Valproate Intake Research Articles

Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.

Bilateral congenital cataract in a child with fetal valproate syndrome

Fetal valproate syndrome (FVS) results from valproate intake during pregnancy. Children with FVS may have various ocular abnormalities such as refractive error, amblyopia, and strabismus. Congenital pediatric cataract has been reported earlier in two cases. We describe a case of FVS, who presented to us with a bilateral total white cataract. The child underwent bilateral lens aspiration + posterior capsulorhexis + anterior vitrectomy + intraocular lens (IOL) implantation under general anesthesia followed by refraction.

The Impact of Levetiracetam and Valproate on Platelet Functions-A Double-Blind, Placebo-Controlled Crossover Study.

It is known that valproate inhibits platelet functions; however, the exact mechanisms are not clearly identified. We studied 12 healthy adult volunteers (1 female, 11 male; age range 31.7 ± 7.8 years) before and after valproate 500 mg and compared the results to levetiracetam 1000 mg as a control substance and placebo. The study had a crossover and double-blind design. A blood sample was taken before and 90 min after medication intake, because the times to maximum serum concentration (Tmax) are 1.5 h for levetiracetam and 1 to 3 h for valproate. We analysed changes in platelet, erythrocyte, and leukocyte cell count and in platelet functions (CD62 expression (P selectin), thrombin binding, and fibrinogen binding). We found no significant differences in all cell counts before and after different study drugs. After valproate intake, but not after placebo or levetiracetam intake, the fibrinogen binding significantly decreased and the CD62 expression significantly increased resulting in decreased platelet aggregation. Our data suggest that the platelet dysfunctions reported for valproate result from decreased fibrinogen binding and from increased CD62 expression. This phenomenon might be one reason for the increased bleeding risk under valproate and cannot be observed for levetiracetam.

Tremor and Movement Slowness Are Two Unrelated Adverse Effects Induced by Valproate Intake

To date, only a few clinical and neurophysiological studies have assessed the features of valproate-induced tremor (VIT), and whether valproate (VPA) affects voluntary movements is underinvestigated. To better characterize the clinical and neurophysiological features of VIT in patients with epilepsy and the effect of VPA on the execution of voluntary movement. We tested 29 patients with VIT (13 taking VPA alone and 16 taking VPA plus other antiepileptics). Patients underwent a neurological examination,video recordingsand kinematic assessments of postural, kinetic, and resting upper limb tremor using a motion analysis system. Movement execution was tested by kinematic assessment of finger tapping. Data of patients with VIT were compared with those of 13 patients with epilepsy taking VPA but without tremor, 13 patients with epilepsy who were not on VPA treatment, 20 patients with Parkinson's disease (PD), and 20 healthy controls (HCs). Clinical and kinematic evaluations showed that tremor in patients taking VPA alone was less severe than tremor in patients taking VPA plus other antiepileptics. All patients taking VPA, regardless of the presence of tremor, performed slower finger tapping compared with HCs, similar to what was observed in PD, although with no sequence effect. Patients with epilepsy without VPA showed a normal motor performance. Tremor and movement slowness are motor signs induced by VPA. VIT severity is exacerbated when VPA is taken in combination with other antiepileptics. VPA-induced slowness occurs regardless of tremor, may precede tremor development, and is not attributed to epilepsy.

Pregnancy after valproate withdrawal-Fetal malformations and seizure control.

To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy. Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases. Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR]0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant. Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.

