Well-tolerated Antiepileptic Drug Research Articles

Neutropenia induced by Valproic Acid: A case report

IntroductionValproic acid (VPA) is considered a well-tolerated antiepileptic drug used in Bipolar Disorder as a mood stabilizer. Nevertheless, VPA has been related to several adverse effects. Neutropenia is included as a potential adverse effect, although in clinical practice it is not often measured with regularity.ObjectivesTo report a case of a patient with Bipolar Disorder type 2 and Personality Disorder Cluster B treated with VPA with a neutropenia caused by VPA.MethodsA 61-year-old woman assists to the outpatient psychiatric unit in order to a pharmacological treatment adjustment. A blood test is performed showing a decrease in the levels of neutrophiles in comparison with previous tests. Psychiatric history is revised finding and association between the prescription of VPA and the reduction of neutrophile levels. When this drug was removed, neutrophile levels had increased again up to normal levels.ResultsDue to the relationship between neutropenia and VPA treatment, we decided to discontinue this drug. At the beginning the patient doesn’t agree with the withdrawal of VPA treatment due to its effectiveness in her mood stabilization. Psychoeducation sessions are performed in order to explain risk and benefits of potentials treatment alternatives versus maintaining the same prescription. Finally the patient accepts the switch of the mood stabilizer treatment to oxcarbazepine with a good tolerability and effectiveness.ConclusionsPeriodical blood test monitoring is needed in order to study adverse effects as neutropenia in patients with VPA treatment.DisclosureThe author has received support from Janssen-Cilag, Otsuka-Lundbeck, Italfármaco, Angelini Pharma and Casen Recordati; and declares no support related to the subject of this article.

The long-term efficacy of cannabidiol in the treatment of refractory epilepsy.

Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access program (EAP). Most studies report efficacy over short time periods (<1year), with little published on longer term efficacy. Here, we investigate the efficacy of CBD for a treatment period of up to 60months (median = 45.5months). We conducted a retrospective review of patient-reported seizure logs and medical records for 54 subjects with refractory epilepsy who enrolled in the Massachusetts General Hospital's open-label EAP for CBD as a new treatment for epilepsy. We analyzed the effect of CBD on seizure frequencies and concomitant antiepileptic drug (AED) use at 1year after starting treatment and the most recent study visit. Our results indicate that CBD maintains its efficacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7%-42.6%), and the seizure response rate was also maintained (p=.12). Efficacy was also seen over a broad dose range, and up to 50mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic spasms and absence seizures. Although CBD use did not lead to an overall decrease in concomitant AEDs, most subjects reduced the dose of at least one concomitant AED compared to baseline. CBD was generally well tolerated, with drowsiness and diarrhea as the primary adverse reactions. This study demonstrates CBD does not lose its efficacy in controlling seizures over a treatment period of up to 60months. Taken alongside other results on the efficacy and tolerability of CBD in the treatment of refractory epilepsies, our results provide evidence that CBD is an effective, safe, and well-tolerated AED for long-term use.

Behavioral Changes Under Levetiracetam Treatment in Dogs.

In veterinary medicine levetiracetam (LEV) is a well-tolerated antiepileptic drug (AED) with only mild to moderate side effects. Behavioral changes are rarely reported in animals. In contrast, in human medicine the impact of LEV on behavior has frequently been described. Since in the Clinic for Small Animals at the University of Veterinary Medicine Hannover single canine patients were observed with behavioral abnormalities after LEV treatment, it was hypothesized that levetiracetam induces behavioral changes or causes an intensifying of pre-existing behavioral abnormalities in dogs with epileptic seizures. This monocentric retrospective study evaluated the incidence of behavioral changes in epileptic dogs treated with the antiepileptic drug LEV based on information obtained in a questionnaire completed by dog owners. Eighty-four client-owned dogs with recurrent seizures receiving LEV as monotherapy, add on treatment or pulse therapy met inclusion criteria. Approximately half of the dogs in the study population were reported to have preexisting behavioral changes before treatment with LEV, and some of these dogs were reported to experience a worsening of behavioral changes (14/44) or the emergence of new behaviors after initiation of LEV therapy (4/44). One quarter of the dogs without pre-existing behavioral abnormalities developed behavioral changes associated with the administration of LEV (10/40). Based on these results, the authors conclude that behavioral changes can occur in dogs being administered LEV, and this should be taken into consideration when discussing treatment options with owners.

