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Comparing the Effects of Atorvastatin With Sodium Valproate (Divalproex) on Frequency and Intensity of Frequent Migraine Headaches: A Double-blind Randomized Controlled Study.
Hesami, O, Sistanizad, M, Asadollahzade, E, Johari, MS, Beladi-Moghadam, N, Mazhabdar-Ghashghai, H
Clinical neuropharmacology. 2018;(3):94-97
Abstract
OBJECTIVES To evaluate the prophylactic effects of atorvastatin on frequency, intensity, and duration of migraine attacks compared with sodium valproate. METHODS In this randomized, double-blind, single-center controlled trial, patients with 6 to 15 migraine attacks per month, which were candidates of preventive treatment, were recruited. The patients were randomly allocated into 2 groups. The first group (A) received atorvastatin 40 mg daily, and the second group (B) received sodium valproate 500 mg daily. All patients were visited each month and followed up for 3 months. The characteristics of migraine headaches including frequency, intensity, and duration of attacks were recorded, as well as the number of analgesics taken per each attack and probable adverse effects. RESULTS From 100 patients enrolled in the study, 18 cases were excluded owing to adverse effects (2 cases) or lost to follow-up (16 cases). From 82 patients who completed the trial, 46 and 36 were in group A (atorvastatin) and group B (sodium valproate), respectively. Mean age of the patients was not significantly different in the 2 arms of the study (33.56 ± 8.51 in group A and 33.25 ± 9.91 years in group B, P = 0.877). Number, duration, and intensity of attacks and number of analgesics taken during attacks decreased significantly in both groups in monthly follow-ups. However, there was no statistically significant difference between 2 arms of the study in terms of attenuation in the characteristics of migraine attacks. On the other hand, patients in group A suffered fewer adverse effects compared with group B. CONCLUSIONS This study indicates that atorvastatin could be an alternative for sodium valproate in migraine prophylaxis with comparable efficacy and fewer adverse effects. Multicenter studies with larger sample size are recommended.
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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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Assessment of the efficacy of omega-3 fatty acids on metabolic and inflammatory parameters in patients with schizophrenia taking clozapine and sodium valproate.
Behdani, F, Roudbaraki, SN, Saberi-Karimian, M, Tayefi, M, Hebrani, P, Akhavanrezayat, A, Amlashi, SV, Ferns, GA, Ghayour-Mobarhan, M
Psychiatry research. 2018;:243-247
Abstract
Omega-3 fatty acid (FA) supplementation has been reported to improve several cardio-metabolic risk factors. We aimed to assess the efficacy of omega-3 fatty acids on metabolic and inflammatory indices in patients with schizophrenia who were taking clozapine and sodium valproate. All patients were on a stable dose of 300-400mg of clozapine for 3 months. Subjects were randomized to treatment with either omega-3 fatty acid (4gr/day) or a placebo for 8 weeks. Height, weight, abdominal circumference, serum lipid profile, fasting blood glucose (FBG), and serum high sensitivity-C-reactive protein (hs-CRP) were determined at baseline and after 8 weeks of treatment. Fifty six subjects were recruited into the study. Patients with schizophrenia who were in the group receiving omega-3 FA capsules had an improvement in some anthropometric indices including weight, BMI, wrist and waist circumference, compared to the placebo group. Only changes in waist circumferences remained significantly different after adjustment for serum fasted TG. Our results showed omega-3 FA supplementation can improve some anthropometric indices in patients with schizophrenia who are taking clozapine pharmacotherapy.
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Valproate and childbearing potential: new regulations.
Sisodiya, SM, ,
Practical neurology. 2018;(3):176-178
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Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency.
Vantroys, E, Smet, J, Vanlander, AV, Vergult, S, De Bruyne, R, Roels, F, Stepman, H, Roeyers, H, Menten, B, Van Coster, R
Orphanet journal of rare diseases. 2018;(1):80
Abstract
BACKGROUND The first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reported in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype). RESULTS Here, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy. At the age of six years, she had an epileptic seizure which was treated with sodium valproate. In the months after treatment was started, she developed acute liver failure and severe progressive encephalopathy. Although valproate was discontinued, she died six months later. Spectrophotometric analysis of the oxidative phosphorylation complexes in liver revealed a deficient activity of complex III and low normal activities of the complexes I and IV. Activity staining in the BN-PAGE gel confirmed the low activities of complex I, III and IV and, in addition, showed the presence of a subcomplex of complex V. Histochemically, a mosaic pattern was seen in hepatocytes after cytochrome c oxidase staining. Using Whole Exome Sequencing two known pathogenic variants were detected in WARS2 (c.797delC, p.Pro266ArgfsTer10/ c.938 A > T, p.Lys313Met). CONCLUSION This is the first report of severe hepatopathy in a subject with WARS2 deficiency. The hepatopathy occurred soon after start of sodium valproate treatment. In the literature, valproate-induced hepatotoxicity was reported in the subjects with pathogenic mutations in POLG and TWNK. This case report illustrates that the course of the disease in the subjects with a mitochondrial defect can be non-progressive during several years. The subject reported here was first diagnosed as having cerebral palsy. Only after a mitochondriotoxic medication was started, the disease became progressive, and the diagnosis of a mitochondrial defect was made.
