Conventional and controlled release valproate in children with epilepsy: a cross-over study comparing plasma levels and cognitive performances.

We studied plasma levels and behavioural effects of a newly developed controlled release formulation of valproate (VPA-CR) in children with epilepsy. Valproate plasma levels and performances in attention and vigilance tasks were monitored during a 12-h period (daytime), both during monotherapy of conventional valproate (VPA) and 4 weeks after switching to a similar dosage of VPA-CR taken once daily. There was no significant difference between the two formulations with respect to mean diurnal trough and peak valproate plasma levels, and to mean fluctuation. The significantly higher Cmax/Cmin ratio during VPA-CR seems mainly due to low valproate plasma levels early in the morning. Neuropsychological assessment showed no significant differences, either between patients and controls, or within patients and controls when comparing the results obtained on the VPA and VPA-CR day. During both VPA and VPA-CR treatment, no correlation was found between cognitive performance and valproate plasma levels. The advantage of VPA-CR is that the once daily regimen may increase compliance and is more convenient for schoolchildren.     

Altered monoamine metabolism in children with epilepsy

Tryptophan (Trp), 5-HTP, 5-HT, 5-HIAA, HVA, and MHPG in CSF and total Trp(T-Trp), free Trp(F-Trp) and serotonin in serum were determined in 80 children with epilepsy and also in a control group. It was found that Trp, 5-HT, 5-HIAA in CSF and F-Trp in blood decreased in children with epilepsy. But the decrease of F-Trp was not the main cause of decreased 5-HT metabolism, because the no positive correlations among the four substances were found. Each of them returned to normal levels after the treatment with phenytoin or valproate. 5-HT concentration was negatively correlated with the frequency of the epilepsy episodes. 5-HIAA and HVA levels were relatively higher in the epileptics with brain damage as with compared with those who had no brain damage. The MHPG level was higher in the patients simple partial seizures. Complex partial epileptics and those patients receiving antiepileptic drugs had a lower serum T-Trp level. T-Trp was negatively correlated with the serum valproate concentration. Both T-Trp and F-Trp levels decreased in the patients treated with phenytoin.     

Effectiveness, safety and practicality of delayed-release minitablets of valproate in bipolar affective disorders

Valproate has recently emerged as a drug of first choice in treating acute mania because of its efficacy and relative safety. It can be administered as an intravenous, oral non-sustained release or oral sustained release loading therapy. A new sustained release formulation of valproate consists of "mini-tablets" with the possible advantage of a less problematic and more reliable administration of the drug. We report on eleven patients with an acute manic exacerbation who were investigated for sufficient control of manic symptoms and the duration of building up and maintaining sufficient blood levels of valproate in once/d versus twice/d administration of valproate delayed release mini-tablets (VPA mrt.). Acute and prophylactic effectiveness in mania were rated with the Young-Mania Rating Scale (YMRS), respectively the Global Clinical Impression Scale for Bipolar Disorder (CGI-BP). RESULTS: Within a short period of time sufficient blood levels in both groups (once/d versus twice/d administration) were built up. Seven of eleven patients were responders according to a reduction of 50% of the YMRS. In respect of prophylactic treatment all of the ten patients showed satisfactory results and no re-exacerbation of manic symptoms or depression.     

Compliance and satisfaction with switching from an immediate-release to sustained-release formulation of valproate in people with epilepsy

OBJECTIVE: The goal of our work was to assess compliance and patient satisfaction with switching from sodium valproate to Depakine Chrono in patients with epilepsy. METHODS: Clinical, demographic, and behavioral details assessing compliance and satisfaction were collected using self-completion questionnaires at the time of inclusion in the study and 3 months after the inclusion day. RESULTS: Data were collected from 2031 respondents from eight European countries. There were significant differences between time 1 and time 2 of the study in seizure frequency, reported side effects, compliance, and patient satisfaction. CONCLUSION: Findings suggest that switching from sodium valproate to Depakine Chrono results in an increase in seizure-free rates, a reduction in reported side effects, an improvement in the level of compliance, and a modest improvement in patient satisfaction.     

Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania

OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (< =55.0 microg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 microg/ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 microg/ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 microg/ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 microg/ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 microg/ml.     

Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine

In patients with bipolar disorder, recent brain imaging studies have reported cingulate cortex volume change. We performed a volumetric magnetic resonance imaging (MRI) study to assess the subregions of the cingulate gyrus; left anterior cingulate (LAC), left posterior cingulate (LPC), right anterior cingulate (RAC), and right posterior cingulate (RPC). Our sample consisted of bipolar patients that are either unmedicated (n=10), on valproate monotherapy (n=10) or on valproate plus quetiapine (n=10) versus healthy comparisons (n=10). Thirty right-handed bipolar disordered patients were recruited. Of them, 10 were first-applying patients who never had taken any drug for this condition (medication-naive group), 10 were on valproate treatment (valproate group) and 10 were on valproate plus quetiapine treatment (valproate plus quetiapine group). Cingulate gyrus volumes included both cortex and white matter. Drug-free patients had significantly smaller LAC and LPC volumes compared with valproate and valproate plus quetiapine groups and healthy controls. In addition, in post hoc comparisons, a trend toward significant difference was found between valproate plus quetiapine group and valproate group in regard to only LAC. Our findings suggest that valproate and quetiapine may have neuroprotective effects.     

Expanded therapeutic range of valproate

Twenty-five pediatric patients with serum valproate levels above 100μg/ml (therapeutic range: 50–100μg/ml) are reviewed for nondose-related side effects and seizure control. The dose of valproate varied from 50–100 mg/kg/day. All patients had generalized or mixed seizure disorders which were difficult to control. Seizure frequency decreased by more than 50% in 14 patients. For those patients with improved control, valproate levels ranged from 111–196 μg/ml. Patients were carefully monitored for side effects; nondose-related side effects were not encountered. Random valproate levels were between 100–200 μg/ml. The clinical response to valproate can be augmented by increasing it to the maximum tolerated dose.     

Valproate sustained release in the treatment of epilepsy

In an observational study under routine clinical setting data after administration of once daily evening dosing of valproate sustained release minitablets were recorded in 359 patients with epilepsy aged between 12 and 86 years. Patients were either newly treated with valproate sustained release minitablets (N = 58) or switched from conventional valproate (N = 124) or from sustained release valproate (N = 138) to the once daily evening dosing. In 39 patients other antiepileptic drugs were replaced. At the end of the 7-week observational period most patients (65.4 %) received a daily dose of 10 to less than 18 mg/kg body weight followed by 17.4 % receiving doses in the therapeutically recommended range of 18 - 24 mg/kg. 8.6 % and 7.4 % of patients received more than 24 mg/kg or less than 10 mg/kg body weight, respectively. As expected, in both groups with valproate pre-treatment the mean morning valproate plasma levels increased by approximately 10 microg/ml after switch to once evening dosing with sustained release minitablets. The mean seizure frequency decreased from 2.1 to 0.5 in the 318 patients with data before the beginning and at the end of the investigation. At the final examination 137 patients (62.3 %) were seizure free, and further 60 patients (27.3 %) experienced a seizure reduction of more than 50 % (responder) of those 220 patients who experienced seizures in the last 7 weeks before the study. The efficacy and tolerability was rated in more than 95 % of the cases by the patient and the investigator as good or very good. The compliance/acceptance of the valproate sustained release minitablets was rated as good or very good in almost all patients. These results confirm the excellent benefit-risk ratio of the valproate sustained release minitablets and underline the importance of a simple compliance-improving dose regimen for effective seizure control.     

