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Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack.
Brookes, RL, Crichton, S, Wolfe, CDA, Yi, Q, Li, L, Hankey, GJ, Rothwell, PM, Markus, HS
Stroke. 2018;(1):54-61
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Abstract
BACKGROUND AND PURPOSE A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. METHODS Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. RESULTS A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P=0.003). CONCLUSIONS These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.
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Clinical features of benign epilepsy of childhood with centrotemporal spikes in chinese children.
Liu, MJ, Su, XJ, Md, XS, Wu, GF, Zhang, YQ, Gao, L, Wang, W, Liao, JX, Wang, H, Mai, JN, et al
Medicine. 2017;(4):e5623
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This multicenter clinical trial was conducted to examine current practice of benign epilepsy with centrotemporal spikes and especially address the question that in what circumstances 1 antiepileptic drug (AED) should be preferred.Twenty-five medical centers participate in this clinical trial. The general information, clinical information, and treatment status were collected under the guidance of clinicians and then analyzed. Difference between different treatment groups was compared, and usefulness of the most commonly used AEDs was evaluated.A total of 1817 subjects were collected. The average age of the subject was 8.81 years. The average age of onset is 6.85 years (1-14 years). Male-to-female ratio is 1.13:1. A total of 62.9% of the patients are receiving monotherapies, and 10.6% are receiving multidrug therapy. Both age and course of disease of treated rolandic epilepsy (RE) patients are significantly different from those of untreated patients. Bilateral findings on electroencephalography (EEG) are less seen in patients with monotherapy compared with patients with multidrug therapy. Except for 25.4% patients not taking any AEDs, oxcarbazepine (OXC), sodium valproate (VPA), and levetiracetam (LEV) are the most commonly used 3 AEDs. VPA and LEV are commonly used in add-on therapy. OXC and LEV are more effective as monotherapy than VPA.Age of onset of Chinese RE patients is 6.85 years. Bilateral findings on EEG could be a risk factor to require multidrug therapy. In Chinese patients, OXC, VPA, and LEV are most commonly used AEDs as monotherapy and OXC and LEV are more effective than VPA.
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Comparative effectiveness of levetiracetam, valproate and carbamazepine among elderly patients with newly diagnosed epilepsy: subgroup analysis of the randomized, unblinded KOMET study.
Pohlmann-Eden, B, Marson, AG, Noack-Rink, M, Ramirez, F, Tofighy, A, Werhahn, KJ, Wild, I, Trinka, E
BMC neurology. 2016;(1):149
Abstract
BACKGROUND Few clinical trials have evaluated the efficacy and tolerability of antiepileptic drugs (AEDs) as initial monotherapy for elderly patients. METHODS This post-hoc subgroup analysis of data from an unblinded, randomized, 52-week superiority study (KOMET) compared the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients aged ≥ 60 years with newly diagnosed epilepsy. The physician chose VPA or CBZ as preferred standard treatment; patients were randomized to standard AEDs or LEV. The primary endpoint was time to treatment withdrawal. Results are exploratory, since KOMET was not powered for a subgroup analysis by age. RESULTS Patients (n = 308) were randomized to LEV (n = 48) or VPA-ER (n = 53) in the VPE-ER stratum or to LEV (n = 104) or CBZ-CR (n = 103) in the CBZ-CR stratum. Mean age was 69.6 years, range 60.2-89.9 years (intention-to-treat population n = 307). Time to treatment withdrawal hazard ratio [HR] (95 % confidence interval [CI]) for LEV vs. standard AEDs was 0.44 (0.28-0.67); LEV vs. VPA-ER: 0.46 (0.16-1.33); LEV vs. CBZ-CR: 0.45 (0.28-0.72). Twelve-month withdrawal rates were: LEV vs. standard AEDs, 20.4 vs. 38.7 %; LEV vs. VPA-ER, 10.4 vs. 23.1 %; LEV vs. CBZ-CR, 25.0 vs. 46.6 %. Time to first seizure was similar between LEV and standard AEDs (HR: 0.92, 95 % CI: 0.63-1.35), LEV and VPA-ER (0.77, 0.38-1.56), and LEV and CBZ-CR (1.02, 0.64-1.63). Adverse events were reported by 76.2, 67.3, and 82.5 % of patients for LEV, VPA-ER, and CBZ-CR, respectively. Discontinuation rates due to AEs were 11.3, 10.2, and 35.0 % for LEV, VPA-ER, and CBZ-CR, respectively. CONCLUSIONS Time to treatment withdrawal was longer with LEV compared with standard AEDs. This finding was driven primarly by the result in the CBZ-CR stratum, which in turn was likely due to the more favorable tolerability profile of LEV. Results of this post-hoc analysis suggest that LEV may be a suitable option for initial monotherapy for patients aged ≥ 60 years with newly diagnosed epilepsy. TRIAL REGISTRATION ClinicalTrials.gov: NCT00175903 ; September 9, 2005.
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Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study.
