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1.
Valproate prescription to women of childbearing age in English primary care: repeated cross-sectional analyses and retrospective cohort study.
Gaudio, M, Konstantara, E, Joy, M, van Vlymen, J, de Lusignan, S
BMC pregnancy and childbirth. 2022;(1):73
Abstract
BACKGROUND Valproate is a teratogenic drug that should be avoided during the preconception period and pregnancy. The aim was to explore general practitioners' (GPs) prescription patterns over time, describe trends, and explore inter-practice variation within primary care. METHODS We identified women of childbearing age (12-46 years old) in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network. We performed repeated cross-sectional analyses from 2004 to 2018 to determine rates of prescription and a retrospective cohort estimated the prevalence of use of valproate during pregnancy. RESULTS In 2004, 0.31% (95% Confidence Interval (95%CI):0.18 to 0.44%) women were prescribed valproate, decreasing to 0.16% (95%CI:0.07 to 0.24%) by 2018. Among women with epilepsy, the rate fell from 15.2% (95%CI:14.4 to 16.0%) to 8.8% (95% CI:8.2 to 9.7%) over the same period. In 2018, almost two thirds (62.2%) of women who were prescribed valproate had epilepsy only, whereas bipolar disorder and migraine accounted for 15.8% and 7.4% respectively. Contraceptive prescriptions did not increase over time, and only in 2018 was there greater odds of being prescribed contraception (OR 1.41, 95%CI:1.08 to 1.45). Just under a fifth (19.7%) of women were prescribed valproate during their pregnancy; two out of three of these pregnancies were preceded by folic acid prescription (5 mg). While some practices reduced their rate of valproate prescription, others did not. CONCLUSIONS Regulatory guidelines have changed GPs' prescription patterns in women of childbearing potential for valproate but not for contraception. Further research is needed to identify the barriers of GPs and women of childbearing potential to undertaking contraception.
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2.
Effects of Sodium Valproate Monotherapy on Blood Liver Enzyme Levels in Patients with Epilepsy: A Meta-Analysis.
Fu, J, Tao, T, Li, Z, Chen, Y, Chen, X, Li, J, Peng, L
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2021;(7):425-434
Abstract
We conducted this meta-analysis to assess the effects of sodium valproate (VPA) monotherapy on blood liver enzymes in patients with epilepsy. PubMed, Web of Science, EBSCO, Cochrane Library, Wanfang, China national knowledge infrastructure databases were searched. Nine studies were included. Results showed: (1) The overall SMD for blood AST, ALT, and GGT levels of VPA monotherapy group versus control group were 0.70 (95% CI=0.31 to 1.09, Z=3.52, p=0.0004), 0.47 (95% CI=- 0.01 to 0.95, Z=1.91, p=0.06), 0.44 (95% CI=0.29 to 0.60, Z=5.55, p<0.00001), respectively. (2) In subgroup meta-analysis, increased blood AST and GGT levels were observed in epileptic minors (AST: total SMD=0.85, 95% CI=0.40 to 1.30, Z=3.69, p=0.0002; GGT: total SMD=0.46, 95% CI=0.29 to 0.63, Z=5.25, p<0.00001). Elevated blood ALT level was observed in Asian patients receiving VPA monotherapy (total SMD=0.70, 95% CI=0.51 to 0.90, Z=7.01, p<0.00001), and the early stage of VPA monotherapy (total SMD=0.93, 95% CI=0.57 to 1.29, Z=5.09, p<0.00001). Overall, our results indicated that blood AST and GGT were significantly increased in epileptic minors receiving VPA monotherapy. The elevation of blood ALT was observed in Asian patients and the early stage of VPA monotherapy. However, due to the small number of included studies, our results should be considered with caution.
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3.
The efficacy of magnesium oxide and sodium valproate in prevention of migraine headache: a randomized, controlled, double-blind, crossover study.
