histone Deacetylase Inhibitors; Retrospective Studies; Proteome; Proteomics; Antineoplastic Agents, Alkylating; Hedgehog Proteins
PubMed: 37892181
DOI: 10.3390/biom13101499