Downloads & Free Reading Options - Results

The possible role of histone deacetylase inhibitors (HDACi) in breast cancer treatment is an area of active investigation. However, its potential as a preventive agent has not been studied. Valproic acid (VPA) is an HDACi which has been used for many decades to safely treat neurological disorders. The rationale for the use of HDACi in breast cancer prevention is a previously unexplored area of research that is based on compelling preclinical data. Epidemiologic studies showing an association between HDACi use and breast cancer incidence would be important evidence to support future prospective clinical trials of HDACi in cancer prevention. The aim of this project is to ascertain whether the risk of incident breast cancer is reduced in patients with a history of VPA use, and if so, to determine whether this effect is proportional to the duration of VPA use and whether all subtypes of breast cancer are impacted similarly. We have developed a database using de-identified data from the Kaiser Permanente of Northern California (KPNC) clinical and pharmacy records between 1997 and 2007. 22,488 breast cancer cases and 224,860 controls have been identified. Controls have been matched to cases

This article is from Genomics & Informatics , volume 11 . Abstract The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p = 0.0057) and the GG genotype (61.0% vs. 39.7%, p = 0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p = 0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs.

http://uf.catalog.fcla.edu/uf.jsp?st=UF021676101&ix=pm&I=0&V=D&pm=1

In this study, experimental methods, cell models, and relevant results from the selected literature will be systematically evaluated. We aim to determine the reliability and validity of in vitro systems using valproate to replicate autistic phenotypes. This review addresses the main research questions, including the consistency of the observed effects, the relevance of the cellular models chosen and the translational potential of the results.

Exposure to valproic acid (VPA) during embryogenesis has become a valuable tool for modeling neurodevelopmental disorders in animal models such as zebrafish (Danio rerio). This article ex-amines the effects of embryonic exposure to VPA in zebrafish on the basis of 39 articles sourced from PubMed and Google Scholar. We conducted a systematic review and meta-analysis to elucidate the common impacts of VPA exposure and reported that VPA significantly altered development at various levels. Behaviorally, zebrafish exposed to VPA exhibit notable changes in their social in-teraction patterns. Physiologically, VPA exposure leads to significant alterations, including de-creased heart rates, increased mortality rates, and pronounced morphological abnormalities. Pharmacological exposure has been linked to neuroanatomical and neurochemical changes. At the genetic level, VPA exposure is associated with the differential expression of genes involved in neurodevelopment and neuronal function. The synthesized data from these studies underscore the utility of zebrafish as a model organism for investigating the effects of teratogen exposure on neu-rodevelopment.

This article is from Clinical Epigenetics , volume 5 . Abstract Several new therapeutic strategies are now considered for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, including modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). These enzymes alter the acetylation of several proteins, including histones and transcription factors, as well as several other proteins directly involved in the regulation of cell proliferation, differentiation and apoptosis. Valproic acid (VPA) is a HDAC inhibitor that has been investigated in several clinical AML studies, usually in combination with all-trans retinoic acid (ATRA) for treatment of patients unfit for intensive chemotherapy, for example older patients, and many of these patients have relapsed or primary resistant leukemia. The toxicity of VPA in these patients is low and complete hematological remission lasting for several months has been reported for a few patients (

This article is from Journal of Korean Neurosurgical Society , volume 51 . Abstract Objective: Valproic acid (VPA), as known as histone deacetylase inhibitor, has neuroprotective effects. This study investigated the histological changes and functional recovery from spinal cord injury (SCI) associated with VPA treatment in a rat model. Methods: Locomotor function was assessed according to the Basso-Beattie-Bresnahan scale for 2 weeks in rats after receiving twice daily intraperitoneal injections of 200 mg/kg VPA or the equivalent volume of normal saline for 7 days following SCI. The injured spinal cord was then examined histologically, including quantification of cavitation. Results: Basso-Beattie-Bresnahan scale scores in rats receiving VPA were significantly higher than in the saline group (p

The possible role of histone deacetylase inhibitors (HDACi) in breast cancer treatment is an area of active investigation. However, its potential as a preventive agent has not been studied. Valproic acid (VPA) is an HDACi which has been used for many decades to safely treat neurological disorders. The rationale for the use of HDACi in breast cancer prevention is a previously unexplored area of research that is based on compelling preclinical data.

This article is from BMC Urology , volume 12 . Abstract Background: Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate) has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium. We speculated that inhibition of angiogenesis by valproate might be mediated by this anti-angiogenic protein. Methods: Bladder cancer cell lines UMUC3 and T24 were treated with valproate or another histone deacetylase inhibitor, vorinostat, in culture for a period of three days. Proliferation was assessed by alamar blue reduction. Gene expression was evaluated by reverse transcription of RNA and quantitative PCR. Results: Proliferation assays showed treatment with valproate or vorinostat decreased proliferation in both cell lines. Histone deacetylase inhibition also increased relative expression of thrombospondin-1 up to 8 fold at 5 mM valproate. Conclusions: Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.