Economic Value of Adjunctive Brivaracetam Treatment Strategy for Focal Onset Seizures in Finland.

IntroductionThere is an unmet need for well-tolerated antiepileptic drugs (AEDs) that effectively control focal onset seizures. This study aimed to evaluate the economic value of new AEDs in the treatment of focal onset seizure, with or without secondary generalization, in Finnish adults and adolescents with epilepsy, comparing brivaracetam with perampanel as adjunctive AEDs.MethodsEconomic value was assessed using cost-utility analysis. Periods of AED initiation, titration, response assessment (seizure freedom, ≥ 50% reduction, no response), switching in no response or treatment-emergent adverse events (TEAEs), and death were simulated using a discrete-event simulation model. Responses and switching were simulated based on a comprehensive Bayesian network meta-analysis. The primary modeled outcome was the 3%/year discounted incremental cost-effectiveness ratio (ICER). Discounted quality-adjusted life-years (QALYs), payer costs (year 2017 Euro) per patient, and net monetary benefit (NMB) were secondary outcomes. Probabilistic and comprehensive deterministic sensitivity analyses were conducted.ResultsBrivaracetam was more efficacious and had fewer TEAEs than perampanel and other AEDs. Modeled average 5-year QALYs and costs were 3.671 and €28,297 for brivaracetam and 3.611 and €27,979 for perampanel, respectively. The resulting ICER for brivaracetam versus perampanel was only €5345/QALY gained in a deterministic base case scenario. Brivaracetam had a positive NMB and high probability of cost-effectiveness of €1190 and 71% or €1944 and 80% with the assumed willingness to pay of €25,358 or €38,036/QALY gained, respectively. The primary result was robust, with a positive NMB persistent in all sensitivity analysis scenarios. When switching from brivaracetam to perampanel was excluded from the modeling or switching from perampanel to brivaracetam was included, brivaracetam was cost-saving and more effective than perampanel (dominant).ConclusionThese simulated comparisons demonstrated that brivaracetam was more effective and potentially also more affordable than perampanel. Thus, brivaracetam is likely a cost-effective and net beneficial alternative to perampanel for treatment of focal onset seizures.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01155-6) contains supplementary material, which is available to authorized users.

Add-on Levetiracetam in Children With Refractory Epilepsy: A Systematic Review

Context: Recently, new anti-epileptic drugs are marketed to be used as an add-on to the traditional drugs in children with refractory epilepsy. Levetiracetam is a second-generation of new anti-epileptic drugs with unknown precise mechanism of action in brain and synaptic vesicle in children with drug resistant epilepsy. Herein, the efficacy and safety of add-on levetiracetam in children with refractory epilepsy is reviewed. Evidence Acquisition: A literature review was performed on efficacy and safety of add-on Levetiracetam in children with refractory epilepsy using international databases with the following terms: levetiracetam, refractory epilepsy, drug resistant epilepsy, seizures/epilepsy, children/pediatric. All articles related to add-on levetiracetam in children with refractory epilepsy written in English and published from 2000 to 2015 were included. The title and abstracts of 542 articles were assessed, of which, 488 were excluded. The full texts of the other 54 articles were assessed for relevance. Results: Of the nine eligible articles, 1036 patients aged ≤ 18 years were identified. Male patients (52%) were more prominent than female ones. Five articles reported that levetiracetam therapy appeared more effective against localization-related than generalized epilepsy. The dosage of levetiracetam ranged from 6 to 70 mg/kg/day, with a mean of 43.2 mg/kg/day based on the mean doses reported by four of nine reviewed articles. The mean duration of follow-up was 39 weeks (ranging from 8 144 weeks). Administration of levetiracetam was effective in 42.24% of the patients (responders with >50% decrease in seizure frequency), of whom 11.8% had become seizure free. The mean number of anti-epileptic drugs tried before introducing levetiracetam treatment was 4.4 (ranging 1 20). The most frequent side effects were psychological and behavioral changes (11.1%), followed by agitation (9.2%) and sleep disturbances (6.7%). Conclusions: The current review demonstrated that levetiracetam, as an add-on therapy, is an effective and well-tolerated antiepileptic drug, associated with reversible and no serious side effects, to control seizure frequency of childhood refractory epilepsy.