Determining risk factors of developing adverse effects of antiepileptic drugs in epileptic patients

Adverse effects (AE) of antiepileptic drugs (AEDs) are common in daily neurological practice. Ensuring that an AE is attributable to an AE and predicting its occurrence remain a challenge. Our aim was to investigate the predictors of AE of AEDs in epileptic patients. We conducted a cross-sectional study at the department of Neurology at Razi hospital (Tunisia), from January 2016 to June 2016. All epileptic patients on AEDs for at least 6 months during the study period were screened for inclusion. Demographic, clinical characteristics, AED regimen and associated AE were recorded. Risk factors for developing AE were assessed. We included 54 epileptic patients with AEDs-related AE were included. Sex ratio was 1.34. Mean age was 36.5 years and mean disease duration was 19 years. About 46% were on monotherapy. Valproate (72%) and Cabamazepine (44%) were the most frequently prescribed AED regardless of regimen. Acute, dose-dependent reactions (neurologic (28.84%) and gastrointestinal symptoms (10.84%)) were the most common AE, followed by hematologic idiosyncratic reactions (14.43%). Increased duration of the disease (p = .014), high frequency of initial seizures (p = .001), patients with interictal EEG abnormalities (P = .005), polytherapy (p = .009), and those receiving carbamazepine (p = .007) and high doses of valproate intake (p = .023) were found to be at higher risk of experiencing AE. Both disease characteristics and AED patterns were found to be determinants in AE development. Clinicians should be aware of these factors when monitoring patients to minimize the risk and to improve compliance.

Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register

PurposeThis paper reports additional data supplementing earlier publications based on Australian Pregnancy Register (APR) data. MethodOver 20 years, the APR has collected Information on pregnancies in Australian women with epilepsy (WWE), untreated WWE and those taking AEDs for other indications. Contact is by telephone, at set intervals. Treatment is not interfered with. Data are analysed using conventional statistical techniques, confidence interval methods, and logistic regression. ResultsBy 2018, the APR contained details of 2148 pregnancies. AEDs were taken throughout 1972 of the pregnancies (91.8%). The remaining 176 (8.2%) did not receive AEDs, at least early in pregnancy.There were (i) dose-related increased incidences of pregnancies carrying foetal malformations associated with maternal intake of valproate and topiramate when topiramate was a component of AED polytherapy (P < .05), (ii) a similar dose-related trend in relation to carbamazepine intake, (iii) no evidence that levetiracetam and lamotrigine were unsafe from the foetal standpoint, (iv) insufficient data to permit conclusions regarding teratogenicity in relation to other AEDs, and (v) no evidence that pre-conception folate supplementation reduced the hazard of AED-associated foetal malformation. AED polytherapy did not increase foetal hazard unless valproate or topiramate was involved in the AED combination. Genetic factors probably contributed to the malformation hazard. Seizures occurring in earlier pregnancy probably did not contribute to the malformation hazard. ConclusionsIf it were not for the importance of maintaining seizure control, the above findings suggest that it would be better to avoid using certain AEDs, particularly valproate and topiramate, during pregnancy.

The cognitive phenotype of idiopathic generalized epilepsy

ObjectiveDysexecutive traits have been described in idiopathic generalized epilepsy (IGE), but studies mainly focused on juvenile myoclonic epilepsy (JME). To better understand the neuropsychology of IGE, more research is needed on syndromes other than JME, controlling potential confounding factors as the cognitive effects of valproate and epileptic discharges (ED). We describe the neuropsychological profile of a group of patients with different syndromes of IGE including simultaneous video electroencephalography (EEG). MethodsWe performed a comprehensive cognitive and neuropsychiatric evaluation with video-EEG on 61 adults with IGE (JME 19; IGE with generalized tonic–clonic seizures [GTCS] alone [IGE-GTCS] 22; childhood absence epilepsy [CAE] or juvenile absences epilepsy [JAE] persisting in adulthood 20). We compared results between patients (globally and by syndrome) and a control group of 21 individuals (similar age, educational level); p-values were adjusted for multiple testing according to a 0.05 false discovery rate. ResultsPatients obtained significantly lower results than controls on visuospatial working memory, processing speed, cognitive flexibility and strategy, abstract visuospatial reasoning, arithmetic, and acquired knowledge. While CAE/JAE showed the lowest scores on cognitive assessment and highest anxiety index, IGE-GTCS showed the most favorable scores. Most tests were not influenced by valproate intake, and the dose did not correlate with cognitive performance in the test that yielded differences between patients and controls. Epileptic discharges during assessment were not frequent (10 patients, 1–4 tests). SignificanceOur findings suggest that patients with IGE have significantly lower abilities in various executive functions and acquired knowledge, compared to population of same age and education. The low frequency of ED on simultaneous video-EEG and absence of correlation of scores with valproate dose reinforce that the obtained results are due to a cognitive phenotype in IGE. This phenotype may be influenced by syndrome, and patients with CAE/JAE persisting in the adult may have a wider neuropsychiatric impairment.