This article is from Oncology Letters , volume 8 . Abstract Adult T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis. Although it has been found that activation of Notch1 signaling occurs in >50% T-ALL patients, γ-secretase inhibitors that target Notch1 signaling are of limited efficacy. However, c-Myc is an important direct target of Notch1 and, thus, c-Myc is another potential therapeutic target for T-ALL. Valproic acid (VPA), a histone deacetylase inhibitor, has been reported to treat various hematological malignancies. In the present study, we showed that c-Myc expression, at a transcriptional level, was dose-dependently downregulated in VPA-induced growth inhibition in T-ALL cell lines, Jurkat and CCRF-CEM cells. 10058-F4, a small molecule c-Myc inhibitor, could increase the downregulation of c-Myc and markedly increase the growth inhibition and cell death induced by VPA in Jurkat and CCRF-CEM cells, which was accompanied by obvious cleavage of capase-3. Z-VAD-FMK, a caspase inhibitor, partially prevented the anti-leukemic effect. The results of the present study suggest that c-Myc inhibitors increase cell death induced by VPA in a caspase-dependent and -independent manner, and their combination could be a potent therapeutic strategy for adult T-ALL patients.

This article is from PLoS ONE , volume 9 . Abstract Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

Aim: The aim of this study is to compare the dosage-related effects of levetiracetam and valproic acid on neural tube defect formation in chick embryos, when applied as monotherapy and in combination. Material and Method: A total of 360 fertilized pathogens-free white-Leghorn eggs were used in the study. The eggs were allowed to incubate for 72 hours. Total of six groups were formed where each medication was administered in low (250 mcg) and high (500 mcg) doses and in combination. Results obtained from the control and sham groups were compared. Results: The prevalence of NTD was found to be significantly lower in the group that received levetiracetam compared to the group that was treated with valproic acid. It was determined that NTD prevalence increased with a dosage increase in both groups. The prevalence of NTD was found to be significantly higher in groups where the two medications were administered in combination compared to the groups that received a single medication. Discussion: Both levetiracetam and valproic acid have the potential to create NTD. Valproic acid has a higher potential of creating NTD compared to levetiracetam. The likeliness of causing NTD significantly increases depending on dosage for both medications. Both medications have the potential to create NTD during pregnancy and must be used with caution.

This article is from Journal of Anaesthesiology, Clinical Pharmacology , volume 30 . Abstract Valproic acid (VPA) is one of the widely prescribed antiepileptic drugs in children with multiple indications. VPA-induced coagulopathy may occur and constitute a pharmacological and practical challenge affecting pre-operative evaluation and management of patients receiving VPA therapy. This review summarizes the different studies documenting the incidence, severity and available recommendations related to this adverse effect.

This article is from Journal of Biomedical Science , volume 18 . Abstract Background: At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis.Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. Methods: Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C.) diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay. Results: In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL. Conclusion: To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IκBα and the activation of NF-κB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior.

Remedial dosing recommendations for delayed or missed doses of valproic acid in patients with epilepsy based on Monte Carlo simulations 作者： Chenyu,Wang 1 Jun-jie Ding 2 Zheng Jiao 1, 5 Er-qian Yu 3 Guo-xing Zhu 4 作者单位： 1. Department of Pharmacy, Huashan Hospital, Fudan University 2. Department of Pharmacy, Children’s Hospital, Fudan University 3. Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University 4. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China 5. Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China 通讯作者： Zheng Jiao 提交时间： 2020-09-07 摘要: Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients. Methods: Monte Carlo simulations are based on all previous population pharmacokinetic models for pediatric, adult and elderly patients with epilepsy. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed. Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas Strategy C was recommended when the delayed dose was close to the next scheduled dose. Strategy D was only suggested for delayed two doses. Conclusion: Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen for each patient based on the individual's status. Abstract: Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients. Methods: Monte Carlo simulations are based on all previous population pharmacokinetic models for pediatric, adult and elderly patients with epilepsy. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed. Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas Strategy C was recommended when the delayed dose was close to the next scheduled dose. Strategy D was only suggested for delayed two doses. Conclusion: Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen for each patient based on the individual's status. " " 癫痫 丙戊酸 群体药动学 非线性混合效应模型 个体化给药 依从性 蒙特卡洛模拟 治疗范围 补救给药 来自： 王琛瑀 期刊： Epilepsy Behav . 分类： 医学、药学 >> 临床医学 引用： ChinaXiv:201907.00014 (或此版本 ChinaXiv:201907.00014V5 ) DOI:10.1016/j.yebeh.2020.107265. CSTR:32003.36.ChinaXiv.201907.00014.V5 推荐引用方式： Chenyu,Wang,Jun-jie Ding,Zheng Jiao,Er-qian Yu,Guo-xing Zhu.(2020).Remedial dosing recommendations for delayed or missed doses of valproic acid in patients with epilepsy based on Monte Carlo simulations.Epilepsy Behav . .doi:10.1016/j.yebeh.2020.107265. 版本历史 [V1] 2022-12-22 20:38:12 ChinaXiv:201907.00014v1 查看此版本 下载全文 [V5] 2020-09-07 11:36:58 ChinaXiv:201907.00014V5 下载全文

