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1.
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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2.
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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3.
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.
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4.
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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5.
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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6.
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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7.
Valproate decreases vitamin D levels in pediatric patients with epilepsy.
Xu, Z, Jing, X, Li, G, Sun, J, Guo, H, Hu, Y, Sun, F, Wen, X, Chen, F, Wang, T, et al
Seizure. 2019;:60-65
Abstract
PURPOSE To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls. METHODS A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed. RESULTS Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses. CONCLUSION This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient.
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8.
CPS1 T1405N polymorphism, HDL cholesterol, homocysteine and renal function are risk factors of VPA induced hyperammonemia among epilepsy patients.
Chen, L, Tian, Q, Zhang, M, Chen, D, Gao, X, Yang, H, Li, H, Li, C, Wen, J, Li, Y, et al
Epilepsy research. 2019;:139-143
Abstract
PURPOSE Valproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl-Phosphate Synthase 1 (CPS1) is an enzyme catalyzing the initial step of removing ammonia from blood. Studies have demonstrated that the CPS1 polymorphism rs1047891-A allele carriers were susceptible to VPA-induced HA. However, the evidences remained controversial. In this study, we sought to validate the association between rs1047891 and VPA-induced HA by combining the association results from previous studies together. METHODS We first conducted a systematic meta-analysis to determine whether rs1047891 was statistically significant. Then, we further evaluated the pleiotropic effects of rs1047891 using published genome-wide association studies (GWAS) and UKBB results. A conditional analysis was conducted to investigate whether the association between rs1047891 and VPA-induced HA was mediated by cardiovascular or renal disease risk factors or vice versa. RESULTS The allelic, dominant and recessive ORs of rs1047891-A were all significant in our fixed-effect meta-analysis. In GWAS catalog and UKBB data, rs1047891 was associated with basal metabolic rate, adiposity and hematology traits, cardiovascular and renal disease risk factors. We further proved that plasma HDL cholesterol and homocysteine level, in addition to eGFR by serum creatinine, were associated with VPA-induced HA risk independently from rs1047891 polymorphism. CONCLUSION In conclusion, the SNP rs1047891 was associated with VPA-induce HA among epilepsy patients. Meanwhile, plasma HDL cholesterol and homocysteine level had independent effects from it.
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9.
Effects of Second-Generation Antiepileptic Drugs Compared to First-Generation Antiepileptic Drugs on Bone Metabolism in Patients with Epilepsy: A Meta-Analysis.
Fu, J, Peng, L, Li, J, Tao, T, Chen, Y
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2019;(8):511-521
Abstract
We conducted this meta-analysis to evaluate effects of second-generation anti-epileptic drugs (AEDs; levetiracetam, lamotrigine) compared to first-generation AEDs (valproic acid, carbamazepine) on bone metabolism in epilepsy patients. PubMed, Web of Science, Clinical trials.gov, Wanfang, and China national knowledge infrastructure databases were searched. Ten trials were included. Results showed: (1) The overall SMD for changes of serum calcium, phosphorus, ALP, and PTH levels from baseline of LEV versus first-generation AEDs were 1.00 (95% CI=0.23-1.77, Z=2.56, p=0.01), 0.98 (95% CI=- 0.05 to 2.01, Z=1.86, p=0.06), - 1.17 (95% CI=- 2.08 to - 0.25, Z=2.50, p=0.01), 0.07 (95% CI=- 0.14 to 0.27, Z=0.63, p=0.53), respectively. (2) The overall SMD for changes of serum calcium, phosphorus, ALP, and PTH levels from baseline of LTG versus first-generation AEDs were -0.16 (95% CI=- 0.47 to 0.16, Z=0.99, p=0.32), -0.05 (95% CI=- 0.55 to 0.44, Z=0.22, p=0.83), 0.10 (95% CI=- 0.53 to 0.73, Z=0.31, p=0.75), -0.05 (95% CI=- 0.52 to 0.42, Z=0.22, p=0.83), respectively. Overall, our results indicate that compared to first-generation AEDs, LEV has less adverse effects on blood bone metabolism markers in epilepsy patients, while LTG does not. However, due to small number of included studies, our results warrant additional research.
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10.
Effects of valproic acid on bone mineral density and bone metabolism: A meta-analysis.
Fan, D, Miao, J, Fan, X, Wang, Q, Sun, M
Seizure. 2019;:56-63
Abstract
PURPOSE Numerous studies have shown that the risk of fracture is increased by long-term antiepileptic drugs (AEDs). Valproic acid (VPA) is one of the most commonly used AEDs. In this meta-analysis, we aimed to assess the effects of VPA on bone mineral density (BMD) and bone metabolism. METHODS PubMed, Embase, Cochrane and Web of Science databases were searched from inception to January 2019 for articles focusing on the effects of VPA on BMD and bone metabolism in adults or children. A meta-analysis was performed using RevMan 5. 3 software. RESULTS 18 studies were included in the meta-analysis. The BMD of lumber spine (MD= -0.06, 95%CI: -0.09 to -0.03, P < 0.0001) and femoral neck (MD= -0.05, 95% CI= -0.08 to -0.01, P = 0.02) was markedly decreased in the VPA group compared to healthy controls. Serum bone-specific alkaline phosphatase (BALP) level (SMD = 0.85, 95% CI: 0.30-1.40, P = 0.002) was notably increased in the VPA group compared to healthy groups. In the child group, the serum parathyroid hormone (PTH) level was higher than in healthy groups (SMD= -0.22, 95% CI: -0.40 to -0.04, P = 0.02); besides, the serum 25-hydroxy vitamin D3 (25(OH)D3) level was decreased (SMD= -0.22, 95% CI: -0.40 to -0.04, P = 0.02), while no significant alteration of these parameters was noted in the adult VPA group (P ≥ 0.05). CONCLUSIONS VPA may reduce the BMD of lumbar spine and femoral neck in patients with epilepsy while increasing the serum BALP level. Serum PTH level are increased and serum 25(OH)D3 level decreased in children with epilepsy treated with VPA. These parameters were unaltered in adults.