Valproate-associated foetal malformations-Rates of occurrence, risks in attempted avoidance.

To gain insight into the main advantages and disadvantages that might result from valproate being unavailable for women who intend to become pregnant. Analysis of data from the Australian Pregnancy Register concerning pregnancies exposed to valproate (N=501) and pregnancies where previous valproate intake had been ceased before pregnancy (N=101). The risk of foetal malformation associated with valproate exposure during pregnancy was dose-related, and there was a tendency for the more major malformations, including those often managed by therapeutic abortion, for example spina bifida, to occur at higher valproate doses. Had there been no exposure to valproate during pregnancy, some 80% of the foetal malformations that occurred might have been avoided. Cessation of previous valproate therapy before pregnancy was associated with an increased hazard of seizure-affected pregnancy. This was particularly the case for women with generalized epilepsies, in whom the incidence of seizure-affected pregnancy was increased by 50% to nearly 100%. Avoiding valproate intake during pregnancy is likely to reduce the incidence of foetal malformation, but at a cost of worsened maternal epilepsy control. Individualization of treatment is particularly important in considering withdrawal of valproate in the light of the fact that it is much more widely used in generalized epilepsy, there being fewer alternative drugs than for focal epilepsy and withdrawal is not without risk for both mother and baby. This study may provide a quantitative basis for assessing the balance between benefit and disadvantage for individual women with valproate-treated epilepsy who are considering pregnancy.

Polycystic Ovary Syndrome in Bipolar Affective Disorder: A Hospital-based Study.

Background:Preliminary studies suggest a multidimensional relationship of mood pathology with endocrine disturbances. Studies have found an increased risk of mood disorders in polycystic ovary syndrome (PCOS), and conversely, many of the medications commonly used in the treatment of bipolar affective disorder (BPAD) can have deleterious effects on blood levels of reproductive hormones and consequently on the hypothalamic–pituitary–gonadal (HPG) axis and reproductive function. Furthermore, there is evidence of reproductive dysfunction in women with BPAD before treatment.Objectives:To assess the comorbidity of PCOS in patients of BPAD and to study risk factors associated with this comorbidity.Materials and Methods:Two hundred female patients with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnosis of BPAD, between ages of 15 and 45 years, were evaluated by an endocrinologist. Patients reporting menstrual disturbances or having any stigmata of PCOS were further subjected to hormonal analysis, which included luteinizing hormone, follicle-stimulating hormone, prolactin, and testosterone, in the early follicular phase of menstrual cycle. Diagnosis of PCOS was made as per the NIH criteria.Results:Of 200 patients, 46 (23%) were diagnosed as having PCOS. Forty-five percent (n = 90) reported menstrual disturbances while 27% (n = 54) had polycystic ovaries on ultrasonography. 19.2% of the patients diagnosed as PCOS had a history of valproate intake while 27.90% patients had no such history (P = 0.15). No significant difference (P = 0.07) was found in the prevalence of PCOS among various drug groups (including group on multiple mood stabilizers).Conclusion:A higher prevalence of PCOS is seen in BPAD, irrespective of pharmacotherapy, suggesting a common link between the disorders which might be in the form of disturbance in HPG axis.

