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Frontiers in Pharmacology 2024Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually...
Valproic acid (VPA) has been widely used as an antiepileptic drug for decades. Although VPA is effective and well-tolerated, long-term VPA treatment is usually associated with hepatotoxicity. However, the underlying mechanisms of VPA-caused hepatotoxicity remain unclear. In this study, a total of 157 pediatric patients with epilepsy were recruited and divided into normal liver function (NLF, 112 subjects) group and abnormal liver function (ABLF, 45 subjects) group. We observed that A1298C and C677T variants may be linked to VPA-induced liver dysfunction ( = 0.001; = 0.023, respectively). We also found that the A1298C polymorphism was associated with a higher serum Hcy level ( = 0.001) and a lower FA level ( = 0.001). Moreover, the serum Hcy levels was strongly correlated with the GSH and TBARS concentrations (r = -0.6065, < 0.001; r = 0.6564, < 0.001, respectively). Furthermore, logistic analysis indicated that A1298C/C677T polymorphisms and increased Hcy concentrations may be risk factors for VPA-induced liver dysfunction. These results suggested that individual susceptibility to VPA-induced liver dysfunction may result from A1298C/C677T polymorphisms and increased Hcy levels. This study may be helpful for the prevention and guidance of VPA-induced liver dysfunction.
PubMed: 38464726
DOI: 10.3389/fphar.2024.1358262 -
Epilepsy Research Sep 2023Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We aimed to evaluate the long-term effects of intravenous phenobarbital on adult patients with GCSE.
METHODS
This randomized clinical trial with a 12-month follow-up was performed in Xuanwu Hospital, Capital Medical University (Beijing, China) between February 2011 and December 2021. After the failure of intravenous diazepam treatment, adult patients with GCSE were randomized to receive either intravenous phenobarbital or valproate. Neurological outcome within 12-month was dichotomized as good (modified Rankin scale, mRS 0-2) or poor (mRS 3-6). Cognitive function was measured by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were tested for mood disorders.
RESULTS
We consecutively recruited 166 patients with GCSE. After excluding individuals with termination after intravenous diazepam (n = 61), and with other exclusion criteria (n = 7), 98 patients were included and 88.0% (66/75) of survivors achieved seizure freedom at 12-month. Forty-five patients (45.92%) had good outcomes at 3-month and 57 patients (58.16%) had good outcomes at 12-month. And 46.67% (35/75) of survivors showed mRS improvement at 12-month (phenobarbital group, n = 17 vs. valproate group, n = 18, P = 0.321). Despite there was no significant difference with respect to good outcomes at 3-month (54.0% vs. 37.5%, P = 0.101), the rate of good outcomes in phenobarbital group was higher than valproate group at 12-month (68.0% vs. 47.92%, P = 0.044). A total of 43 patients successfully participated cognitive and emotional tests. Mild cognitive impairment was found in 7.14% of phenobarbital group and 50.0% in valproate group (P = 0.026). In addition, there were no significant differences with respect to anxiety (36.36% vs. 38.10%) and depression (31.82% vs. 47.62%) between the phenobarbital and valproate groups.
CONCLUSIONS
Combined with long term conventional therapy, intravenous phenobarbital group had more good outcomes than intravenous valproate group in Chinese adult patients with GCSE up to 12-month follow-up. This finding may prompt the option of intravenous phenobarbital especially in patients with limited access to new antiseizure drugs.
Topics: Humans; Adult; Valproic Acid; Anticonvulsants; Follow-Up Studies; Treatment Outcome; Status Epilepticus; Phenobarbital; Diazepam
PubMed: 37467704
DOI: 10.1016/j.eplepsyres.2023.107187 -
Molecular Biology Research... 2024Among leading causes of the ischemic stroke pathogenesis, oxidative stress strongly declines rate of stem cell engraftment at the injury site, and disables stem...
Valproic acid and/or rapamycin preconditioning protects hair follicle stem cells from oxygen glucose serum deprivation-induced oxidative injury via activating Nrf2 pathway.
