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BMJ Clinical Evidence Feb 2012About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. (Review)
Review
INTRODUCTION
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant generalised epilepsy? What are the effects of surgery in people with drug-resistant generalised epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 8 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: monotherapy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs (lamotrigine or levetiracetam) for drug-resistant epilepsy; and hemispherectomy for drug-resistant epilepsy.
Topics: Anticonvulsants; Carbamazepine; Epilepsy; Epilepsy, Generalized; Humans; Incidence; Phenytoin; Remission Induction; Valproic Acid
PubMed: 22348419
DOI: No ID Found -
The American Journal of Hospice &... May 2022Antipsychotics and benzodiazepines do not improve delirium. Valproic acid (VPA) has been used recently to treat agitation in delirium.
CONTEXT
Antipsychotics and benzodiazepines do not improve delirium. Valproic acid (VPA) has been used recently to treat agitation in delirium.
OBJECTIVES
To review the evidence for VPA in the management of Delirium.
METHODS
Systematic review. English language, age 19 and above, from 1946 to January 12, 2021.
MESH TERMS
"Valproic acid", "valproate", "sodium valproate", "delirium", "acute mania with delirium" in PubMed and Ovid.
EXCLUSION
Studies of VPA used for diagnoses other than delirium.
RESULTS
21 abstracts were identified and 10 studies were included in the review (252 patients): One prospective open label study (n: 7), 2 case series (n: 22), 4 retrospective studies (n: 219) and 3 case reports (n: 4). No randomized controlled trial (RCT) evaluates the effect of VPA in delirium. 237/250 (94.8%) patients were in the ICU. Mean age was 59.7 (27-87). 153/204 (74%) were male. The mean starting dose was 733 mg/day in 148 patients and the mean dose at follow up was 1061 mg/day in 205 patients. CAM ICU was used to diagnose delirium in 6 reviews. Delirium improved in case series in 19/22 patients. Delirium improved in retrospective studies at day 3 compared to day 1. VPA levels were not consistently reported. Hyperammonemia (12-19%) and thrombocytopenia (9-13%) were the most common side effects. No deaths were attributed to VPA.
CONCLUSION
VPA is being used more frequently for delirium. The evidence is limited to retrospective studies and case series. There is a need for RCT to evaluate the effect of VPA in delirium compared to other alternatives and placebo.
Topics: Adult; Antipsychotic Agents; Benzodiazepines; Delirium; Humans; Male; Middle Aged; Psychomotor Agitation; Valproic Acid; Young Adult
PubMed: 34409869
DOI: 10.1177/10499091211038371 -
Seizure Nov 2014Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, and patients that undergo the maximum tumor resection that is safely possible and standard... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, and patients that undergo the maximum tumor resection that is safely possible and standard radiochemotherapy only achieve a median survival time of 14.6 months. Several clinical studies have reported that valproic acid could prolong survival of GBM patients. However, the results of these studies are inconsistent. We examined relevant studies and conducted a meta-analysis to assess the effects of VPA on survival times and recurrence.
METHODS
A bibliographic search was performed in the EMBASE, MEDLINE, ClinicalTrials.gov and Cochrane Central Register of the Controlled Trials databases to identify potentially relevant articles or conference abstracts that investigated the effects of VPA on the outcome of glioma patients. Five observational studies were included.
RESULTS
Pooled estimates of the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Our meta-analysis confirmed the benefit of using VPA (HR, 0.56; 95% CI, 0.44-0.71). Sub-group analysis shows that patients treated with VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59-0.94 vs. patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence interval of 0.52-0.84 vs. patients treated by administration of non-AEDs. No heterogeneity was observed in the subset analysis.
CONCLUSION
The results of our study suggest that glioblastoma patients may experience prolonged survival due to VPA administration. Sub-analysis confirmed the benefit of VPA use compared to a non-AEDs group and an other-AEDs group. Further RCTs of this subject should be performed.
Topics: Adult; Brain Neoplasms; Glioblastoma; Humans; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome; Valproic Acid
PubMed: 25066904
DOI: 10.1016/j.seizure.2014.06.015 -
Clinical Pharmacokinetics Oct 2022Current guidelines recommend therapeutic drug monitoring as a critical component of valproic acid (VPA) therapy. Due to high protein binding, the active unbound (free)...