Karimi, N, Razian, A, Heidari, M
Acta neurologica Belgica. 2021;(1):167-173
Abstract
Migraine is a disabling disorder that affects the quality of life of patients. Different medications have been used in prevention of migraine headache. In this study, we evaluated the effectiveness of magnesium oxide in comparison with valproate sodium in preventing migraine headache attacks. This is a single-center, randomized, controlled, crossover trial which is double-blind, 24-week, 2-sequence, 2-period, 2-treatment. After patient randomization into two sequences, the intervention group received magnesium oxide 500 mg and the control group received valproate sodium 400 mg two tablets each day (every 12 h) for 8 weeks. The primary efficacy variable was reduction in the number of migraine attacks and number of days with moderate or severe headache and hours with headache (duration) per month in the final of 8 weeks in comparison with baseline. Seventy patients were randomized and seven dropped out, leaving 63 for analysis. In an intention-to-treat analysis, 31 patients were in group 1 (magnesium oxide-valproate) and 32 patients were in group 2 (valproate-magnesium oxide). The mean number of migraine attacks and days per month was 1.72 ± 1.18 and 2.09 ± 1.70, with a mean duration of 15.50 ± 21.80 h in magnesium group and 1.27 ± 1.27 and 2.22 ± 1.96, with a mean duration 13.38 ± 14.10 in valproate group. This study has shown that 500 mg magnesium oxide appears to be effective in migraine prophylaxis similar to valproate sodium without significant adverse effect.
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4.
Intravenous sodium valproate in status epilepticus: review and Meta-analysis.
Liampas, I, Siokas, V, Brotis, A, Zintzaras, E, Stefanidis, I, Dardiotis, E
The International journal of neuroscience. 2021;(1):70-84
Abstract
Objective: Status epilepticus (SE) is a common neurologic emergency. The present study constitutes a meta-analysis of published randomized control trials (RCTs) evaluating the use of intravenous sodium valproate (VPA) in SE.Methods: MEDLINE and Cochrane databases were comprehensively searched, while retrieved RCTs and meta-analyses were manually screened. Prespecified outcome measures included seizure-cessation, 24 h-efficacy, constitute (liver enzyme increase, arrhythmias, bone-marrow suppression, hypotension and respiratory depression) and severe (life-threatening) adverse events (AEs). Evidence synthesis was performed when appropriate, using Random-Effects (RE) or Fixed-Effects (FE) model based on heterogeneity between trials (homogeneity assumed when PQ > 0.1 and I2 < 50%). Outcomes were assessed using Odds-Ratios (ORs) and 95%Confidence-Intervals (95% CIs). Every available comparison was investigated in terms of efficacy and tolerability.Results:Thirteen studies were retrieved and five comparisons were available, four of which involved two or more studies. Results were compatible with no significant difference between VPA and Phenytoin both in terms of efficacy and tolerability [seizure-cessation: FE-OR = 1.99, 95% CI = (0.83-4.75), 24 h-efficacy: FE-OR = 1.32, 95% CI = (0.60-2.89), composite AEs: FE-OR = 0.45, 95% CI = (0.17-1.21)]. Phenobarbital proved more commonly associated with composite AEs than VPA [seizure-cessation: RE-OR = 0.68, 95% CI = (0.05-9.44), 24 h-efficacy: RE-OR = 0.88, 95% CI = (0.02-33.9), composite AEs: FE-OR = 0.26, 95% CI = (0.09-0.82), severe AEs: FE-OR = 0.30, 95% CI = (0.04-2.28)]. Diazepam was determined inferior to VPA concerning safety issues [seizure-termination: FE-OR = 0.77, 95% CI = (0.34-1.79), severe respiratory depression: FE-OR = 0.06, 95% CI = (0.01-0.48), severe hypotension: FE-OR = 0.09, 95% CI = (0.01-0.72)]. The combination of Lorazepam (LZP) with VPA and the combination of LZP with Levetiracetam presented no difference in efficacy [24h-efficacy: FE-OR = 0.68, 95% CI = (0.37-1.24)].Conclusions: Although, additional high-quality RCTs are warranted, according to our results, VPA can be considered a safe and effective option in the management of SE.
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5.
Association of SCN1A, SCN2A, and UGT2B7 Polymorphisms with Responsiveness to Valproic Acid in the Treatment of Epilepsy.