Among leading causes of the ischemic stroke pathogenesis, oxidative stress strongly declines rate of stem cell engraftment at the injury site, and disables stem cell-based therapy as a key treatment for ischemia stroke. To overcome this therapeutic limitation, preconditioning has been represented a possible approach to augment the adaptation and viability of stem cells to oxidative stress. Here, we illustrated protective impacts of valproic acid (VPA) and/or rapamycin (RAPA) preconditioning unto oxygen glucose and serum deprivation (OGSD)-stimulated cell damage in hair follicle-derived stem cells (HFSCs) and surveyed the plausible inducement mechanisms. OGSD, as an cell injury model, was established and HFSCs viability was observed using MTT assay after VPA, RAPA, and VPA-RAPA preconditioning under OGSD. ROS and MDA production was assessed to reflect oxidative stress. Real-time PCR and western blotting were employed to investigate Nrf2 expression. The activity of Nrf2-related antioxidant enzymes including NQO1, GPx and GSH level were examined. and mRNA expression levels were analyzed. Our results showed that VPA and/or RAPA preconditioning ameliorated OGSD-induced decline in HFSCs viability. In addition, they considerably prohibited ROS and MDA generation in the OGSD-treated HFSCs. Furthermore, VPA and/or RAPA preconditioning stimulated Nrf2 nuclear repositioning and NQO1 and GPx activity and GSH amount, as well as expression of paracrine factors and in OGSD-treated HFSCs. Thus, the protective effects afforded by VPA and/or RAPA preconditioning, which involved Nrf2-modulated oxidant stress and regulation of and expression, display a simple strategy to augment cell-transplantation efficiency for ischemic stroke.
PubMed: 38915453
DOI: 10.22099/mbrc.2024.49302.1922 -
Pediatric Neurology Jan 2024Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this...
BACKGROUND
Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population.
METHODS
A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel.
RESULTS
The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%).
CONCLUSION
Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.
Topics: Child; Young Adult; Humans; Female; Male; Cannabidiol; Drug Resistant Epilepsy; Anticonvulsants; Retrospective Studies; Quality of Life; Seizures; Lennox Gastaut Syndrome
PubMed: 37995414
DOI: 10.1016/j.pediatrneurol.2023.10.012 -
Biomolecules Apr 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal... (Review)
Review
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.
Topics: Autism Spectrum Disorder; Humans; Epigenesis, Genetic; Neuroglia; Valproic Acid; Propionates; Animals; Acetaminophen; Neurons; DNA Methylation
PubMed: 38672454
DOI: 10.3390/biom14040437 -
Current Treatment Options in Oncology Mar 2024Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms... (Review)
Review
Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.
Topics: Humans; Anticonvulsants; Levetiracetam; Epilepsy; Seizures; Brain Neoplasms
PubMed: 38353859
DOI: 10.1007/s11864-024-01182-8 -
Pharmacogenomics and Personalized... 2024To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic...
PURPOSE
To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic variants and standardized blood levels of Valproic Acid (VPA) in schizophrenic patients, and evaluate the effects of age, gender, and Body Mass Index (BMI) on standardized VPA blood concentrations.
PATIENTS AND METHODS
Between February and December 2022, 192 Zhuang and Han schizophrenia patients treated with VPA were studied. Steady-state VPA concentrations were determined using homogeneous enzyme immunoassays, and *1, *2, and *3 loci via q-PCR. genotype distributions between Zhuang and Han groups in Nanning were compared using chi-square tests and contrasted with other ethnicities. Non-parametric tests analyzed VPA variations, identifying critical factors through multivariate stepwise regression.
RESULTS
The study identified five genotypes at the *2 and *3 loci, with the *3/*3 genotype absent in both cohorts. The distribution in Guangxi Zhuang and Han mirrors, yet diverges significantly from Hui and Kazakh groups. Among 192 subjects, VPA blood levels remained consistent across metabolic types and ages 18-60 but varied significantly by gender. Multivariate analysis revealed gender and BMI as significant factors, overshadowing genotype and age.
CONCLUSION
In Guangxi, genetic variants in Zhuang and Han schizophrenia patients demonstrate statistically indistinguishable allelic and metabolic distributions. Gender and BMI can influence standardized VPA blood concentrations in schizophrenia patients. However, in our study cohort, the genotype and age are not the primary determinants of standardized VPA blood levels.
PubMed: 38765788
DOI: 10.2147/PGPM.S457805 -
Frontiers in Neurology 2023We evaluate the effect of distinct clinical features on anti-seizure medication (ASM) doses in seizure-free and not seizure-free patients aged ≥16 years with new-onset...
OBJECTIVE
We evaluate the effect of distinct clinical features on anti-seizure medication (ASM) doses in seizure-free and not seizure-free patients aged ≥16 years with new-onset epilepsy.