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Sodium valproate compared to phenytoin in treatment of status epilepticus.
Amiri-Nikpour, MR, Nazarbaghi, S, Eftekhari, P, Mohammadi, S, Dindarian, S, Bagheri, M, Mohammadi, H
Brain and behavior. 2018;(5):e00951
Abstract
BACKGROUND Status epilepticus (SE) is a neurological emergency which can be life-threatening. Several medical regimens are used in order to control it. In this study, we intended to evaluate the clinical efficacy and tolerability of sodium valproate and intravenous phenytoin (IV PHT) in the control of SE. METHODS One hundred and ten consecutive patients suffering from benzodiazepine refractory SE who were referred to the emergency ward from March 2014 to March 2015 were randomly divided into two groups. The first group received intravenous sodium valproate, 30 mg/kg as loading dose and then 4-8 mg/kg every 8 hr as maintenance regimen. The second group received IV PHT 20 mg/kg as loading dose and then 1.5 mg/kg for 8 hr as maintenance therapy. All patients were monitored for vital signs every 2 hr up to 12 hr. The patients were also followed up for 7 days regarding drug response and adverse effects. RESULTS The administration of sodium valproate and phenytoin respectively resulted in seizure control in 43 (78.18%) and 39 (70.90%) of the patients within 7 days of drug administration (p = .428). Seven-day mortality rate was similar in both groups (12.73% vs. 12.73%; p = .612). There was no significant difference in adverse effects between two groups. CONCLUSION Sodium valproate is preferred to IV PHT for treatment and control of SE due to its higher tolerability and lower hemodynamic instability.
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The critical interaction between valproate sodium and warfarin: case report and review.
Zhou, C, Sui, Y, Zhao, W, Dong, C, Ren, L, Song, P, Xu, B, Sun, X
BMC pharmacology & toxicology. 2018;(1):60
Abstract
BACKGROUND Valproic acid (VPA) and warfarin are commonly prescribed for patients with epilepsy and concomitant atrial fibrillation (AF). When VPA and warfarin are prescribed together, clinically important interactions may occur. VPA may replace warfarin from the protein binding sites and result in an abnormally increased anticoagulation effect. This is commonly underrecognized. CASE PRESENTATION In our case, we report a 78-year-old woman with a glioma who presented with status epilepticus. The patient was on warfarin to prevent cardiogenic embolism secondary to AF. Intravenous loading dose of VPA was administered, but international normalized ratio (INR) increased significantly to 8.26. Intravenous vitamin K1 was then given and the patient developed no overt bleeding during the hospitalization. CONCLUSION By reviewing the literature and discussing the critical interaction between valproate sodium and warfarin, we conclude that intravenous VPA and the co-administrated warfarin may develop critical but underrecognized complications due to effects on the function of hepatic enzymes and displacement of protein binding sites.
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Sodium valproate versus phenytoin monotherapy for epilepsy: an individual participant data review.
Nevitt, SJ, Marson, AG, Weston, J, Tudur Smith, C
The Cochrane database of systematic reviews. 2018;(8):CD001769
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BACKGROUND Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free, and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, sodium valproate and phenytoin are commonly used antiepileptic drugs for monotherapy treatment. It is generally believed that phenytoin is more effective for focal onset seizures, and that sodium pvalproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001, and updated in 2013 and 2016. OBJECTIVES To review the time to treatment failure, remission and first seizure of sodium valproate compared to phenytoin when used as monotherapy in people with focal onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS We searched the Cochrane Epilepsy Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP on 19 February 2018. We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing monotherapy with either sodium valproate or phenytoin in children or adults with focal onset seizures or generalised onset tonic-clonic seizures DATA COLLECTION AND ANALYSIS This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure and our secondary outcomes were time to first seizure post-randomisation, time to six-month, and 12-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS We included 11 trials in this review and IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to focal onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes, a HR of less than 1 indicates an advantage for phenytoin, and for first seizure and treatment failure outcomes a HR of less than 1 indicates an advantage for sodium valproate.The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type 0.88, 95% CI 0.61 to 1.27; 5 studies; 528 participants; moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type 0.77, 95% CI 0.44 to 1.37; 4 studies; 418 participants; moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants 1.16 (95% CI 0.71 to 1.89; 5 studies; 451 participants; moderate-quality evidence). These results suggest that treatment failure for any reason related to treatment and treatment failure due to adverse events may occur earlier on phenytoin compared to sodium valproate, while treatment failure due to lack of efficacy may occur earlier on sodium valproate than phenytoin; however none of these results were statistically significant.Results for time to first seizure (pooled HR adjusted for seizure type 1.08, 95% CI 0.88 to 1.33; 5 studies; 639 participants; low-quality evidence) suggest that first