Evaluation of safety and efficacy of zonisamide in adult patients with partial, generalized, and combined seizures: an open labeled, noncomparative, observational Indian study.

A prospective, multicentric, noncomparative open-label observational study was conducted to evaluate the safety and efficacy zonisamide in Indian adult patients for the treatment of partial, generalized, or combined seizures. A total of 655 adult patients with partial, generalized, or combined seizures from 30 centers across India were recruited after initial screening. Patients received 100 mg zonisamide as initiating dose as monotherapy/adjunctive therapy for 24 weeks, with titration of 100 mg every 2 weeks if required. Adverse events, responder rates, and seizure freedom were observed every 4 weeks. Efficacy and safety were also assessed using Clinicians Global Assessment of Response to Therapy and Patients Global Assessment of Tolerability to Therapy, respectively. Follow-up was conducted for a period of 24 weeks after treatment initiation. A total of 655 patients were enrolled and received the treatment and 563 completed the evaluation phase. A total of 20.92% of patients received zonisamide as monotherapy or alternative monotherapy and 59.85% patients received zonisamide as first adjunctive therapy. Compared with baseline, 41.22% of patients achieved seizure freedom and 78.6% as responder rate at the end of 24 week study. Most commonly reported adverse events were loss of appetite, weight loss, sedation, and dizziness, but discontinuation due to adverse events of drug was seen in 0.92% of patients. This open label real-world study suggests that zonisamide is an effective and well-tolerated antiepileptic drug in Indian adults for treatment of partial, generalized as well as combined seizures type. No new safety signals were observed.

Rufinamide treatment for refractory epilepsy in a largely pediatric population

To determine the safety, tolerability, and efficacy of rufinamide in treating refractory epilepsy in a largely pediatric population. A retrospective chart review was conducted of all patients prescribed rufinamide from December 2008 to July 2010 in the Pediatric Epilepsy Program at Massachusetts General Hospital for Children. Eighty-eight patients on rufinamide with sufficient data for analysis were included in the study. Eight (9.1%) patients had >90% seizure reduction, 40 (45.5%) patients had 50-90% seizure reduction, 19 (21.6%) patients had <50% seizure reduction, and 21 (23.9%) patients had no change in seizure frequency. Generally mild side effects were reported by 28 (31.8%) patients, with the two most common side effects being decreased appetite in seven (8.0%) patients, and somnolence in six (6.8%) patients. Rufinamide appears to be an effective, safe, and well-tolerated antiepileptic drug in the treatment of broad-spectrum intractable epilepsy, expanding outside its specific Food and Drug Administration approved usage in treatment of Lennox-Gastaut syndrome.

P88. Identification of genome-based biomarkers for response to specific antiepileptic drugs in focal and idiopathic generalized epilepsies

Pharmacoresistance is a major burden in the treatment of epilepsy. The search for an effective and well-tolerated antiepileptic drug (AED) is overall achieved by trial and error. This process often turns out to be challenging and irksome for both, the patient and the clinician. Genetic biomarkers can help in the choice of AEDs in order to individualize the treatment. In the framework of the EpiPGX consortium, a European research project on epilepsy pharmacogenomics, 5000 patients were recruited and meticulously phenotyped. Patient samples were supplied by 10 specialized epilepsy centers. More than 500 phenotype items were assessed. Detailed definitions for pharmacogenomics phenotypes such as multiresistance or late response – i.e. response to a second or later given AED, see below – were created. The consistency of the supplied phenotypes across the participating centers was guaranteed by repeated phenotyping workshops and two rounds of validation exercises on a set of 10 anonymized medical records. Mean inter-rater agreement was 82% for AED outcome classification. True misclassifications accounted for only 5–9% of all cases. We identified and phenotyped patients with focal epilepsies that were late responders to specific AEDs. Late response was defined as 12 months of seizure freedom after failure of at least one well-tolerated AED. We identified 338 late responders to levetiracetam, lamotrigine, or lacosamide. Those are currently being analyzed in the setting of a genome wide association study (GWAS) against a much larger group of non-reponders to the same drugs and to a group of normal controls. For idiopathic generalized epilepsies, we are comparing responders and non-responders to lamotrigine and valproate (VPA). For VPA we identified 487 responders and 164 non-responders; for LTG 158 responders and 217 non-responders. Furthermore we identified 53 subjects that were responders only to the combination of VPA and LTG. The results of the GWAS analysis are pending and are expected in February 2015.