Salpekar, JA, Joshi, PT, Axelson, DA, Reinblatt, SP, Yenokyan, G, Sanyal, A, Walkup, JT, Vitiello, B, Luby, JL, Wagner, KD, et al
Journal of the American Academy of Child and Adolescent Psychiatry. 2015;(12):999-1007.e4
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OBJECTIVE To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder. METHOD The Treatment of Early Age Mania (TEAM) study is a multicenter, prospective, randomized, masked comparison of divalproex sodium (VAL), lithium carbonate (LI), and risperidone (RISP) in an 8-week parallel clinical trial. A total of 279 children and adolescents with DSM-IV diagnoses of bipolar I disorder, mixed or manic, aged 6 to 15 years were enrolled. The primary outcome measure was improvement on the Clinical Global Impression scale for depression (CGI-BP-I-D). Secondary outcome measures included the Children's Depression Rating Scale (CDRS-R) and suicidality status. Statistics included longitudinal analysis of outcomes using generalized linear mixed models with random intercept both for the complete data set and by using last observation carried forward. RESULTS CGI-BP-I-D ratings were better in the RISP group (60.7%) as compared to the LI (42.2%; p = .03) or VAL (35.0%; p = .003) groups from baseline to the end of the study. CDRS scores in all treatment groups improved equally by study end. In week 1, scores were lower with RISP compared to VAL (mean = 4.72, 95% CI = 2.67, 6.78), and compared to LI (mean = 3.63, 95% CI = 1.51, 5.74), although group differences were not present by the end of the study. Suicidality was infrequent, and there was no overall effect of treatment on suicidality ratings. CONCLUSION Depressive symptoms, present in the acutely manic or mixed phase of pediatric bipolar disorder, improved with all 3 medications, though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome. Clinical trial registration information-Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (TEAM); http://clinicaltrials.gov; NCT00057681.
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Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.
Sarchielli, P, Messina, P, Cupini, LM, Tedeschi, G, Di Piero, V, Livrea, P, Pini, LA, Bernardi, G, Bono, G, Sandrini, G, et al
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2014;(8):1289-97
Abstract
OBJECTIVE To assess the efficacy, safety and tolerability of sodium valproate (800mg/die) compared with placebo in medication-overuse headache patients with a history of migraine without aura. METHODS This is a multicenter, randomized, double-blind, placebo-controlled study enrolled medication-overuse headache patients for a 3-month treatment period with sodium valproate (800mg/day) or placebo after a 6 day outpatient detoxification regimen, followed by a 3-month follow-up. Primary outcome was defined by the proportion of patients achieving ≥50% reduction in the number of days with headache per month (responders) from the baseline to the last 4 weeks of the 3-month treatment. Multivariate logistic regression models were used on the primary endpoint, adjusting for age, sex, disease duration, comorbidity and surgery. The last-observation-carried-forward method was used to adjust for missing values. RESULTS Nine sites enrolled 130 patients and, after a 6-day detoxification phase, randomized 88 eligible patients. The 3-month responder rate was higher in the sodium valproate (45.0%) than in the placebo arm (23.8%) with an absolute difference of about 20% (p=0.0431). Sodium valproate had safety and tolerability profiles comparable to placebo. CONCLUSIONS The present study supports the efficacy and safety of sodium valproate in the treatment of medication overuse headache with history of migraine after detoxification.
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Early detection of bone metabolism changes under different antiepileptic drugs (ED-BoM-AED)--a prospective multicenter study.
Bauer, S, Hofbauer, LC, Rauner, M, Strzelczyk, A, Kellinghaus, C, Hallmeyer-Elgner, S, Oertel, WH, Rosenow, F
Epilepsy research. 2013;(3):417-22
Abstract
PURPOSE To determine early changes in bone turnover markers induced by treatment with oxcarbazepine or valproate. METHODS In this prospective study, 31 adults with newly diagnosed epilepsy were included who were started on therapy with either oxcarbazepine (OXC, n=16, mean age 45.6 years, 37.5% female) or valproate (VPA, n=15, mean age 42.2 years, 33.3% female). Clinical characteristics were obtained at baseline, after 2 weeks and 3 months. In addition, blood samples were drawn at each visit. Calcium, phosphate, alkaline phosphatase (AP), receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), osteocalcin (OC) and cathepsin K were determined. RESULTS In OXC treated patients, OPG increased by 0.06 pmol/L (p=0.0004) after 2 weeks and remained elevated by 0.05 pmol/L (p=0.02) after 3 months. Between 2 weeks and 3 months of OXC treatment, OC increased by 1.98 ng/mL (p=0.02). During the first 3 months of OXC treatment, total serum AP increased by 11%±9% (p=0.02). Compared to baseline, serum calcium raised by 0.06 mmol/L (p=0.04) after 2 weeks and by 0.07 mmol/L (p=0.004) after 3 months of OXC treatment. In VPA treated patients, a late OPG increase by 0.07 pmol/L (p=0.007) occurred after 3 months. During the first 3 months of OXC treatment, total serum AP decreased by by 7%±15% (p=0.03). No changes in OC or calcium were seen. RANKL was below detection limit in 16 out of 31 patients (52%) and did not change significantly during treatment. Cathepsin K was below detection limit at baseline in 27 out of 31 patients (87%) and was therefore not further evaluated. Phosphate did not change during treatment. CONCLUSION Increased bone turnover can be measured within few weeks of newly started treatment with OXC, while significant changes under VPA treatment occurred only after 3 months. Our data suggest distinct mechanisms of increased bone turnover in different anticonvulsants. These variable mechanisms may require individual prevention and treatment strategies.