This article is from PLoS ONE , volume 9 . Abstract Cloning of mammals by somatic cell nuclear transfer (SCNT) is still plagued by low efficiency. The epigenetic modifications established during cellular differentiation are a major factor determining this low efficiency as they act as epigenetic barriers restricting reprogramming of somatic nuclei. In this regard, most factors that promote chromatin decondensation, including histone deacetylase inhibitors (HDACis), have been found to increase nuclear reprogramming efficiency, making their use common to improve SCNT rates. Herein we used valproic acid (VPA) in SCNT to test whether the treatment of nuclear donor cells with this HDACi improves pre- and post-implantation development of cloned cattle. We found that the treatment of fibroblasts with VPA increased histone acetylation without affecting DNA methylation. Moreover, the treatment with VPA resulted in increased expression of IGF2R and PPARGC1A, but not of POU5F1. However, when treated cells were used as nuclear donors no difference of histone acetylation was found after oocyte reconstruction compared to the use of untreated cells. Moreover, shortly after artificial activation the histone acetylation levels were decreased in the embryos produced with VPA-treated cells. With respect to developmental rates, the use of treated cells as donors resulted in no difference during pre- and post-implantation development. In total, five clones developed to term; three produced with untreated cells and two with VPA-treated cells. Among the calves from treated group, one stillborn calf was delivered at day 270 of gestation whereas the other one was delivered at term but died shortly after birth. Among the calves from the control group, one died seven days after birth whereas the other two are still alive and healthy. Altogether, these results show that in spite of the alterations in fibroblasts resulting from the treatment with VPA, their use as donor cells in SCNT did not improve pre- and post-implantation development of cloned cattle.

The possible role of histone deacetylase inhibitors (HDACi) in breast cancer treatment is an area of active investigation. However, its potential as a preventive agent has not been studied . Valproic acid (VPA) is an HDACi which has been used for many decades to safely treat neurological disorders. The rationale for the use of HDACi in breast cancer prevention is a previously unexplored area of research that is based on compelling preclinical data. Epidemiologic studies showing an association between HDACi use and breast cancer incidence would be important evidence to support future prospective clinical trials of HDACi in cancer prevention. We sought to ascertain whether the risk of incident breast cancer is reduced in patients with a history of VPA use, and if so, to determine whether this effect is proportional to the duration of VPA use and whether all breast cancer subtypes are impacted similarly. We developed a database using de-identified data from the Kaiser Permanente of Northern California (KPNC) clinical and pharmacy records of members of the KPNC Healthplan between 1997 and 2007. 20,864 breast cancer cases and 208,640 controls matched for birth year and duration of KNPC pharmacy coverage were identified. 68 incident breast cancers were seen among women with history of VPA use; 486 were in women without history of VPA use. Mean age at diagnosis of the cohort was 61 .8 years; mean years of prescription drug coverage was 7.4 years. Among cases, 73% of the cohort was non-hispanic white, 7.6% were African American, and 10.5% were Asian/Pacific Islander. When compared to never users, patients with at least 2 years of VPA use had an increased odds of a breast cancer diagnosis (OR 1.37; 95% Cl 1.06-1.76). This effect was only significant for HR-positive incident tumors, although the numbers of HR-negative cases was small (n=12). These findings support that VPA use is not associated with reduction of breast cancer incidence.

The gene mutation of coding sodium channel is one of the most important mechanisms in the pathogenesis of epilepsy. There exists a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. What are the genetic polymorphism influences of sodium channels on VPA response is still under discussion. In this study, a meta-analysis was used to further explore the effects of SCN1A and SCN2A gene polymorphism on VPA response in children with epilepsy.

This article is from Iranian Journal of Basic Medical Sciences , volume 14 . Abstract Objective(s): The purpose of this study was assessment of the influence of acute manic phase on the steady state pharmacokinetics of valproic acid (VPA) in bipolar patients in comparison with those of epileptic patients. Materials and Methods: Ninteen acutely manic and 25 epileptic patients who fulfilled inclusion and exclusion criteria were entered in this prospective study. Blood samples were collected at trough time in steady state and plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). VPA apparent oral clearance (CL/F) values were calculated in each patient and were compared between groups. As VPA clearance is affected by different factors such as age, total body weight, VPA dosage and the use of concurrent medications, all of these confounding factors were made similar in both groups. Results: Comparison between two groups showed that CL/F values in acutely manic patients were significantly higher than epileptic patients (10.35±5.77 vs. 7.70±2.63 ml/kg/h, P= 0.047). Conclusion: Acutely manic patients require more VPA dosage to achieve serum concentrations in comparison with those found in epileptic patients. It may be suggested that this increased VPA clearance in acute manic phase may be related to abnormalities in membrane transport systems that may affect on cellular uptake of the drug and its volume of distribution. Since our study is a preliminary investigation in this field, further detailed pharmacokinetic study in acute manic patients are warranted to confirm results of this study.