seizure recurrence may occur slightly earlier on sodium valproate compared to phenytoin. There were no clear differences between drugs in terms of time to 12-month remission (pooled HR adjusted for seizure type 1.02, 95% CI 0.81 to 1.28; 4 studies; 514 participants; moderate-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type 1.05, 95% CI 0.86 to 1.27; 5 studies; 639 participants; moderate-quality evidence).Limited information was available regarding adverse events in the trials and we could not make comparisons between the rates of adverse events on sodium valproate and phenytoin. Some adverse events reported with both drugs were drowsiness, rash, dizziness, nausea and gastrointestinal problems. Weight gain was also reported with sodium valproate and gingival hypertrophy/hyperplasia was reported on phenytoin.The methodological quality of the included trials was generally good, however four out of the five trials providing IPD for analysis were of an open-label design, therefore all results were at risk of detection bias. There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to first seizure' and heterogeneity was present in analysis of treatment failure outcomes which could not be explained by subgroup analysis by epilepsy type or by sensitivity analysis for misclassification of seizure type. Therefore, for treatment failure outcomes we judged the quality of the evidence to be moderate to low, for 'time to first seizure' we judged the quality of the evidence to be low, and for remission outcomes we judged the quality of the evidence to be moderate. AUTHORS' CONCLUSIONS We have not found evidence that a significant difference exists between valproate and phenytoin for any of the outcomes examined in this review. However detection bias, classification bias and heterogeneity may have impacted on the results of this review. We did not find any outright evidence to support or refute current treatment policies. We recommend that future trials be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.
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Upregulation of CD54 and downregulation of HLA‑ABC contribute to the novel enhancement of the susceptibility of HL-60 cells to NK cell-mediated cytolysis induced by ATRA plus VPA.
Zou, H, Li, L, Han, Y, Ma, R, Liao, Q, Tian, J, Zhang, X, Ren, X, Song, G, Guo, Q, et al
Oncology reports. 2017;(1):105-114
Abstract
Enhancement of the susceptibility of HL-60 cells to NK cell-mediated cytolysis induced by all-trans-retinoic acid (ATRA) plus valproate (VPA) was evaluated. In addition to the synergistic effect of ATRA plus VPA on HL-60 cells, the optimal concentration of 1 mM VPA plus 0.5 µM ATRA increased the cytotoxic sensitivity of HL-60 cells to NK cells. The expression of the activated receptors NKp30 and NKG2D on NK-92 cells was higher compared with the levels noted for the other receptors, and the expression of NKG2D ligands MICA/B on HL-60 cells was not significantly upregulated in the ATRA plus VPA goup compared with the control. Moreover, it was observed that the ligands of NKp30 on HL-60 cells presented the same variation trend. As to the co-stimulatory and adhesion molecules on NK-92 and their ligands on HL-60 cells post exposure to ATRA and VPA alone or their combination, there was no obvious change in the expression of CD112, CD48 and CD70 on the HL-60 cells. However, the expression of CD54 on HL-60 cells was significantly upregulated. In contrast, the expression of NKG2A ligands HLA-ABC on HL-60 cells was obviously downregulated. In addition, the expression of HLA-E on the HL-60 cells in the group treated with ATRA plus VPA was not significantly increased. In conclusion, the combination of VPA and ATRA not only induced the differentiation of HL-60 cells, but also induced enhancement of the sensitivity of HL-60 cells to NK cells by downregulating the expression of HLA-ABC and upregulating the expression of CD54, but not MICA/MICB. The results provide experimental and theoretical basis for the clinical combination of a low-dose of ATRA plus VPA for the treatment of leukemia.
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A randomized controlled trial of acupressure as an adjunctive therapy to sodium valproate on the prevention of chronic migraine with aura.
Xu, JH, Mi, HY
Medicine. 2017;(27):e7477
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BACKGROUND The primary objective of the present study was to evaluate the efficacy and safety of using acupressure as an adjunctive therapy to sodium valproate (SV) combined with acupressure (ASV) on the prevention of chronic migraine with aura (CMA). METHODS A total of 98 patients with CMA were randomly divided into an intervention group and a control group, with 49 patients in each group. The patients in the intervention group received ASV, while the participants in the control group received SV alone. The primary outcome was measured by the numeric rating scale (NRS). The secondary outcomes including frequency of migraine attacks, the times of using analgesics, and quality of life, measured by the short-form 36 Health Survey Scale (SF-36) score. In addition, adverse events (AEs) were also recorded throughout the trial. The outcomes were measured at the end of the 8-week treatment, and 4-week follow-up. RESULTS After the 8-week treatment and 4-week follow-up, ASV efficacy was not greater than that of SV alone regarding pain relief, as measured using the NRS, and frequency of migraine attacks, consumption of analgesics, and quality of life, as measured using the SF-36. However, ASV can significantly reduce the nausea when compared with SV (P = .04). CONCLUSION The present results indicate that ASV can decrease migraine-related nausea during treatment, but cannot relieve pain or enhance quality of life in patients with CMA.