Lu, Y, Su, Q, Li, M, Dayimu, A, Dai, X, Wang, Z, Che, F, Xue, F
BioMed research international. 2020;:8096235
Abstract
PURPOSE The efficacy of valproic acid (VPA) varies widely in clinical treatment of epileptic patients. Our study is aimed at exploring a potential association between polymorphisms of SCN1A, SCN2A, and UGT2B7 genetic factors and VPA responses. METHODS In this observational study, a total of 114 epileptic patients only treated with VPA for at least 1 year were included to explore the genetic polymorphisms of drug responses (mean follow-up time: 3.68 ± 1.78 years). Thirty-one single-nucleotide polymorphisms (SNPs) in three candidate genes that related with drug-metabolizing enzymes and receptors were genotyped. RESULTS Of the 31 SNPs, eight were significantly associated with VPA responses, including rs1381105, rs2162600, rs10197716, rs2119068, rs2119067, rs353116, rs353112 and rs6740895. The interaction between rs10197716 and rs2119068 was the most significantly correlated with VPA responses compared with other combinations (the highest VPA-responsive rate 0.92 versus the lowest VPA-responsive rate 0.33, p = 0.007). CONCLUSION The study indicated that eight SNPs and SNP-SNP interaction may be associated with VPA responses in Chinese Han epileptic patients. The SNPs were rs1381105 (SCN1A), rs2162600 (SCN1A), rs10197716 (SCN2A), rs2119068 (SCN2A), rs2119067 (SCN2A), rs353116 (SCN2A), rs353112 (SCN2A) and rs6740895 (SCN2A), respectively. The interaction between the three pairs of rs10197716-rs2119068, rs10197716-rs11889342 and rs7598931-rs12233719 was the most significant for VPA. This implied that these SNPs may play an important role in the pharmacogenomics mechanism of valproic acid.
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6.
Cinnarizine and sodium valproate as the preventive agents of pediatric migraine: A randomized double-blind placebo-controlled trial.
Amanat, M, Togha, M, Agah, E, Ramezani, M, Tavasoli, AR, Azizi Malamiri, R, Fashandaky, F, Heidari, M, Salehi, M, Eshaghi, H, et al
Cephalalgia : an international journal of headache. 2020;(7):665-674
Abstract
BACKGROUND Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents. METHODS We carried out a randomized double-blind placebo-controlled trial in the Children's Medical Center and Sina hospital, Tehran, Iran. Eligible participants were randomly assigned in 1:1:1 ratio via interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The primary endpoints were the mean change in frequency and intensity of migraine attacks from baseline to the last 4 weeks of trial. The secondary endpoint was the efficacy of each drug in the prevention of migraine. The drug was considered effective if it decreased migraine frequency by more than 50% in the double-blind phase compared with the baseline. Safety endpoint was adverse effects that were reported by children or their parents. RESULTS A total of 158 children participated. The frequency of migraine attacks significantly reduced compared to baseline in cinnarizine (difference: -8.0; 95% confidence interval (CI): -9.3 to -6.6), sodium valproate (difference: -8.3; 95% confidence interval: -9.3 to -7.2), and placebo (difference: -4.4; 95% confidence interval: -5.4 to -3.4) arms. The decrease was statistically greater in cinnarizine (difference: -3.6; 95% confidence interval: -5.5 to -1.6) and sodium valproate (difference: -3.9; 95% confidence interval: -5.8 to -1.9) arms, compared to placebo group. Children in all groups had significant reduction in intensity of episodes compared to baseline (cinnarizine: -4.6; 95% confidence interval: -5.2 to -4.0; sodium valproate: -4.0; 95% confidence interval: -4.8 to -3.3; placebo: -2.6; 95% confidence interval: -3.4 to -1.8). The decrease was statistically greater in cinnarizine (difference: -2.0; 95% confidence interval: -3.2 to -0.8) and sodium valproate (difference: -1.5; 95% confidence interval: -2.7 to -0.3) arms, compared to the placebo group. Seventy-one percent of individuals in the cinnarizine group, 66% of cases in the sodium valproate group, and 42% of people in the placebo arm reported more than 50% reduction in episodes at the end of the trial. The odds ratio for >50% responder rate was 3.5 (98.3% confidence interval: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% confidence interval: 1.0 to 6.9) for sodium valproate versus placebo. Nine individuals reported adverse effects (three in cinnarizine, five in sodium valproate, and one in the placebo group) and one case in the sodium valproate group discontinued the therapy due to severe sedation. CONCLUSION Cinnarizine and sodium valproate could be useful in migraine prophylaxis in children and adolescents. Trial registration: IRCT201206306907N4.
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7.
Valproate and folate: Congenital and developmental risks.