This article is from International Clinical Psychopharmacology , volume 29 . Abstract Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P

This article is from PLoS ONE , volume 9 . Abstract Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.

This article is from Biomolecules & Therapeutics , volume 21 . Abstract Although the role of α-synuclein aggregation on Parkinson’s disease is relatively well known, the physiological role and the regulatory mechanism governing the expression of α-synuclein are unclear yet. We recently reported that α-synuclein is expressed and secreted from cultured astrocytes. In this study, we investigated the effect of valproic acid (VPA), which has been suggested to provide neuroprotection by increasing α-synuclein in neuron, on α-synuclein expression in rat primary astrocytes. VPA concentrationdependently increased the protein expression level of α-synuclein in cultured rat primary astrocytes with concomitant increase in mRNA expression level. Likewise, the level of secreted α-synuclein was also increased by VPA. VPA increased the phosphorylation of Erk1/2 and JNK and pretreatment of a JNK inhibitor SP600125 prevented the VPA-induced increase in α-synuclein. Whether the increased α-synuclein in astrocytes is involved in the reported neuroprotective effects of VPA awaits further investigation.

This article is from Annals of Indian Academy of Neurology , volume 15 . Abstract Valproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug especially in children, with various side-effects reported with its usage. Hematologic toxicity is dose related and intracranial bleeding complications have been reported. We are reporting a rare case of massive scalp hematoma requiring surgical intervention, following a trivial fall associated with high-VPA levels.

Perma.cc archive of https://www.drugs.com/mtm/valproic-acid.html created on 2022-09-01 14:48:52.571975+00:00.

Traumatic brain injury (TBI) is a leading cause of death in young adults, and effective treatment strategies have the potential to save many lives. TBI results in coagulopathy, endothelial dysfunction, inflammation, cell death, and impaired epigenetic homeostasis, ultimately leading to morbidity and/ or mortality. Commonly used resuscitation fluids such as crystalloids or colloids have several disadvantages and might even be harmful when administered in large quantities. There is a need for next generation treatment strategies (especially in the prehospital setting) that minimize cellular damage, improve survival, and enhance neurological recovery. Pharmacologic treatment with histone deacetylase inhibitors, such as valproic acid, has shown promising results in animal studies of TBI and may therefore be an excellent example of next-generation therapy. This review briefly describes traditional resuscitation strategies for TBI combined with hemorrhagic shock and describes preclinical studies on valproic acid as a new pharmacologic agent in the treatment of TBI. It finally discusses limitations and future directions on the use of histone deacetylase inhibitors for the treatment of TBI.

This article is from Disease Models & Mechanisms , volume 5 . Abstract Lipid droplet formation and subsequent steatosis (the abnormal retention of lipids within a cell) has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the antiepileptic drug valproic acid (VPA). In this study, we have developed a simple model system (Dictyostelium discoideum) to investigate the effects of VPA and related compounds in lipid droplet formation. In mammalian hepatocytes, VPA increases lipid droplet accumulation over a 24-hour period, giving rise to liver cell damage, and we show a similar effect in Dictyostelium following 30 minutes of VPA treatment. Using 3H-labelled polyunsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown that VPA treatment of Dictyostelium gives rise to an increased accumulation of both types of fatty acids in phosphatidylcholine, phosphatidylethanolamine and non-polar lipids in this time period, with a similar trend observed in human hepatocytes (Huh7 cells) labelled with [3H]arachidonic acid. In addition, pharmacological inhibition of β-oxidation in Dictyostelium phenocopies fatty acid accumulation, in agreement with data reported in mammalian systems. Using Dictyostelium, we then screened a range of VPA-related compounds to identify those with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation by using human hepatocytes. Structure-activity relationships for these VPA-related compounds suggest that lipid accumulation is independent of VPA-catalysed teratogenicity and inositol depletion. These results suggest that Dictyostelium could provide both a novel model system for the analysis of lipid droplet formation in human hepatocytes and a rapid method for identifying VPA-related compounds that show liver toxicology.

This article is from Blood Cancer Journal , volume 3 . Abstract Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins.

This article is from The Journal of Biological Chemistry , volume 287 . Abstract Background: Dysregulation of T cell survival and apoptosis is the common cause of autoimmune diseases including multiple sclerosis (MS).Results: Valproic acid (VPA) treatment restores the dysregulated apoptosis of T cells and reduces the symptoms of EAE.Conclusion: In addition to the antiepileptic activity, VPA also regulates T cell homeostasis.Significance: As an orally available drug, VPA might be used to treat autoimmune diseases, such as MS.