苯妥英钠和丙戊酸钠预防术后癫痫的对照研究

目的　对比苯妥英钠和丙戊酸钠预防术后癫痫的作用、毒副反应以及和血药浓度的关系。方法　采用随机前瞻对照性研究 ,选择幕上开颅手术病人 ,苯妥英纳组 72例 ,丙戊酸钠组 80例 ,术前术后分别规则服用苯妥英钠和丙戊酸钠 ,监测抗癫痫药物的血药浓度和术后癫痫及毒副反应发生情况。结果　两组共 15例术后发生早期癫痫 ,10例 (10 /15 )达到有效血浓度 ;其中 ,苯妥英钠组 6例 (8 3 % )发生早期癫痫 ,2例达到有效血浓度 ,丙戊酸钠组 9例 (11 3 % )发生早期癫痫 ,8例达到有效血浓度 ;远期癫痫发作 7例中丙戊酸钠组 5例 ,苯妥英钠组 2例。苯妥英钠组 11例 (15 3 % )及丙戊酸钠组2例 (2 5 % )出现了毒副反应。经χ2 检验 ,两组术后癫痫发生率无显著性差异 ,术后未发癫痫组和癫痫发作组间药物血浓度无显著性差异 (P >0 0 5 ) ,苯妥英钠组毒副反应发生率高于丙戊酸钠组。结论　苯妥英钠和丙戊酸钠预防控制术后癫痫无差别 ,苯妥英钠毒副反应较丙戊酸钠严重。     

丙戊酸钠对氯氮平血药浓度和疗效的影响

目的:探讨合用丙戊酸钠对氯氮平治疗精神分裂症时的血药浓度和疗效的影响。方法:将80例男性精神分裂症患者随机分为两组,单用组40例患者单服氯氮平,合用组40例患者同时服用氯氮平及丙戊酸钠,分别于治疗前、治疗1周和4周末测定氯氮平的血药浓度,同时评定阳性与阴性症状量表(PANSS)、治疗中出现的症状量表(TESS)。结果:合用组治疗1周和4周末有部分患者氯氮平血药浓度升高,部分患者降低,与基线期相比,治疗4周末有显著降低。结论:合用丙戊酸钠后氯氮平血药浓度治疗4周末显著降低;丙戊酸钠可以提高氯氮平对阳性症状的疗效。     

Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients.

IV valproate may be given to patients requiring rapid elevation of serum valproate or for patients unable to take oral medication. Previously we established the loading dose of IV valproate needed to achieve serum concentrations of > 100 ug/ml. This study evaluated the safety of rapid infusion of valproate to achieve high therapeutic levels. Twenty-four infusions of IV valproate were carried out electively in twenty-one patients with epilepsy (ages 2-54 years). The dose ranged from 21-28 mg/kg (mean 24.2 mg/kg). Target infusion rates were 3 or 6 mg/kg per min, yielding an infusion duration of 4.17 or 8.34 min. ECG was monitored; blood pressure was measured before and after infusion. Post infusion serum valproate concentrations were 64-204.1 ug/ml (mean 132.6). There were no significant changes in blood pressure and no ECG abnormalities observed. Transient pain occurred at the site of injection in five patients, associated with redness in two. This appeared to related to the concentration of valproic acid in the infusion fluid. We conclude that a loading dose of IV valproate can be administered safely and rapidly. This finding enables further studies evaluating IV valproate as a non-sedative anticonvulsant in the management of status epilepticus.     

Survival of children with malignant brain tumors receiving valproate: a retrospective study

Purpose

The treatment of pediatric patients with malignant brain tumors has evolved considerably in the past decades. However, results are still unsatisfactory for some patients. Valproate has been shown to positively affect the survival of adult glioblastoma patients. We have been giving prophylactic antiepileptic drugs to newly diagnosed children with brain tumors. Since then, we noted a trend towards a better survival from our patients. In order to study this, we performed a retrospective evaluation in our institution.

