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Annals of Translational Medicine May 2021Valproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that gene...
BACKGROUND
Valproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that gene polymorphisms are associated with interindividual variability of VPA metabolism, the results are debatable. Therefore, in the present study, we conducted a meta-analysis to evaluate the correlation between gene polymorphisms and adjusted plasma VPA concentration.
METHODS
The EMBASE, MEDLINE, and Cochrane Library databases were searched to obtain relevant studies. Eligible articles were reviewed, and data extraction was performed. We calculated 95% confidence intervals (CIs) and mean differences (MDs) to assess the strength of the relationship of gene polymorphisms with adjusted plasma VPA concentration.
RESULTS
The meta-analysis included 6 studies involving 847 patients with epilepsy. The pooled analysis showed that the A1075C (AA AC) polymorphism was related to the adjusted plasma concentration of VPA (P=0.02, I= 82%). Additionally, the AC phenotype statistically significantly increased the adjusted plasma VPA concentration in children compared with the mixed age subgroup (P=0.04, I= 48%). A similar association was observed between the AC phenotype for Asians (P<0.00001, I=0%) but not for Caucasians (P=0.34, I=87%).
DISCUSSION
Age might be a crucial covariate influencing the dosage-adjusted VPA concentration in patients with epilepsy. A reduced VPA dosage may be recommendable for children, particularly Asian children, who are A1075C AC carriers. Further studies could provide high-quality evidence to confirm the correlation between VPA pharmacokinetics and A1075C polymorphisms.
PubMed: 34164480
DOI: 10.21037/atm-21-1459 -
Seizure Mar 2016Warnings of L-carnitine induced seizures are recorded on product monographs and pharmacy databases, without any referenced literature. This medication can potentially... (Review)
Review
OBJECTIVE
Warnings of L-carnitine induced seizures are recorded on product monographs and pharmacy databases, without any referenced literature. This medication can potentially improve the hospital course in those patients with valproic acid (VPA) induced hyperammonemic encephalopathy, but may be withheld because of this warning. The goal was to perform an extensive systematic review of the literature to document the incidence of levocarnitine (L-carnitine) induced seizures in those patients on VPA therapy.
METHODS
Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to June 2015), and reference lists of relevant articles were searched. The strength of evidence was to be adjudicated using both the Oxford and GRADE methodology by two independent reviewers.
RESULTS
We failed to identify a single study implicating L-carnitine supplementation leading to seizures in any patient on VPA therapy. This contradicts all quoted, but unsubstantiated, concerns on product monographs and pharmacy databases related to seizure induction/propagation with L-carnitine supplementation.
CONCLUSION
There is no literature available to support claims of L-carnitine induced seizures during supplementation in patients on VPA therapy for seizures. This contradicts quoted, but not referenced, concerns on the product monograph. In patients suffering from hypocarnitinemia or hyperammonemic encephalopathy while on VPA, L-carnitine supplementation can be considered knowing there is no data to support seizure propagation or induction with administration of this supplement.
Topics: Anticonvulsants; Carnitine; Databases, Factual; Humans; Seizures; Valproic Acid
PubMed: 26889779
DOI: 10.1016/j.seizure.2016.01.020 -
European Journal of Clinical... Aug 2020Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However,... (Meta-Analysis)
Meta-Analysis
PURPOSE
Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA.
METHODS
The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6).
RESULTS
In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01).
CONCLUSION
This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.
Topics: Anticonvulsants; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2C9; Epilepsy; Humans; Valproic Acid
PubMed: 32385545
DOI: 10.1007/s00228-020-02872-6 -
CNS Drugs Sep 2023Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories.... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories. However, in contrast to ordinary migraine, vestibular migraine patients have distinct characteristics, and the detailed treatment strategy for vestibular migraine is different and more challenging than ordinary migraine treatment. Currently, there is no conclusive evidence regarding its management, including vestibular migraine prophylaxis.
AIM
The objective of this current network meta-analysis (NMA) was to compare the efficacy and acceptability of individual treatment strategies in patients with vestibular migraine.
METHODS
The PubMed, Embase, ScienceDirect, ProQuest, Web of Science, ClinicalKey, Cochrane Central, and ClinicalTrials.gov databases were systematically searched for randomized controlled trials (RCTs), with a final literature search date of 30 December 2022. Patients diagnosed with vestibular migraine were included. The PICO of the current study included (1) patients with vestibular migraine; (2) intervention: any active pharmacologic or non-pharmacologic intervention; (3) comparator: placebo-control, active control, or waiting list; and (4) outcome: changes in migraine frequency or severity. This NMA of RCTs of vestibular migraine treatment was conducted using a frequentist model. We arranged inconsistency and similarity tests to re-examine the assumption of NMA, and also conducted a subgroup analysis focusing on RCTs of pharmacological treatment for vestibular migraine management. The primary outcome was changes in the frequency of vestibular migraines, while the secondary outcomes were changes in vestibular migraine severity and acceptability. Acceptability was set as the dropout rate, which was defined as the participant leaving the study before the end of the trial for any reason. Two authors independently evaluated the risk of bias for each domain using the Cochrane risk-of-bias tool.