Effects of nucleosides on glia - neuron interactions open up new vistas in the development of more effective antiepileptic drugs.

One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine (Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels, metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Adoreleasing implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity. However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex, bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy.

Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood.

Lacosamide (LCM) is a novel anti-epileptic drug (AED) that enhances the slow inactivation of voltage-gated sodium channels. Its efficacy as adjunctive therapy for focal seizures is confirmed in adult placebo controlled trials with >50% reduction in seizure frequency in up to 50% patients. There is paucity of data on its efficacy and tolerance in treatment-resistant epilepsy in childhood (TREC). This study aims to assess efficacy and tolerance of LCM as adjunct therapy in TREC. Audit of medical records and seizure diaries in children with TREC on LCM. A response (RR) was defined as ≥50% reduction in seizure frequency. Forty children (age range: 2-19 years) with TREC received LCM as add-on therapy. All had abnormal electroencephalograms, and 36 had abnormal neuroimaging. All children failed >2 AED trials, nine had trialled the ketogenic diet, five had failed the vagal nerve stimulator and 11 had failed resective epilepsy surgery. Median dose and duration of LCM therapy were 5.7 mg/kg/day and 10.5 months, respectively. RR was seen in 20% with persistence of RR in 8/36, 8/30 and 8/26 children on LCM at 3-, 6- and 9-month follow-up. Two children became seizure free. Retention on LCM was 65% at 9 months. LCM was well tolerated with minor side effects in seven children; no child discontinued LCM because of side effects. LCM is a well-tolerated AED with RR in 20%: in 5%, it resulted in seizure freedom. LCM may be useful even in TREC when seizures have not responded to intervention with multiple modalities.

Validation of a multigenic model to predict seizure control in newly treated epilepsy

A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly-diagnosed epilepsy cohort using a k-nearest neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n=281; SANAD, n=491). A "leave-one-out" cross-validation was also employed, with training sets derived internally from the UK datasets. The multigenic classifier using the Australian cohort as the training set was unable to predict treatment response in either UK cohort. In the "leave-one-out" analysis, the five SNPs collectively predicted treatment response in both Glasgow and SANAD patients prescribed either carbamazepine or valproate (Glasgow OR=3.1, 95% CI=1.4-6.6, p=0.018; SANAD OR=2.8, 95% CI=1.3-6.1, p=0.048), but not those receiving lamotrigine (Glasgow OR=1.3, 95% CI=0.6-2.8, p=1.0; SANAD OR=2.2, 95% CI=0.9-5.4, p=0.36) or other AEDs (Glasgow OR=0.6, 95% CI=0.2-2.0, p=1.0; SANAD OR=1.9, 95% CI=0.9-4.2, p=0.36). The Australian-based multigenic kNN model is not predictive of initial treatment response in UK cohorts of newly-diagnosed epilepsy. However, the five SNPs identified in the original Australian study appear to collectively have a predictive influence in UK patients prescribed either carbamazepine or valproate.