Methods

Standard survival analysis was used, calculating survival until death by all causes or censoring. Comparisons were made by Cox’s proportional hazards model regression.

Results

Between 2000 and 2010, 94 patients were treated (12 with high-grade gliomas, 56 medulloblastomas, and 26 ependymomas); median and mean ages were 7.7 and 7.8 years. Median follow-up was 60 months (35 for treated and 109 for untreated patients). Of these, 47 received valproate 10–15 mg/kg/day every 8–12 h and 47 did not. Patients who received valproate had a median survival of 34 months, whereas the other group had a median survival of 24 months (hazard ratios?=?0.99, 0.57–1.75, p?=?0.99).

Conclusions

These results do not prove that valproate prophylactic treatment in pediatric patients with malignant brain tumors had an influence on their survival. However, our cohort showed an effect of higher size than the recent European Organization for Research and Treatment of Cancer trial analysis, even though not significant. Clinical trials with valproate in pediatric malignant brain tumors should be carefully planned, in order to detect a possible effect of this drug in survival.     

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy

BACKGROUND: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. OBJECTIVE AND METHODS: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years. RESULTS: Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. CONCLUSIONS: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.     

Homeostatic effects of plasma valproate levels on corticospinal excitability changes induced by 1Hz rTMS in patients with juvenile myoclonic epilepsy.

OBJECTIVE: The preliminary results of noninvasive brain stimulation for epilepsy treatment have been encouraging, but mixed. Two important factors may contribute to this heterogeneity: the altered brain physiology of patients with epilepsy and the variable presence of antiepileptic drugs. Therefore, we aimed to study the effects of 1 Hz rTMS on corticospinal excitability in patients with juvenile myoclonic epilepsy (JME) in two different conditions: low- or high-plasma valproate levels. METHODS: Fifteen patients with JME and 12 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS was assessed in JME patients with low- and high-plasma valproate levels; and these results were compared with those in healthy subjects. RESULTS: In patients with chronic use of valproate and low-plasma concentrations, 1 Hz rTMS had a similar significant inhibitory effect on corticospinal excitability as in healthy subjects. However, in the same patients when the serum valproate concentration was high, 1 Hz rTMS increased the corticospinal excitability significantly. In addition, there was a significant positive correlation between plasma valproate levels and the motor threshold changes after 1 Hz rTMS. CONCLUSIONS: Our findings can be accounted for by mechanisms of homeostatic plasticity and illustrate the dependency of the modulatory effects of rTMS on the physiologic state of the targeted brain cortex. SIGNIFICANCE: The therapeutic use of rTMS in epilepsy should take into consideration the interaction between rTMS and drugs that change cortical excitability.     

An observational study of first-line valproate monotherapy in focal epilepsy

The objective of this multinational open-label, prospective study was to collect, under naturalistic conditions, data on the effectiveness and tolerability of first-line monotherapy with valproate in subjects newly or recently diagnosed with focal onset epilepsy. Patients were treated with sustained release sodium valproate. Seizure control and occurrence of adverse events were assessed after 6 months. Around 1192 adults and 792 children were included. The mean daily valproate dose was 683 mg in children and 987 mg in adults. The retention rate at 6 months was 90.0%. At this time, 77% of subjects were seizure free (83.7% of children and 72.7% of adults). Adverse events possibly related to treatment were observed in 10.2% of subjects, leading to treatment modification for 1.7%. The most common adverse events were weight gain, gastro-intestinal, neurological and skin disorders. Sustained release sodium valproate is effective and shows acceptable tolerability as first-line monotherapy in focal onset epilepsy.     

Urinary excretion of indican in progressive myoclonus epilepsy without Lafora bodies. The effect of sodium valproate.