This article is from Frontiers in Behavioral Neuroscience , volume 8 . Abstract Antiepileptic medications are the frontline treatment for seizure conditions. However, these medications are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin and carbamazepine-treated rats. In the experiment reported here, the effects of valproic acid (VPA) have been studied using the same instrumental training tasks. VPA-treated rats displayed a severe deficit in acquiring a tone-signaled avoidance response. This deficit was attenuated in animals that had prior training in an appetitive context. Thus, this deficit is specific to learning in an aversive context, and does not result from difficulties in transferring associations from an appetitive to aversive context. Learning transfer deficits were previously observed in rats treated with phenytoin, and to a lesser extent, carbamazepine. On the other hand, rats treated with VPA fail to suppress inappropriate responsiveness across aversive training whether they had undergone prior appetitive training or not.

This article is from Oncotarget , volume 1 . Abstract In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy.Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.

This article is from BMC Genomics , volume 15 . Abstract None

This article is from Indian Journal of Psychological Medicine , volume 36 . Abstract None

Remedial dosing recommendations for valproic acid in nonadherence patients with epilepsy 作者： Chenyu,Wang 1 作者单位： 1. Department of Pharmacy, Huashan Hospital, Fudan University 2. Department of Pharmacy, Children’s Hospital, Fudan University 3. Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University 4. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China 5. Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China 提交时间： 2022-12-22 摘要: 目的与背景癫痫（Epilepsia）作为一种常见的神经系统疾病。药物治疗是目前主要的治疗手段。丙戊酸（Valproic acid, VPA）是临床常用的一线抗癫痫药物（Antiepileptic drugs, AEDs）。由于该药个体间变异大，治疗窗窄，目前推荐对VPA进行治疗药物监测（Therapeutic drug monitoring, TDM）和个体化药物治疗。由于癫痫需要长期治疗，药物依从性是临床关注的重要问题。漏晚或服药物事件发生时，一个合理的补救给药方案，对于控制癫痫发作，避免严重不良药物反应，具有重要的临床意义。而目前缺乏相关的研究报道。本研究以VPA为研究药物，旨在：1.检索查阅VPA药代动力学文献，收集不同地区使用VPA癫痫患者的群体药动学特征；2.建立典型病例与用药依从性不佳及用药补救场景，以收集的VPA群体药动学群体参数为基础，采用蒙特卡洛模拟评估依从性不佳对VPA药动学过程的影响以及制定相应的补救给药方案。方法本研究通过检索数据库，对VPA药代动力学评价分析，并收集并建立了群体药动学人群特征的文献。先使用文献管理软件进行初筛，再按照一定的入排标准纳入合适的文献。收集文献中的病人数，建模浓度点数，男女比例，年龄，体重，采样时间点，药物剂型等建模信息，以及群体药动学固定效应参数和随机效应参数等描述人群特征信息。使用NONMEM（Nonlinear mixed effect modeling）程序进行人群特征的还原。以纳入的癫痫患者VPA群体药动学特征为基础，以蒙特卡洛模拟产生漏延迟服药场景下的VPA血药浓度随时间变化的数据。定义1000例典型病例的P5-P95浓度波动范围为该典型病例的个体治疗范围。使用个体治疗范围评估不同依从性场景下对VPA药动学过程的影响，并以此设计相应的药物补救方案。此外，对以上场景进行敏感性分析，进一步考察吸收速率Ka、合并其抗癫痫药物（卡马西平，苯妥英，左乙拉西坦等）、服药时间（计划服药前后30min）以及不同的给药间隔对补救给药方案的影响。结果最终共纳入11篇VPA既往群体药动学研究，并收集群体药动学特征。模拟结果显示，延迟服药事件发生时，VPA浓度低于治疗范围的风险随着延迟服药时间的延长呈升高趋势，并且具有剂量依赖性，剂量越大风险越高；最佳补救给药剂量与给药方案和延迟服药时间有关，不同的给药方案的补救剂量有所不同。敏感性分析显示Ka、合并用药以及在计划给药时间前后30min服药对补救给药方案无显著影响。结论基于以上分析，本研究最终制定了癫痫患者VPA120-240mg q12h和缓释片500mg，750mg q12h以及500mg,750mg,1000mg q24h治疗方案下的延迟服药或漏服药的补救给药方案方案。蒙特卡罗法为制定依从性不佳时的补救剂量推荐方案提供了强有力的工具。本研究基于上述原理，首次计算了针对VPA患者依从性不佳时的补救剂量推荐方案，供临床参考。 癫痫 丙戊酸 群体药动学 非线性混合效应模型 个体化给药 依从性 蒙特卡洛模拟 治疗范围 补救给药 来自： 王琛瑀 分类： 医学、药学 >> 临床医学 投稿状态： 已被期刊接收 引用： ChinaXiv:201907.00014 (或此版本 ChinaXiv:201907.00014V1 ) DOI:10.12074/201907.00014V1 CSTR:32003.36.ChinaXiv.201907.00014.V1 推荐引用方式： Chenyu,Wang.(2022).Remedial dosing recommendations for valproic acid in nonadherence patients with epilepsy.中国科学院科技论文预发布平台.doi:10.12074/201907.00014V1 版本历史 [V1] 2022-12-22 20:38:12 ChinaXiv:201907.00014V1 下载全文 [V5] 2020-09-07 11:36:58 ChinaXiv:201907.00014v5 查看此版本 下载全文