RESULTS
Seven randomized controlled trials (N = 828, mean age 37.6 years, 78.4% female) and seven active regimens were included. We determined that only valproic acid (standardized mean difference [SMD] -1.61, 95% confidence interval [CI] -2.69, -0.54), propranolol (SMD -1.36, 95% CI -2.55, -0.17), and venlafaxine (SMD -1.25, 95% CI -2.32, -0.18) were significantly associated with better improvement in vestibular migraine frequency than the placebo/control groups. Furthermore, among all the investigated pharmacologic/non-pharmacologic treatments, valproic acid yielded the greatest decrease in vestibular migraine frequency among all the interventions. In addition, most pharmacologic/non-pharmacologic treatments were associated with similar acceptability (i.e. dropout rate) as those of the placebo/control groups.
CONCLUSIONS
The current study provides evidence that only valproic acid, propranolol, and venlafaxine might be associated with beneficial efficacy in vestibular migraine treatment.
TRIAL REGISTRATION
CRD42023388343.
Topics: Adult; Female; Humans; Male; Migraine Disorders; Network Meta-Analysis; Propranolol; Valproic Acid; Venlafaxine Hydrochloride
PubMed: 37676473
DOI: 10.1007/s40263-023-01037-0 -
The Cochrane Database of Systematic... 2001Although lithium has been the most commonly used maintenance treatment in bipolar disorder for several decades, valproate is being used increasingly - especially in the... (Review)
Review
BACKGROUND
Although lithium has been the most commonly used maintenance treatment in bipolar disorder for several decades, valproate is being used increasingly - especially in the United States of America. There is a need to clarify whether the increasingly prominent prophylactic role of valproate in bipolar disorder is justified.
OBJECTIVES
To review the effectiveness of valproate, relative to placebo, other mood stabilisers and antipsychotics, in the prevention and/or attenuation of acute episodes of bipolar disorder. The effectiveness of valproate was considered in terms of mood symptoms, mortality, general health, social functioning, adverse effects and overall acceptability to patients.
SEARCH STRATEGY
The CCDAN group search strategy was used. The following databases were searched: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Controlled Clinical Trials Register (CCCTR), EMBASE, MEDLINE, LILACS, PsycLIT and Psyndex. Reference lists of relevant papers and major textbooks of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials.
SELECTION CRITERIA
Randomised controlled trials which compared valproate with placebo, alternative mood stabilisers (including lithium and carbamazepine) or neuroleptics, where the stated intent of intervention was the maintenance treatment of bipolar disorder. Participants were males and females of all ages with a diagnosis of bipolar disorder however diagnosed, approximating to ICD 10 Code F31 and DSM IV 296, but including patients diagnosed as ICD-9 manic depressive psychosis and DSM-III and DSM-IIIR bipolar disorder.
DATA COLLECTION AND ANALYSIS
Data were extracted from the original reports individually by two reviewers. The main outcomes to be assessed were: 1. The effectiveness of valproate treatment in preventing or attenuating further episodes of bipolar disorder, including its effectiveness in rapid cycling disorder. 2. The acceptability of valproate treatment to patients. 3. The prevalence of side-effects. 4. Mortality on valproate treatment. Outcomes concerning relapse/recurrence were analysed excluding data from discontinuation studies, which were to be analysed separately. Sub-group analyses were to be performed to examine the effects of valproate treatment in rapid cycling bipolar disorder and previous mood stabiliser non-responders. Data were analysed using Review Manager version 4.1.