MATERIALS AND METHODS
This study included 459 patients with a validated diagnosis of epilepsy. The most prescribed ASMs were oxcarbazepine (OXC; = 307), followed by valproic acid (VPA; = 115), carbamazepine (CBZ; = 81), and lamotrigine (LTG; = 67). The seizure freedom rate with their first or subsequent ASM was 88.0%. A retrospective analysis of patient records was performed to determine any association between doses of ASMs and patient characteristics.
RESULTS
The median OXC dose in seizure-free patients aged >60 years was 600 mg compared to 900 mg in younger patients. When controlling for age but not in an unadjusted model, the median dose of OXC was lower (300 mg, = 0.018) for seizure-free patients compared to non-seizure-free patients, and the median dose of OXC was also 300 mg lower among older patients aged >60 years ( < 0.001). The median OXC doses for men aged ≤60 years were 300 mg higher than for women aged >60 years (900 mg vs. 600 mg, = 0.021). The median dose of VPA was 400 mg higher in men than in women ( < 0.001) and 400 mg higher in not seizure-free patients compared to seizure-free patients only when adjusting for sex ( < 0.001). Higher median doses for CBZ were registered with FAS compared with FBTCS (difference in median doses of 200 mg; = 0.017).
CONCLUSION
Significant OXC dose differences were detected between age groups, whereas VPA dosing was different in men and women. Moreover, CBZ doses were dependent on some seizure types. These data allow for the individualization of the initial target dosing based on key clinical characteristics.
PubMed: 37609660
DOI: 10.3389/fneur.2023.1159339 -
American Journal of Cancer Research 2023Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic...
Children and young adult with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. We present 19 patients diagnosed with anaplastic astrocytoma (AA) or glioblastoma (GBM) treated with concomitant and adjuvant 20-30 mg/m/dose of vinorelbine and 30 mg/kg/day valproic acid (VA) in combination to consolidated TMZ and focal RT after maximal surgery. We evaluated the feasibility of treating children diagnosed with HGG. The median follow-up time was 51.4 months (range, 6.2-106.6 months). The 5-year OS was 57.9% (CI 95%, 33.2-76.3) and the 5-year PFS was 57.9% (CI 95%, 33.2-76.3). Eight patients (42.1%) have progressed so far, with a median time to progression of 9 months from diagnosis (range, 4.6-34.7 months). All of them died for disease progression. At time of analysis, 11 patients were still alive with no evidence of disease. It is notable that all events occurred within 35 months from the start of therapy. All 19 treated patients reported low-grade drug-related adverse events (AEs). The treatment was well tolerated in our limited cohort of patients without significant toxicity. Further studies of the efficacy and safety of combination of vinorelbine/VA to consolidated RT/TMZ therapy in children with HGG are underway in a clinical trial setting.
PubMed: 37693163
DOI: No ID Found -
Oncology Letters May 2024Oral squamous cell carcinoma (OSCC) is a frequent human malignancy that demonstrates a range of genetic and epigenetic alterations. Histone deacetylases (HDACs) are key... (Review)
Review
Oral squamous cell carcinoma (OSCC) is a frequent human malignancy that demonstrates a range of genetic and epigenetic alterations. Histone deacetylases (HDACs) are key epigenetic regulators of cell-cycle progression, differentiation and apoptosis and their dysregulation is implicated in cancer development. HDACs are promising targets for anticancer therapy through the utilisation of HDAC inhibitors (HDACis). OSCC cells have been shown to have low levels of histone acetylation, suggesting that HDACis may produce beneficial effects in patients with OSCC. Valproic acid (VPA) is a class I and IIa HDACi and, therefore, may be useful in anticancer therapy. VPA has been reported as a chemo-preventive epigenetic agent in individuals with high-risk oral dysplasia (OD) and thus associated with a reduced risk of HNSCC. It is hypothesised that HDAC inhibition by VPA triggers a change in the expression levels of different HDAC family gene-members. The present review summarises the current literature on HDAC expression changes in response to VPA in oral cancer patients and studies in an effort to better understand the potential epigenetic impact of VPA treatment. The present review outlined the need for exploring supportive evidence of the chemo-preventive role played by VPA-based epigenetic modification in treating oral pre-cancerous lesions and, thus, providing a novel tolerable chemotherapeutic strategy for patients with oral cancer.
PubMed: 38516679
DOI: 10.3892/ol.2024.14330