This article is from PLoS ONE , volume 9 . Abstract A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by neutrophils and present in COPD serum and sputum. Valproic acid (VPA) is an inhibitor of PE and could possibly have an effect on the severity of chronic inflammation. Here the interaction site of VPA to PE and the resulting effect on the secondary structure of PE is investigated. Also, the potential inhibition of PGP-generation by VPA was examined in vitro and in vivo to improve our understanding of the biological role of VPA. UV- visible, fluorescence spectroscopy, CD and NMR were used to determine kinetic information and structural interactions between VPA and PE. In vitro, PGP generation was significantly inhibited by VPA. In vivo, VPA significantly reduced cigarette-smoke induced neutrophil influx. Investigating the molecular interaction between VPA and PE showed that VPA modified the secondary structure of PE, making substrate binding at the catalytic side of PE impossible. Revealing the molecular interaction VPA to PE may lead to a better understanding of the involvement of PE and PGP in inflammatory conditions. In addition, the model of VPA interaction with PE suggests that PE inhibitors have a great potential to serve as therapeutics in inflammatory disorders.

This article is from PLoS ONE , volume 9 . Abstract In this study, we aimed to elucidate the effects and mechanism of action of valproic acid on hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. Human induced pluripotent stem cells were differentiated into endodermal cells in the presence of activin A and then into hepatic progenitor cells using dimethyl sulfoxide. Hepatic progenitor cells were matured in the presence of hepatocyte growth factor, oncostatin M, and dexamethasone with valproic acid that was added during the maturation process. After 25 days of differentiation, cells expressed hepatic marker genes and drug-metabolizing enzymes and exhibited drug-metabolizing enzyme activities. These expression levels and activities were increased by treatment with valproic acid, the timing and duration of which were important parameters to promote differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells into hepatocytes. Valproic acid inhibited histone deacetylase activity during differentiation of human induced pluripotent stem cells, and other histone deacetylase inhibitors also enhanced differentiation into hepatocytes. In conclusion, histone deacetylase inhibitors such as valproic acid can be used to promote hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells.

This article is from EMBO Molecular Medicine , volume 5 . Abstract The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas.

This article is from Molecular Genetics and Metabolism , volume 112 . Abstract Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity.Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.

Diabetes mellitus, encompassing Type 1 (T1DM) and Type 2 Diabetes Mellitus (T2DM), represents a significant global health challenge characterized by chronic hyperglycemia resulting from insulin dysfunction. This review explores the therapeutic potential of Valproic Acid (VPA), traditionally used in epilepsy and mood disorders, in managing diabetes. VPA has demonstrated various beneficial effects, including the protection of pancreatic β-cells from apoptosis, enhancement of insulin sensitivity, and modulation of glucose and lipid metabolism. Preclinical studies indicate VPA’s capability to improve glycemic control and reduce inflammation, critical in T1DM and T2DM. However, clinical evidence remains sparse, with current studies yielding inconclusive results. Adverse effects such as weight gain and hepatotoxicity pose significant challenges to its application in diabetic patients. The review highlights the need for large-scale clinical trials to assess the efficacy and safety of VPA in diverse diabetic populations, investigate optimal dosing strategies, and explore its integration into existing therapeutic regimens. Future research should focus on personalized medicine approaches, targeting subgroups that may benefit most from VPA, and evaluating the long-term implications of its use in diabetes management. If successful, VPA could represent a novel adjunct therapy in the complex treatment landscape of diabetes mellitus. 

Valproic acid (VPA) is the most widely prescribed antiepileptic drug due to its ability to treat a broad spectrum of seizure types. However, potential complications of this drug include anticonvulsant polytherapy metabolism, organ toxicity and teratogenicity which limit its use in a variety of epilepsy patients. Direct delivery of VPA intracerebroventricularly (ICV) could circumvent the toxic effects normally seen with the oral route of administration. An additional potential benefit would be significantly reduced dosing while achieving high brain concentrations. Epileptogenic tissue from patients with intractable seizures has shown significant cell death which may be mitigated by maximizing cerebral VPA exposure. Here we show ICV administration of VPA localized to the periventricular zone increased pro-survival phospho-proteins (pAktSer473, pAktThr308, pGSK3beta-Ser9, pErk1/2Thr202/Tyr204) and growth cone associated proteins (2G13p, GAP43) in a whole animal system. No significant changes in DCX, NeuN, synaptotagmin, and synaptophysin were detected. Assessment of possible behavioral alterations in rats receiving chronic central infusions of VPA was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the drug infusion process.