Lacosamide in children with refractory status epilepticus. A multicenter Italian experience

ObjectiveStatus epilepticus (SE) is considered a life-threatening medical emergency. First-line treatment with antiepileptic drugs (AEDs) consists of intravenous benzodiazepines followed by phenytoin. SE is considered refractory (RSE) when unresponsive to standard doses of the first two AEDs. Scarce evidence is available to support specific guidelines for the management of RSE in either adults or children. This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE. MethodChildren with RSE who were treated with ivLCM were included in the study. Efficacy was defined as the cessation of seizures after administration of ivLCM, with no need for any further antiepileptic drug. All patients had been unsuccessfully treated following standard protocols before ivLCM was administered. ResultsEleven children entered the study (mean age: 9.4 years). Etiology was symptomatic in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported. ConclusionsLCM might be an effective and well-tolerated AED in children with RSE.

Clobazam: Effect on Frequency of Seizures and Safety Profile in Different Subgroups of Children With Epilepsy

BackgroundClobazam has been used in clinical practice as an adjunctive treatment for diverse seizure types and epilepsy syndromes. We evaluated the efficacy and safety of clobazam in a large sample of patients with refractory epilepsy at a tertiary pediatric center. MethodsWe retrospectively reviewed patients treated with clobazam between January 2001 and July 2013 who had a follow-up visit at least one month after starting clobazam. Response was defined as ≥50% reduction in seizure frequency compared with baseline seizure frequency during the 3 months before the introduction of clobazam. We examined the relationship between dose range and response rate. ResultsFour-hundred twenty-five patients were prescribed clobazam, of whom 300 (median age 9.1 years, interquartile range 4.7-13.3 years) had follow-up data greater than 1 month. Median follow-up was 5 months (interquartile range 3-11 months). Response to treatment with clobazam was observed in 203 of 300 (67.7%) patients, of whom 84 (28%) became seizure-free. The median starting dose was 0.2 (interquartile range 0.13-0.33) mg/kg/day with a target dose of 0.48 (0.26-0.80) mg/kg/day. Twenty-seven (9%) patients discontinued clobazam, 16 (59.3%) because adverse effects, 10 (37%) because of a lack of efficacy, and one (3.7%) because of a combination of adverse effects and lack of efficacy. The most common adverse effects were tiredness in 44 of 300 (14.6%) and mood or behavioral changes in 23 (7.7%). ConclusionsClobazam is a well-tolerated antiepileptic drug with good response rates in pediatric patients with refractory epilepsy.

Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy

BackgroundLacosamide is effective and well-tolerated antiepileptic drug (AED) in both children and adults. AimThis multicentric, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in children aged less than four years presenting with refractory focal seizures. MethodsLacosamide was added to the baseline therapy at a starting dose of 1–2 mg/kg/day and titrated to the final dose, ranging from 7 to 15.5 mg/kg/day. Efficacy was evaluated after a three-month period of therapy. When possible, we compared the initial efficacy and the retention after a minimum of 12 months of lacosamide, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). ResultsTwenty-four children were enrolled in the study. Mean age was 2.7 years. After a minimum three-month period of lacosamide add-on therapy, ten (42%) patients were responders (more than a 50% decrease in seizure frequency), of whom 4 (17%) became seizure free. Retention rate, after a minimum of 12 months of lacosamide, was evaluated in a group of 18 patients. In the latter group, eight patients (44%) were initial responders (three of whom seizure free). After 12 months of follow-up, four of them (22%) maintained the improvement, 2 (11%) of whom remained seizure free. A loss of efficacy was observed in 4 of the initial responders (50%). Adverse events were seen in 8 (33%) patients. ConclusionWe conclude that lacosamide is an effective and a well-tolerated antiepileptic drug in an etiologically wide range of focal seizures. Therefore, lacosamide might represent a possible therapeutic option in infants and young children affected by uncontrolled focal epilepsy.