Acute generalized exanthematous pustulosis secondary to Valproate: An uncommon cutaneous reaction of a common drug

Objective: There are various adverse drug reaction (ADR) associated with pharmacological therapy that differ in clinical presentation, prognosis and therapy. Among these, cutaneous eruptions are the most common type of all ADRs.Theclinical presentation of cutaneous drug eruptions ranges from common transient and benign erythema to the most severe forms such as Steven-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN). Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous drug reaction accounting for 1–5 cases/1,000,000 per year. Antibiotics like β‑lactams and macrolides are the usual offending agents. Among anticonvulsants-carbamazepine, phenobarbital and phenytoin are commonly associated with AGEP. Sodium valproate is relatively free from cutaneous drug reaction. Thus, we hereby, report a rare case of AGEP in a 24 years old male, reaction following valproate intake used to control post traumatic seizure. Key words: Acute generalized exanthematous pustulosis, Valproate, Adverse drug reaction.

Hesperidin safeguards hepatocytes from valproate-induced liver dysfunction in Sprague-Dawley rats

Hesperidin (HDN), a polyphenolic flavonoid, had drawn attention due to its free radical scavenging and antioxidant activity. Valproate (VPA) is one of the routinely used antiepileptic drugs that has also been associated with hepatotoxicity and its metabolites, like 4-ene VPA and 2,4-diene. VPA are the main contributory compounds in inducing hepatic damage. As lifelong intake of valproate has been recommended, ameliorating its toxicity by administration of safe antioxidants might be beneficial in protecting the liver. The current experiment was designed to test the efficacy of hesperidin on counteracting valproate-induced hepatotoxicity. Male Sprague-Dawley rats were randomly assigned into four groups: Control, VPA, HDN+VPA and HDN. VPA (300mg/kg bwt/day) and HDN (100mg/kg bwt/day) were administered orally for 60 days. At the end of the experimental period, rats were sacrificed and liver was excised for biochemical, mRNA and protein analysis. The extent of hepatotoxicity was assessed by liver marker enzymes, oxidative stressors, antioxidant enzymes, mRNA and protein expression of apoptotic proteins. The efficacy of hesperidin was assessed by the ability to safeguard the liver and prevent apoptosis of the hepatocytes in valproate-treated rats. The activities of liver marker enzymes, macromolecular damage and gene expression of pro- and anti-apoptotic proteins were altered in valproate-treated rats when compared to control rats whereas hesperidin co-treated rats showed significant protection. Hesperidin protects the liver from valproate-induced toxicity by curtailing lipid peroxidation and preventing the cells from entering into apoptosis.

P01-235 - Lithium and valproate combination: Therapeutic strategies in a sample of patients with bipolar disorder

IntroductionLithium is the agent that has shown more efficacy for the treatment of Bipolar Disorder (BD), anyway a single agent isn’t effective to control all aspects of the syndrome.The mood-stabilizer frequently used, in combination with Lithium, is Valproate which presents different methabolism and side effects. Further both molecules are glycogen synthase kinase-3 (GSK-3b) inhibitors and have synergistic neuroprotective action.ObjectivesWe underline the need to better investigate Lithium and Valproate combination therapy in BD.AimsObservation of Lithium and Valproate combination therapy in a sample of patients with BD, considering doses and serum levels.Methods56 patients with BD (mean age 38 ± 0,02), followed at the day hospital of the Psychiatric Clinic, University of Pisa, were studied. Serum levels evaluated at the Section of Pharmacology, Department of Neuroscience, University of Pisa.ResultsWe identified 5 comparison groups depending on the dose intake of Lithium (11 subjects: 300 mg /die, 9: 450 mg/die, 19: 600 mg/die, 7: 750 mg/die, 10: 900 mg/die) with increased serum levels of the medication (0.27 mEq/l, 0.37 mEq/l, 0.50 mEq/l, 0.52 mEq/l, 0,70 mEq/l). There are not significant differences between groups related to both, the mean dose intake of Valproate (772 mg/die, 744.4 mg/die, 867.5 mg/die, 821.4 mg/die, 845 mg/die) and its serum levels (45.2 mg/L, 46.6 mg/L, 53.2 mg/L, 47.4 mg/L, 48.4 mg/L).ConclusionsThis study aims to identify the effective dose of Lithium in combination with Valproate able to determine the prevention of relapse in BD patients. The use of the lower dose of Lithium maintaining therapeutic effectivness, means reducing side effects, toxicity and the need for constant monitoring.