This article is from The Journal of Veterinary Medical Science , volume 76 . Abstract Adipose tissue-derived stem cells (ADSCs) isolated from adult tissue have pluripotent differentiation and self-renewal capability. The tissue source of ADSCs can be obtained in large quantities and with low risks, thus highlighting the advantages of ADSCs in clinical applications. Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to affect ADSC differentiation in mice and rats; however, few studies have been performed on dogs. We aimed to examine the in vitro effect of VPA on canine ADSCs. Three days of pretreatment with VPA decreased the proliferation of ADSCs in a dose-dependent manner; VPA concentrations of 4 mM and above inhibited the proliferation of ADSCs. In parallel, VPA increased p16 and p21 mRNA expression, suggesting that VPA attenuated the proliferative activity of ADSCs by activating p16 and p21. Furthermore, the effects of VPA on adipogenic, osteogenic or neurogenic differentiation were investigated morphologically. VPA pretreatment markedly promoted neurogenic differentiation, but suppressed the accumulation of lipid droplets and calcium depositions. These modifications of ADSCs by VPA were associated with a particular gene expression profile, viz., an increase in neuronal markers, that is, NSE, TUBB3 and MAP2, a decrease in the adipogenic marker, LPL, but no changes in osteogenic markers, as estimated by reverse transcription-PCR analysis. These results suggested that VPA is a specific inducer of neurogenic differentiation of canine ADSCs and is a useful tool for studying the interaction between chromatin structure and cell fate determination.

This article is from Scientific Reports , volume 4 . Abstract The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.

This article is from BMC Cancer , volume 14 . Abstract Background: Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is reported to exert anti-tumor effects by upregulating the expression of the natural killer group 2D (NKG2D) ligands on tumor cells; however, the mechanisms vary in different tumor types, and the effect and mechanism of action of VPA in pancreatic cancer cells are unknown. Methods: The present study evaluated the effect of VPA to susceptibility of pancreatic cancer cells to the NK cell-mediated lysis in vitro and in vivo. Then we investigated the mechanism which the effect of VPA depend on. Results: The lactate dehydrogenase assay (LDH) and xenograft experiment demonstrated that VPA significantly sensitized pancreatic cancer cells to NK cell-mediated lysis in vitro and in vivo. Quantitative real time- polymerase chain reaction (qRT-PCR) and flow cytometry demonstrated that VPA upregulated the mRNA and cell surface expression of the NKG2D ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) in pancreatic cancer cells. Effects of VPA both in vitro and in vivo were significantly attenuated by the PI3K/Akt pathway inhibitor LY294002 or a siRNA targeting PI3K catalytic subunit alpha isoform (PI3KCA). Conclusion: VPA enhances the susceptibility of pancreatic cancer cells to NK cell-mediated cytotoxicity both in vitro and in vivo by upregulating the expression of MICA and MICB via a PI3K/Akt signaling pathway-dependent mechanism.

This article is from Upsala Journal of Medical Sciences , volume 117 . Abstract Background. Valproic acid (VPA) apparent clearance (CL) estimated from total serum concentrations is analogous in elderly and non-elderly adult patients. As drug–protein binding decreases in old age, the aim of our study was to evaluate the confounding effect of the serum albumin concentration on the VPA apparent CL in elderly patients. Methods. In 102 epileptic out-patients treated with VPA in monotherapy, serum total steady-state trough concentrations (Css) were determined. Css concentrations were normalized for a 42 g/L albumin concentration (CssN), and the apparent CL and normalized apparent CLN were calculated. Results. A poor concordance of 53% was found in the classification of Css and CssN levels of VPA as subtherapeutic, therapeutic, or supratherapeutic dose. In the elderly (≥65 years) and non-elderly adult patients, the VPA apparent CL was similar; however, normalized apparent CLN was significantly lower in older patients (P < 0.01), with a 40% median decrease. Conclusions. Total VPA concentrations should be interpreted with caution, mainly in older patients, in which determination of unbound or normalized total drug concentrations may be clinically useful. Normalization of total concentrations permits an estimation of the masking effect of serum albumin concentrations on the VPA apparent CL in elderly patients.

This article is from The Journal of Reproduction and Development , volume 59 . Abstract We examined effects of treatment with valproic acid (0, 0.2, 1 or 2 mM, VPA), an inhibitor of class I and IIa histone deacetylases (HDACs), of mouse somatic cell nuclear transfer (SCNT) embryos for 24 h from 48 h (4-cell stage), 24 h (2-cell stage) or immediately after oocyte activation on blastocyst formation rates and qualities of the resultant blastocysts. Blastocyst formation rates (33.4–37.0%) were not improved by VPA treatments compared with the untreated control (35.1–36.4%). However, immunofluorescence staining revealed that Oct4 expression levels, evaluated from percentages of embryos expressing Oct4 strongly and having more than 10 Oct4-positive cells, in blastocysts from SCNT embryos treated with 1 mM VPA for 24 h from the 4-cell stage (VPA-4C) were highest among all the groups and that the proportion of cells with a normal nuclear distribution of histone H3 trimethylated at lysine 27 (H3K27me3), a marker of the state of X-chromosome inactivation, significantly increased in the VPA-4C group (36.6%) compared with the control group (12.4%, P