Increased urinary excretion of indican was detected in earlier studies of patients with the form of progressive myoclonus epilepsy (PME) where no Lafora bodies are present in the brain and other tissues. Since then, all PME patients have been given sodium valproate and/or clonazepam. In a series of 10 patients now examined the mean excretion was on the same level as that of other epileptic and non-epileptic neurological patients (53 +/- 27 mg/g creatinine). Alternate reduction of the two drugs in one patient over a period of 24 days increased the excretion up to the high level measured earlier (96 mg/g creatinine) and caused marked worsening of the clinical condition while no remarkable changes were observed in another PME patient who received her normal medication. The highest values ever measured were found in one PME patient just before his death. In two patients who had no medication the excretion was also high but returned to the normal level during medication with sodium valproate. It is unknown at the moment whether this change is due to the improved clinical condition of the patients or to the compound itself.     

Effect of antiepileptic drug comedication on lamotrigine clearance

OBJECTIVE: To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL). DESIGN: We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication. RESULTS: Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. CONCLUSION: Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.     

丙戊酸钠对癫痫患儿血糖及血清胰岛素的影响

目的通过检测服用丙戊酸钠癫患儿血糖及血清胰岛素水平,观察丙戊酸钠对癫患儿血糖及血清胰岛素的影响。方法采用葡萄糖氧化酶法测定葡萄糖浓度,采用放射免疫分析法测定胰岛素浓度。结果丙戊酸钠治疗3个月、6个月时癫患儿的血清胰岛素、胰岛素抵抗指数较治疗前均明显增高(P<0.05),治疗3个月时和6个月时相比差异无统计学意义(P>0.05),但血糖无明显变化(P>0.05)。结论丙戊酸钠不引起癫患儿血糖明显变化,但血清胰岛素明显增加。     

Intravenous sodium valproate aborts migraine headaches rapidly

Shahien R, Saleh SA, Bowirrat A. Intravenous sodium valproate aborts migraine headaches rapidly.
Acta Neurol Scand: 2011: 123: 257–265.
© 2010 John Wiley & Sons A/S. Objectives – This preliminary study was designed to evaluate the efficacy and safety of intravenous sodium valproate in managing severe migraine headache. Design/methods – In a preliminary prospective open‐label study, we treated patients with severe migraine headache using intravenous sodium valproate, after obtaining written informed consent. Thirty‐six patients, hospitalized with acute established migraine, were infused with sodium valproate. The diagnosis of migraine was based on the International Headache Society classification criteria. Severity of headache was reported on 10‐point visual analog. Disability was assessed on a five‐point scale. Primary and secondary endpoints were measured as sustained pain relief and symptoms improvement at 2 h, respectively. Results  – The study participants had a mean ± SD age of 35.7 ± 9.3 years. The loading dose of sodium valproate was 900–1200 mg, and the average time to best response for headache severity was 50 min. A reduction in pain from severe or moderate to mild or no pain in 60 min was reported in 75% of patients [OR = 7.187 (95% confidence intervals: 1.32–38.95)]. After treatment with sodium valproate, headache severity was significantly decreased (P < 0.0001). No serious adverse events were reported. Conclusions – Intravenous Sodium Valproate (iVPA) seems to be safe and rapidly effective for intractable migraine attack. Randomized, double‐blinded, controlled studies are warranted.     

Concentration of valproate during pregnancy, in the newborn and in breast milk

The serum-valproate level of four patients with epilepsy was followed during pregnancy. A decrease in serum level occurred late in pregnancy and was followed by a pronounced increase in the first week after delivery. The maternal serum concentration of valproate was compared to that of the umbilical cord. The level in cord blood was 145-219% higher than that in maternal blood. The concentration of valproate in breast milk was found to be 5-10% of the maternal serum concentration. The serum concentration was measured in one breastfed child. The level was 7.6% of the maternal serum concentration. All children were healthy without any signs of intoxication or malformation. Based on our experience, pregnant patients treated with valproate must be carefully controlled especially during the last month of pregnancy and in the first two weeks after delivery. The amount of valproate excreted into the breast milk was negligible and should not prevent breast feeding.