Letters to the Editor

11 December 2008 Dear Editor, UNILATERAL LUNG AGENESIS: COINCIDENCE OR ASSOCIATION WITH MATERNAL VALPROATE THERAPY? Management of epilepsy in pregnant women is a complex issue as use of antiepileptic medications increase the risk of congenital malformation in the foetus.1 The antiepileptic drug, sodium valproate, is a known teratogen with a constellation of recognised facial features and congenital malformations described in foetal valproate syndrome.2 Infants of mothers receiving valproate more than 1000 mg are at increased risk of congenital malformation, particularly neural tube defects.1 Exposure of foetus to valproate uncommonly results in pulmonary anomalies. Bilateral pulmonary hypoplasia with immature histology was reported in a series of three cases as a possible teratogenic effect of valproate.3 Other reported but rare pulmonary malformations in foetal valproate syndrome include tracheomalacia, abnormal lobulation of right lung, severe laryngeal hypoplasia and oligaemic right lung.4 Association of unilateral lung hypoplasia with maternal exposure to a combination of phenytoin and carbamazepine has been reported.1 A male infant was born at 38 weeks gestation with a birth weight of 2915 grams. The mother was a 32-year-old multiparous lady. During pregnancy, she continued to take sodium valproate, 1000 mg/day, to control grand mal epilepsy. This pregnancy was complicated by the detection of a possible left congenital diaphragmatic hernia on antenatal ultrasound at 18 weeks gestation. An amniocentesis performed at 19 weeks gestation demonstrated a normal male karyotpye. A foetal magnetic resonance imaging scan performed at 21 weeks gestation suggested hypoplasia of the left lung with a normal diaphragm. The infant delivered normally with Apgar scores of 6 and 6 at 1 and 5 min, respectively. There were no dysmorphic features of foetal valproate syndrome. He was managed in a neonatal intensive care unit with continuous positive airway pressure (CPAP) and received a single dose of surfactant. He was treated with phenobarbitone to manage symptoms of valproate withdrawal at approximately 24 h of age. Chest X-rays demonstrated dense opacification with loss of lung volume in the left hemithorax. The computed tomography scan showed absence of lung, bronchial tree, pulmonary artery and veins on the left side (Fig. 1). Echocardiogram showed a structurally normal heart with absence of the left pulmonary artery and left pulmonary veins. He was treated with nasal mask CPAP support for 7 weeks and was weaned successfully to room air at the age of 8 weeks. A polysomnography study showed no oxygen desaturation or hypercapnia while ventilating in room air. He was discharged home with paediatric respiratory follow-up. Computed tomography scan of chest showing absence of carina and left lung. Pulmonary agenesis is complete absence of carina, bronchial tree and lung tissue, and the trachea continues as main bronchus. In pulmonary aplasia, carina and rudimentary main bronchus are present, but lung tissue is absent.5 Pulmonary agenesis is a rare malformation. The prevalence of agenesis of lung was reported to be 0.0034% among hospital admissions.6 The aetiology of lung agenesis is not certain, but possible genetic predisposition has been described.6 Our literature review did not find any other case of unilateral lung agenesis in association with maternal valproate intake. Given the rarity of pulmonary agenesis, it is possible that the foetal exposure to valproate in this report is a chance association. However, this observation will add to previously known pulmonary pathologies seen in association with maternal valproate use and could be relevant from a prenatal counselling point of view.