This article is from Indian Journal of Dermatology , volume 58 . Abstract Anti-epileptic drugs can be associated with a wide spectrum of cutaneous adverse reactions ranging from simple maculopapular rashes to more severe and life threatening reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis. These rashes are well documented with older antiepileptic drugs like phenytoin, phenobarbitone and carbamazapine. Lamotrigine is a newer, unrelated antiepileptic drug that causes skin rashes in 3-10% of new users. Higher starting dose or rapid escalation, concurrent treatment with valproic acid, and a previous history of a rash with other antiepileptic drugs are well recognized risk factors for lamotrigine related serious rashes. We report two patients with toxic epidermal necrolysis, resulting from concomitant use of lamotrigine and valproic acid. It is emphasized that clinicians adhere to the recommended dosage guidelines and adopt a slow dose titration when initiating treatment with lamotrigine.

This article is from Frontiers in Cellular Neuroscience , volume 7 . Abstract Cell replacement therapy using embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) is a promising strategy for the treatment of neurologic diseases such as Parkinson's disease (PD). However, a limiting factor for effective cell transplantation is the low survival rate of grafted cells, especially neurons. In this study, we modified the host environment and investigated whether the simultaneous administration of soluble factors can improve the survival and differentiation of murine iPSC-derived dopaminergic (DA) neurons in host brains. With the goal of applying this technology in clinical settings in the near future, we selected drugs that were already approved for clinical use. The drugs included two commonly used anti-convulsants, valproic acid (VPA) and zonisamide (ZNS), and estradiol (E2), also known as biologically active estrogen. Following neural induction of murine iPSCs, we collected neural progenitor cells (NPCs) by sorting PSA-NCAM+ cells, then treated the PSA-NCAM+ cells with drugs for 4 days. An immunofluorescence study revealed that 0.01 mM and 0.1 mM of VPA and 10 nM of E2 increased the percentage of tyrosine hydroxylase+ (TH: a DA neuron marker) cells in vitro. Furthermore, 0.1 mM of VPA increased the percentage of TH+ cells that simultaneously express the midbrain markers FOXA2 and NURR1. Next, in order to determine the effects of the drugs in vivo, the iPSC-derived NPCs were transplanted into the striata of intact SD rats. The animals received intraperitoneal injections of one of the drugs for 4 weeks, then were subjected to an immunofluorescence study. VPA administration (150 mg/kg/daily) increased the number of NeuN+ post-mitotic neurons and TH+ DA neurons in the grafts. Furthermore, VPA (150 mg/kg/daily) and ZNS (30 mg/kg/daily) increased the number of TH+FOXA2+ midbrain DA neurons. These results suggest that the systemic administration of VPA and ZNS may improve the efficiency of cell replacement therapy using iPSCs to treat PD.

This article is from Frontiers in Cellular Neuroscience , volume 8 . Abstract Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

This article is from Toxicological Research , volume 29 . Abstract Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup’s plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations ( < 0.5 μg/ml) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.

This article is from Oncology Letters , volume 7 . Abstract Valproic acid (VPA) is a well-tolerated drug that is used to treat seizure disorders and that has recently been shown to inhibit histone deacetylase. The present study investigated the effects of VPA on the radiosensitization of the rat C6 glioma cell line in vitro. To select an appropriate treatment concentration and time, MTT and flow cytometry assays were performed to measure the inhibitory effects of VPA at various concentrations and incubation time-points. The radiosensitizing effect of VPA was determined using clonogenic experiments. VPA- and radiation-induced C6 apoptosis was analyzed using quantitative polymerase chain reaction and western blot analysis. Cell proliferation was significantly inhibited by VPA in a time- and dose-dependent manner (P

This article is from Disease Models & Mechanisms , volume 5 . Abstract Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current study, we show that the reduction in phosphoinositide [PtdInsP (also known as PIP) and PtdInsP2 (also known as PIP2)] production caused by VPA is acute and dose dependent, and that this effect occurs independently of phosphatidylinositol 3-kinase (PI3K) activity, inositol recycling and inositol synthesis. In characterising the structural requirements for this effect, we also identify a family of medium-chain fatty acids that show increased efficacy compared with VPA. Within the group of active compounds is a little-studied group previously associated with seizure control, and analysis of two of these compounds (nonanoic acid and 4-methyloctanoic acid) shows around a threefold enhanced potency compared with VPA for protection in an in vitro acute rat seizure model. Together, our data show that VPA and a newly identified group of medium-chain fatty acids reduce phosphoinositide levels independently of inositol regulation, and suggest the reinvestigation of these compounds as treatments for epilepsy.