BACKGROUND
Current guidelines recommend therapeutic drug monitoring as a critical component of valproic acid (VPA) therapy. Due to high protein binding, the active unbound (free) portion of VPA can be misrepresented by total VPA serum levels in certain clinical scenarios. Monitoring free VPA serum levels may be warranted when assessing the clinical response to VPA therapy.
OBJECTIVES
The aims were to conduct a systematic review to identify a therapeutic range for free VPA serum levels; to explore the correlation of free VPA serum levels with clinical toxicity and therapeutic benefit; and to examine predictors of discordance between free and total VPA levels.
METHODS
Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, BIOSIS Previews, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from the time of database inception to June 20, 2021. Randomized controlled trials and observational studies that evaluated any patient receiving VPA with free VPA level monitoring were included.
RESULTS
Of 189 citations, we identified 27 relevant studies, which included 14 observational studies, two case series, and 11 case reports. Three studies provided a therapeutic range for free VPA levels between 20 and 410 μmol/L. Two studies suggested the occurrence of hyperammonemia and thrombocytopenia at free VPA serum levels above 60 µmol/L and 103.3 µmol/L, respectively. Two studies suggested an upper limit for neurotoxicity at free VPA serum levels of 70 µmol/L and 207.9 µmol/L. Hypoalbuminemia was identified as a predictor of therapeutic discordance.
CONCLUSIONS
This review demonstrates a paucity of data informing the clinical utility of free VPA serum levels. Further high-quality trials are needed to validate an optimal therapeutic range for free VPA levels.
Topics: Anticonvulsants; Drug Monitoring; Humans; Hypoalbuminemia; Protein Binding; Valproic Acid
PubMed: 36040614
DOI: 10.1007/s40262-022-01171-w -
World Neurosurgery Feb 2024To systematically evaluate the efficacy of valproic acid (VPA) in rats with spinal cord injury (SCI) to reduce the risk of clinical conversion and provide a valuable... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To systematically evaluate the efficacy of valproic acid (VPA) in rats with spinal cord injury (SCI) to reduce the risk of clinical conversion and provide a valuable reference for future animal and clinical studies.
METHODS
We searched scientific databases, including PubMed, Ovid-Embase, Web of Science, and Scopus databases. The relevant literature was searched from the establishment date of the database to June 28, 2023. The search results were screened, data were extracted, and the quality of the literature was evaluated independently by 2 reviewers.
RESULTS
Among 656 nonduplicated references, 14 articles were included for meta-analysis. The summary results showed that the overall Basso, Beattie and Bresnahan scores of the VPA intervention group were significantly higher than those in the control group at 1-6 weeks after VPA intervention. Subgroup analysis showed that the injury model, administration dose, rat strain, country of study, or follow-up duration had no significant effect on the efficacy of VPA on rats with SCI. In addition, mesh analysis showed that high doses of the VPA group had a better effect on SCI rats, compared with the low dose group and the medium dose group.
CONCLUSIONS
To date, this is the first systematic evaluation of the potential effects of VPA on motor recovery in rats with SCI. We concluded that VPA can promote motor recovery in rats with SCI, and higher doses of VPA seem to be more effective in rats with SCI. However, the limited quality and sample of included studies reduced the application of this meta-analysis. In the future, more high-quality, direct comparative studies are needed to explore this issue in depth.
Topics: Rats; Animals; Valproic Acid; Spinal Cord Injuries; Spinal Cord; Recovery of Function; Disease Models, Animal
PubMed: 37923014
DOI: 10.1016/j.wneu.2023.10.135 -
BMJ Clinical Evidence Jun 2010About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. (Review)
Review
INTRODUCTION
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant generalised epilepsy? What are the effects of surgery in people with drug-resistant generalised epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found eight systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: monotherapy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs (lamotrigine or levetiracetam) for drug-resistant epilepsy; and hemispherectomy for drug-resistant epilepsy.
Topics: Anticonvulsants; Carbamazepine; Epilepsy; Epilepsy, Generalized; Humans; Incidence; Phenytoin; Remission Induction; Valproic Acid
PubMed: 21418687
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Oct 2015Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses... (Meta-Analysis)
Meta-Analysis Review
Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty-nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, the risks of VPA-associated CMs are 2-7-fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient.