Management of epilepsy in pregnancy

Pregnancies in women with epilepsy need careful management, by both the medical and obstetric teams, owing to the increased incidence of complications and adverse outcomes of pregnancy. By the time a pregnant woman with epilepsy presents, the major fetal organs are significantly formed, apart from the brain, and the development of which may be impaired by the maternal intake of valproate. Women of child-bearing age need to be counseled and told to seek advice regarding their anticonvulsant antiepileptic drug (AED) therapy, should they wish to become pregnant. All major AEDs are teratogenic, but the main risk to the developing fetus appears to be when the mother is on polytherapy, especially if sodium valproate forms part of the combination. Other issues that need to be discussed include the methods and consequences of prenatal screening, genetics of seizure disorder, folic acid and vitamin K supplements, labor, breast feeding and care and safety of the child.

Apparent autoinduction of valproate beta-oxidation in humans.

The study aimed to show whether autoinduction of valproate (VPA) along its beta-oxidation pathway occurred upon chronic dosing in humans. Twelve young volunteers without active illness took sodium valproate (NaVPA) 200 mg orally 12 hourly for 3 weeks. On days 7 and 21, serial blood samples and all urine passed over an interdosing interval from 08.00 to 20.00 h were collected for analysis of VPA and certain metabolites. Plasma AUC(0,12 h) of VPA was significantly lower on day 21 than on day 7 (2.40 vs 2.84 micromol ml-1 h, 95% CI for the difference 0.13-0.81 micromol ml-1 h). Significant differences in plasma AUC(0,12 h) of the beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA were not found. However, formation clearances of plasma VPA to urinary E-2-en-VPA and 3-oxo-VPA were significantly increased from day 7 to day 21 (0. 010 vs 0.024 and 2.57 vs 3.60 ml kg-1 h-1, respectively, 95% CI for the differences -0.025 to -0.004 and -1.72 to -0.34 ml kg-1 h-1, respectively). Formation clearances to VPA-glucuronide (0.534 vs 0. 505 ml kg-1 h-1) and 4-OH-VPA (0.112 vs 0.110 ml kg-1 h-1) were not significantly different. Regular low dose VPA intake in humans over a period of 3 weeks appears to be associated with a small induction of its metabolism by the beta-oxidation pathway, but not by glucuronidation or 4-hydroxylation.

Low CSF GABA concentration in children with febrile convulsions, untreated epilepsy, and meningitis.

In 14 children with epilepsy, 51 with febrile convulsions and 22 with meningitis gamma-aminobutyric acid (GABA) concentrations in lumbar CSF were determined. While the mean for CSF GABA concentrations for all epileptic children was unchanged [144 (range: 73-285) pmol/ml; controls: 148 (range: 90-243) pmol/ml] extraordinarily high GABA levels were found in the CSF of two children on valproate (525 and 557 pmol/ml) and remarkably low GABA concentrations in hitherto untreated epileptic children [109 (range: 67-176) pmol/ml]. Children with febrile convulsions [103 (range: 63-170) pmol/ml] and acute meningitis [105 (range: 65-171) pmol/ml] had significantly decreased CSF GABA concentrations (P less than 0.001 and P less than 0.02 compared with controls). The data indicate that valproate intake increases dramatically the GABA concentrations in the CSF of epileptic children. Furthermore, the study supports the concept that low GABAergic activity within the CNS may be one cause for an increased seizure frequency.

Factors Influencing Simultaneous Concentrations of Carbamazepine and Its Epoxide in Plasma

Simultaneous steady-state plasma concentrations of carbamazepine and carbamazepine-10, 11-epoxide were measured by high performance liquid chromatography in 295 patients. Plasma carbamazepine epoxide correlated more closely with carbamazepine dose than did plasma levels of the drug itself. Plasma carbamazepine epoxide levels tended to the higher, relative to drug dose, in children than in adults, whereas age did not seem to influence the relationship between plasma carbamazepine level and drug dose. Simultaneous phenytoin intake lowered the plasma carbamazepine levels relative to drug dose but left plasma carbamazepine epoxide levels largely unaltered. However, simultaneous valproate intake was associated with raised plasma carbamazepine epoxide levels relative to carbamazepine dose, whereas plasma carbamazepine epoxide levels were unaltered. The amount of conversion of carbamazepine to its epoxide thus appears to vary in different circumstances in human.