MAIN RESULTS
One trial of 12 months duration with 372 participants was identified comparing lithium, divalproex and placebo. It had several methodological limitations. The primary analysis of time to occurrence of mood episode described in the main trial report found no reliable difference between the treatments, although there was a trend for divalproex to be more effective than lithium. In the analysis in this review, patients taking divalproex who left the study because of the occurrence of an mood episode were significantly less in number than those on placebo (RRR 37%; RR 0.63; 95% CI 0.44 to 0.90). There was no significant difference in the numbers of patients in receipt of divalproex compared with those in receipt of lithium who left the study because they suffered any mood episode. (RRR 22%; RR 0.78; 95% C.I. 0.52 to 1.17). There was insufficient information to allow sub-group analyses of rapid-cycling disorder. The divalproex group had significantly more patients suffering tremor (RRI 223%; RR 3.23; 95% C.I. 1.85 to 5.62), weight gain (RRI 187%; RR 2.87; 95% C.I. 1.34 to 6.17) and alopecia (RRI 143%; RR 2.43; 95% C.I. 1.05 to 5.65) than the placebo group. In comparison with the lithium, divalproex was associated with more frequent sedation (RRI 58%; RR 1.58; 95% C.I. 1.08 to 2.32) and infection (RRI 107%; RR 2.07; 95% C.I. 1.16 to 3.68), but less suffered thirst (RRR 62%; RR 0.38; 95% C.I. 0.18 to 0.81) and polyuria (RRR 57%; RR 0.43; 95% C.I. 0.22 to 0.82).
REVIEWER'S CONCLUSIONS
In view of the equivocal findings of this review, conclusions about the efficacy and acceptability of valproate compared to placebo and lithium cannot be made with any degree of confidence. With current evidence, patients and clinicians would probably wish to use lithium before valproate for maintenance treatment. At present, the observed shift of prescribing practice to valproate is not based on reliable evidence of efficacy
Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium; Randomized Controlled Trials as Topic; Valproic Acid
PubMed: 11687047
DOI: 10.1002/14651858.CD003196 -
Clinical Neurology and Neurosurgery Nov 2018Glioblastoma (GBM) can often present with seizure. Attempts have been made to associate the use of anti-epileptic medication valproic acid (VPA) in standard of care... (Meta-Analysis)
Meta-Analysis
Glioblastoma (GBM) can often present with seizure. Attempts have been made to associate the use of anti-epileptic medication valproic acid (VPA) in standard of care management with survival benefit in the past; however, results to date have been conflicting, and most likely subjected to historical bias. This study aimed to quantify the overall survival (OS) effect of VPA in patients with GBM based on the current literature, and identify potential trend-modifying covariates. Searches of 7 electronic databases from inception to April 2018 were conducted following the appropriate guidelines. Hazard ratios (HRs) derived from Cox proportional hazard models, and mean differences (MDs), were analyzed using the random effects model. Meta-regression was used to identify potential trend-modifying covariates. Seven retrospective cohort studies satisfied selection criteria describing 2181 primary GBM diagnoses, with 534 (24%) receiving VPA in their treatment. Overall, VPA was shown to confer a statistically significant OS advantage (HR, 0.71; 95% CI, 0.56-0.91; p < 0.01) compared to the control group by up to 2.4 months (95% CI, 1.51-3.21; p < 0.01). However, upon meta-regression, this survival advantage as inferred by HRs trended towards the null in newer studies (slope, 1.15; p = 0.02) or in studies with older participants (slope, 1.13; p = 0.02). A similar result was seen with MDs. Based on the literature to date, VPA was significantly associated with better OS in GBM patients by 2.4 months when managed by current standard of care. However, this effect was particularly emphasized among older studies or studies conducted in younger participants indicating the need to exercise caution in assuming generalizability of the pooled effect. Overall, there is considerable bias risks in the current interpretation of the literature, and larger, prospective studies are required for validating our findings.
Topics: Anticonvulsants; Brain Neoplasms; Cohort Studies; Glioblastoma; Humans; Retrospective Studies; Survival Rate; Valproic Acid
PubMed: 30243186
DOI: 10.1016/j.clineuro.2018.09.019 -
Frontiers in Medicine 2018Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum...
Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum disorders. With increasing administration, reports of intoxications are more frequently reported. The most common findings of VPA intoxication are central nervous system depression, respiratory depression, hypotension, metabolic acidosis, and elevated lactate, among others. We describe a case report of VPA intoxication with hemodiafiltration (HDF) as extracorporeal treatment (ECTR) for removal of VPA. This treatment modality has only rarely been reported in the current literature. In addition, we performed an updated systematic literature review (SLR) of additional cases on the topic ranging from December 1st, 2014 to April 20th, 2018. We searched MEDLINE and Web of Science for relevant references. In the presented case, VPA intoxication occurred in a 46-year-old female patient after oral ingestion of 56 g of VPA. In addition to vasopressors and endotracheal intubation, we administered L-Carnitine (L-Car) and performed hemodiafiltration treatment. After intravenous therapy with L-Car and simultaneous HDF sessions, we observed full recovery without neurological sequelae. The SLR identified 8 additional articles reporting favorable outcomes with extracorporeal treatments in most cases. HDF and other extracorporeal procedures are safe and effective therapeutic options in patients with VPA intoxication. The choice of ECTR modality mainly depends on local experience and the setting. In the present case, ingestion of 56 g was successfully treated with HDF. These findings are in line with several other case reports describing positive outcomes. Extracorporeal treatment, including HDF, should be considered early in the management of VPA intoxication. Supporting evidence is emerging, but it is of limited quality.