Topics: Abnormalities, Drug-Induced; Anticonvulsants; Female; Humans; Maternal Exposure; Odds Ratio; Pregnancy; Risk Assessment; Risk Factors; Time Factors; Valproic Acid
PubMed: 26044279
DOI: 10.1002/cpt.158 -
Epileptic Disorders : International... Dec 2022We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants,...
We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.
Topics: Breast Feeding; Cannabidiol; Carbamazepine; Child; Clobazam; Clonazepam; Epilepsy; Ethosuximide; Everolimus; Felbamate; Female; Fenfluramine; Gabapentin; Humans; Infant; Lacosamide; Lamotrigine; Levetiracetam; Oxcarbazepine; Phenobarbital; Phenytoin; Prospective Studies; Tiagabine; Topiramate; Valproic Acid; Vigabatrin; Zonisamide
PubMed: 36193017
DOI: 10.1684/epd.2022.1492 -
British Journal of Clinical Pharmacology May 2018Population pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning...
AIMS
Population pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of valproic acid (VPA) and to identify factors influencing VPA pharmacokinetic variability.
METHODS
PubMed and Embase databases were systematically searched from inception to June, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of VPA conducted in humans and that employed a nonlinear mixed effect modelling approach were included in this review.
RESULTS
Twenty-six studies were included in this review. Most studies characterized VPA pharmacokinetics as a one-compartment model. Three studies reported a two-compartment model. Body weight, dose and age were significant predictors for VPA volume of distribution (V ). The estimated V for one-compartment models ranged from 8.4 to 23.3 l. For two-compartment models, peripheral volumes of distribution ranged from 4.08 to 42.1 l. Frequently reported significant predictors for VPA clearance (CL ) included body weight, VPA dose, concomitant medications, gender and age. The estimated CL ranged from 0.206 to 1.154 l h and the inter-individual variability ranged from 13.40 to 35.90%. Two studies reported population pharmacokinetics/pharmacodynamics of VPA in patients with epilepsy. Seventeen studies evaluated the performance of their final models.
CONCLUSIONS
Significant predictors influencing VPA pharmacokinetics as well as model methodologies are highlighted in this review. For clinical application, CL could be predicted using body weight, VPA dose, concomitant medications, gender or age. For future research, there is a knowledge gap regarding population pharmacokinetics/pharmacodynamics of VPA in a population other than epileptic patients.
Topics: Anticonvulsants; Humans; Models, Biological; Valproic Acid
PubMed: 29328514
DOI: 10.1111/bcp.13510 -
CNS & Neurological Disorders Drug... 2022Although Valproate (VPA) has several advantages in controlling seizures, it may cause serious hematological consequences. Hematotoxicity of VPA is particularly important...
PURPOSE
Although Valproate (VPA) has several advantages in controlling seizures, it may cause serious hematological consequences. Hematotoxicity of VPA is particularly important in pediatrics because patients at this age are at a growing risk of leukemia. For a conclusive agreement about the toxicity of VPA, in this study, we systematically reviewed the literature in which the hematological consequences of VPA had been emphasized.
METHODS
A systematic literature search was performed in June 2021 on electronic databases to find original research on the association between VPA therapy and hematotoxicity in pediatric patients. For this purpose, the following search terms "hematotoxicity", "valproic acid" and "pediatrics" with different spellings and similar terms, were searched in the title, keywords, and abstracts of articles. The data were collected and used for qualitative data description.
RESULTS
A total of 36 relevant articles with an overall 1381 study population were included. The results showed that VPA could cause severe hematotoxicity in children even at therapeutic doses. Neutropenia, thrombocytopenia, and bone marrow depression are the most common complications associated with VPA therapy. Also, findings showed that after discontinuation of VPA and starting other antiepileptic drugs or reducing the administered VPA dose, hematologic damages were entirely resolved, and all the hematological parameters improved during two weeks.
CONCLUSION
This review showed that VPA therapy could cause hematotoxicity in children; hence, it is recommended to monitor hematological indices during VPA therapy. Also, according to the suggested mechanistic pathways of VPA side effects, a combination of VPA with antioxidants may reduce hematological side effects.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Female; Hematologic Diseases; Humans; Infant; Male; Seizures; Valproic Acid; Young Adult
PubMed: 34382515
DOI: 10.2174/1871527320666210811162345