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Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder.
Lee, SY, Chen, SL, Chang, YH, Chen, PS, Huang, SY, Tzeng, NS, Wang, YS, Wang, LJ, Lee, IH, Yeh, TL, et al
Journal of psychiatric research. 2013;(10):1343-8
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UNLABELLED Memantine is a noncompetitive NMDA receptor antagonist. As an augmenting agent, it has an antidepressant-like and mood-stabilizing effect. Memantine also reduces binge eating episodes and weight. We investigated whether memantine added on to valproate (VPA) is more effective than VPA alone for treating BP-II depression and improving the patient's metabolic profile. This was a randomized, double-blind, controlled study. BP-II patients undergoing regular VPA treatments were randomly assigned to one of two groups: VPA plus either add-on [1] memantine (5 mg/day) (n = 62) or [2] placebo (n = 73) for 12 weeks. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate clinical response. Height, weight, fasting serum glucose, fasting total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were followed regularly. Multiple linear regressions with generalized estimating equation methods were used to analyze the effects of memantine on clinical performance. There were no significant differences in pre- and post-treatment YMRS and HDRS scores between the VPA + memantine and VPA + placebo groups. Although there were no significant differences in the pre- and post-treatment values of most metabolic indices between the two groups, there was a significant increase of HDL-C (p = 0.009) in the VPA + memantine group compared with the VPA + placebo group. This increase remained significant even after controlling for body mass index (BMI) (p = 0.020). We conclude that add-on memantine plus VPA treatment of BP-II depression increases the blood level of HDL-C even in the absence of change in affective symptoms. TRIAL REGISTRATION NCT01188148 (https://register.clinicaltrials.gov/), Trial date was from 1st August, 2008 to 31st July, 2012 in National Cheng Kung University and Tri-Service General Hospital.
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SCN1A IVS5N+5 polymorphism and response to sodium valproate: a multicenter study.
Haerian, BS, Baum, L, Tan, HJ, Kwan, P, Raymond, AA, Saruwatari, J, Nakagawa, K, Mohamed, Z
Pharmacogenomics. 2012;(13):1477-85
Abstract
AIM: Approximately 30% of epilepsy patients do not response to antiepileptic drugs (AEDs). The functional SCN1A IVS5N+5 polymorphism may play a role in response to some AEDs. The purpose of this study was to examine this hypothesis in a cohort study of Malaysian and Hong Kong Chinese epilepsy patients on sodium valproate (VPA) monotherapy and in a meta-analysis. PATIENTS & METHODS The SCN1A IVS5N+5 polymorphism was genotyped in 583 Malaysian (84%) and Hong Kong Chinese (16%) epilepsy patients receiving VPA monotherapy. The related association studies, including the current study, were meta-analyzed by using fixed- and random-effects models under various genetic models. RESULTS A total of 277 (47.5%) and 306 (52.5%) patients were VPA nonresponsive and responsive, respectively. Unlike Chinese and Indian patients, Malay nonresponsive patients with idiopathic generalized epilepsy showed significant association, probably caused by the small sample size. CONCLUSION The cohort study and meta-analysis did not demonstrate an association between AED responsiveness and this polymorphism. Future studies with a larger sample size of Malays with idiopathic generalized epilepsy are suggested.
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Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome.
Raffoux, E, Cras, A, Recher, C, Boëlle, PY, de Labarthe, A, Turlure, P, Marolleau, JP, Reman, O, Gardin, C, Victor, M, et al
Oncotarget. 2010;(1):34-42
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.
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Sodium Valproate versus Propranolol in paediatric migraine prophylaxis.
Ashrafi, MR, Shabanian, R, Zamani, GR, Mahfelati, F
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2005;(5):333-8
Abstract
In a randomized clinical trial the effect of Sodium Valproate in pediatric migraine prophylaxis was compared with that of Propranolol. One hundred and twenty patients with common migraine (migraine without aura) aged from 3 to 15 years who met the defined criteria enrolled into the study. Randomly the patients were divided in two groups of A and B, treating with sodium Valproate and Propranolol, respectively. Three phases of baseline period (phase I), titration and adjustment period (phases II) and fixed -dose treatment period (phase III) have been designed. A total of 57 patients in group A, and 58 patients in group B completed all phases of the trial. Seventy two percent of patients in group A and 69% of patients in group B have responded to Sodium Valproate and Propranolol, respectively, as a reduction of more than 50% in headache frequency per month. Further more both drugs have shown efficacy in reducing the severity and duration of headache and also better response to rescue medications (p value <0.01). There was no significant difference in all previously mentioned therapeutic effects between two groups (p value <0.05).