Reynolds, EH, Green, R
Epilepsy & behavior : E&B. 2020;:107068
Abstract
Increasing awareness of the congenital and developmental risks associated with the use of sodium valproate (VPA) has led to recent European guidelines designed to avoid the use of this drug in pregnancy if effective alternative treatments are available. In the general population, it is well established that periconceptual folic acid reduces the risk of neural tube defects (NTDs) and possibly other congenital abnormalities. We here review the evidence 1) that VPA interferes with one-carbon metabolism, including the transport of methylfolate into the brain and the placenta by targeting folate receptors; 2) that VPA effects on the folate metabolic system contribute to congenital and developmental problems associated with VPA exposure; and 3) that genetic factors, notably polymorphisms related to one-carbon metabolism, contribute to the vulnerability to these VPA-induced risks. Based on these facts, we propose that the standard periconceptual use of 400 μg of folic acid may not adequately protect against VPA or other antiepileptic drug (AED)-induced congenital or developmental risks. Pending definitive studies to determine appropriate dose, we recommend up to 5 mg of folic acid periconceptually in at-risk women with the caveat that the addition of supplementary vitamin B12 may also be prudent because vitamin B12 deficiency is common in pregnancy in some countries and is an additional risk factor for developmental abnormalities.
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8.
An investigation on the effects of carbamazepine and sodium valproate on neuromuscular transmission.
Ay, H, Ethemoğlu, Ö
Acta neurologica Belgica. 2020;(3):545-548
Abstract
The aim of this study was to investigate the effects of sodium valproate (SV) and carbamazepine (CBZ) on neuromuscular transmission using single-fibre electromyography (SFEMG) in patients with epilepsy. We performed SFEMG during the voluntary contraction of extensor digitorum communis muscle. 30 epileptic patients taking SV, 25 epileptic patients taking CBZ, and 25 age-matched healthy volunteers were included in the study. Mean jitter values (MCD) of subjects taking SV and CBZ were compared with normal controls. MCD values of subjects taking SV and CBZ were statistically significantly higher than those of control group. Review of the correlation between disease duration and MCD values of patients showed that MCD values were increased with the prolonged use of drugs, and thus, indicated a positive relationship between these two parameters. These results suggest that both SV and CBZ reduce neuromuscular transmission in patients without a neuromuscular junction disease.
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9.
Incidence, Presentation, and Risk Factors for Sodium Valproate-Associated Hyperammonemia in Neurosurgical Patients: A Prospective, Observational Study.
Woo, PYM, Woo, AWY, Lam, SW, Ko, NMW, Ho, JWK, Chu, ACH, Kwan, MCL, Chan, Y, Wong, HT, Chan, KY
World neurosurgery. 2020;:e597-e604
Abstract
OBJECTIVE Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH. METHODS This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction. RESULTS In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 μmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 μmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed. CONCLUSIONS Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.
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10.
Intravenous sodium valproate for acute migraine in the emergency department: A meta-analysis.
Wang, F, Zhang, H, Wang, L, Cao, Y, He, Q
Acta neurologica Scandinavica. 2020;(6):521-530
Abstract
The role of intravenous sodium valproate (iVPA) in acute migraine attack has not been completely established. The aim of this updated review was to evaluate the efficacy and safety of iVPA in patients with acute migraine in the emergency department. We searched the PubMed, Web of Science, and Cochrane Library databases for relevant randomized controlled trials (RCTs). The primary outcome was improvement of headache intensity and headache relief. The need for rescue therapy, recurrence of headache, and number of adverse events was also assessed. Seven double-blinded RCTs involving 682 patients were analyzed. Overall, patients receiving iVPA had less improvement of headache intensity (SMD: -0.39, 95% CI: -0.73 to -0.06, P = .02) and lower rate of headache relief (OR: 0.51, 95% CI: 0.33 to 0.77, P = .002) than those receiving other active comparators. In addition, iVPA increased the odds of rescue therapy compared with other active drugs (OR: 3.76; 95% CI: 1.96 to 7.20, P < .0001). Subgroup analysis showed that iVPA was comparable to dexamethasone, with similar improvement of headache intensity, and recurrence of headache. For migraine without aura, we found no significant difference in headache intensity improvement when iVPA was compared with active comparators (SMD: -0.00, 95% CI: -0.54 to 0.54, P = 1.00). iVPA was inferior to the studied comparators and was comparable to dexamethasone for aborting migraine attack. Based on the available evidence, iVPA may be a reasonable alternative or salvage therapy. In particular, iVPA might be a promising agent for migraine with aura and migraine status.