PubMed: 30148132
DOI: 10.3389/fmed.2018.00224 -
CNS Drugs Nov 2017The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial. (Review)
Review
BACKGROUND
The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial.
OBJECTIVE
We investigated the need for annual laboratory follow-up of liver enzymes, electrolytes, and full blood count (FBC) in patients treated with VPA.
PATIENTS AND METHODS
A systematic search in Evidence-Based Medicine Reviews (EBMR), MEDLINE, and EMBASE was undertaken in December 2016 to identify all published articles investigating or citing valproic acid, liver function disorders, electrolyte disorders, and FBC deviations.
RESULTS
This review included 108 articles. As the number of participants and duration of the study was not adequate in most studies to detect rare adverse events, studies did not demonstrate a clear prevalence of hepatotoxicity. While a transient increase of transaminases is common and seldom harmful, severe hepatotoxicity is a rare phenomenon and is not prevented by routine laboratory monitoring. VPA had no relevant effect on serum calcium, sodium, potassium, and albumin. The prevalence of FBC varied from 0.6 to 27.8%, occurred mostly in the first 2 years of therapy, and was usually asymptomatic.
CONCLUSIONS
Long-term monitoring in VPA treatment is only necessary when there have been dose adjustments, co-medication switches, or co-morbidity. In uncomplicated cases, annual laboratory follow-up may be discontinued after 2 years of VPA treatment. Encouraging patients to be vigilant is more effective in the detection of hepatotoxicity than laboratory testing. Follow-up of FBC at 3-6 months, 1 year, and 2 years after start or after a dose increase of VPA or interacting medication is sufficient.
Topics: Anticonvulsants; Blood Cell Count; Clinical Enzyme Tests; Clinical Laboratory Techniques; Diagnostic Tests, Routine; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Time Factors; Valproic Acid
PubMed: 29214384
DOI: 10.1007/s40263-017-0479-z -
Brain and Behavior Jun 2023Sydenham's chorea (SC), prevalent in developing countries and occasionally affecting developed ones, poses a clinical challenge due to the lack of systematic guidelines... (Review)
Review
INTRODUCTION
Sydenham's chorea (SC), prevalent in developing countries and occasionally affecting developed ones, poses a clinical challenge due to the lack of systematic guidelines for diagnosis and treatment. Resulting from Group A Beta-Hemolytic Streptococcus infection, SC presents various symptoms. This review aims to collect and evaluate available data on SC management to propose a cohesive treatment plan.
METHODS
We searched PubMed, the Cochrane Library, Google Scholar, and ClinicalTrials.gov for literature on SC management from inception until 24th July 2022. Studies were screened by titles and abstracts. Cochrane Collaboration's Risk of Bias tool (RoB-1) assessed Randomized Controlled Trials, while the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool evaluated nonrandomized studies.
RESULTS
The review includes 11 articles assessing 579 patients. Excluding one study with 229 patients, of the remaining 550 patients, 338 (61.5%) were females. Treatments used were dopamine antagonists in 118 patients, antiepileptics in 198, corticosteroids in 134, IVIG in 7, and PE in 8 patients. Dopamine antagonists, particularly haloperidol, were the primary treatment choice, while valproic acid (VPA) was favored among antiepileptics. Prednisolone, a corticosteroid, showed promising results with weight gain as the only side-effect. Our review emphasizes the importance of immunomodulators in SC, contrasting previous literature.
CONCLUSION
Despite limitations, dopamine antagonists can serve as first-line agents in SC management, followed by antiepileptics. The role of immunomodulators warrants further investigation for conclusive recommendations.
Topics: Female; Humans; Male; Chorea; Anticonvulsants; Valproic Acid; Haloperidol; Dopamine Antagonists
PubMed: 37150977
DOI: 10.1002/brb3.3035 -
Clinical Biochemistry Oct 2013Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and... (Review)
Review
Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity.
Topics: Anticonvulsants; Antipsychotic Agents; Drug Hypersensitivity; Endocrine System; Epilepsy; Humans; Hyperammonemia; Liver; Mitochondria; Nervous System; Psychotic Disorders; Teratogenesis; Valproic Acid
PubMed: 23792104
DOI: 10.1016/j.clinbiochem.2013.06.012