Balancing clinical benefits of vigabatrin with its associated risk of vision loss

Vigabatrin is an effective and well-tolerated antiepileptic drug (AED) for the treatment of refractory complex partial seizures (rCPS) and infantile spasms (IS), but its benefits must be evaluated in conjunction with its risk of retinopathy with the development of peripheral visual field defects (pVFDs). Vigabatrin should be considered for rCPS if a patient has failed appropriate trials of other AEDs or is not a suitable candidate for other AEDs, is not an optimal surgical candidate, and continues to experience debilitating effects from seizures. Vigabatrin is indicated as monotherapy for pediatric patients with IS. Its efficacy in achieving improved seizure control should be apparent within 12 weeks in patients with rCPS and within 2-4 weeks after attaining appropriate dosage for patients with IS. Because 12 weeks is well less than the known time of onset of visual defects, the risk of developing pVFDs may be minimized by discontinuing vigabatrin early during the course of therapy for patients with inadequate response. Appropriate vision screening is recommended at baseline, every 3 months during continued vigabatrin treatment, and at 3-6 months after discontinuation (if therapy has spanned more than a few months). If a pVFD is detected at any point and the decision is made to discontinue therapy, the pVFD is not likely to progress after discontinuation of vigabatrin. Although some patients will be at risk of retinopathy, vigabatrin is an appropriate treatment option for patients who achieve substantial clinical benefit, especially given the severe consequences of rCPS and uncontrolled IS. While retinopathy with the development of pVFDs is a serious adverse event, it is not life-threatening and its risk can be effectively managed.

Valproic Acid, a Histone Deacetylase Inhibitor, Induces Apoptosis, Inhibits Proliferation, and Synergizes With Chemotherapy: The Rationale to Combine it for the Treatment of B-Cell Chronic Lymphocytic Leukemia

Brief Abstract In this work, we showed that valproic acid (VPA) induces apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. VPA also inhibits proliferation by disturbing many cell cycle messenger RNAs and potentiates cytotoxic effects of chemotherapeutic agents, suggesting its introduction in B-CLL treatment. Full Abstract Background Epigenetic code modifications by histone deacetylase (HDAC) inhibitors have recently been proposed as potential new therapies for hematologic malignancies. B-cell chronic lymphocytic leukemia (B-CLL) remains incurable despite the introduction of new treatments. B-CLL cells are characterized by an apoptosis defect rather than an excessive proliferation, but proliferation areas can be found in some organs such as bone marrow and lymph nodes. Patients and Methods In this study, we analyzed the gene expression modifications in B-CLL cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. B-CLL cells obtained from 14 patients were exposed in vitro to a concentration of 1 mM VPA during 4 h. VPA effects on gene expression were studied before and after exposure using Affymetrix technology, and some identified genes were validated by real-time polymerase chain reaction and Western blot. Results We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. VPA inhibited the proliferation of CpG/IL2-stimulated B-CLL cells and modulated many cell cycle messenger RNAs. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide, and lenalidomide. Conclusion (1) Exposure of B-CLL cells to VPA induces apoptosis, inhibits proliferation, and potentiates cytotoxic effects of chemotherapeutic agents. (2) These data strongly suggest that VPA combined with cytotoxic chemotherapy is particularly appealing in B-CLL treatment. Based on our data and literature data (Bokelmann et al; Bouzar et al), we have planed to study, in a multicentric phase I/II Belgian clinical trial, the combination of VPA and 2CDA (cladribine).

Effectiveness and tolerability of zonisamide in children with epilepsy: A retrospective review

Purpose To evaluate the effectiveness and tolerability of zonisamide in children with epilepsy. Method Retrospective case note review of young people (less than 19 years) with epilepsy from three UK tertiary centres who received treatment with zonisamide and were followed up for a minimum of 12 months. Results Fifty-seven children were included, aged 1.5–18.5 (median, 12) years. Thirty-three (57.9%) patients had generalised epilepsy, 21 (36.8%) focal epilepsy, and three (5.3%) a mixed, generalised and focal, epilepsy. Fifty-six of the 57 patients had been refractory to at least three previous antiepileptic drugs. The maintenance dose of zonisamide was [range (median)] 0.7–14 (5) mg/kg/day. The median duration of treatment for all patients was 12 (range 0.25–35) months. After 2 months of treatment, 51 patients remained on zonisamide, 18 (35.3%) of whom demonstrated a ≥50% reduction in seizure frequency. At the end of the follow-up period, there was a loss of effect for some patients. Thirteen (25.5%) of the 51 patients continued to demonstrate a ≥50% reduction in seizure frequency whilst two who had become seizure-free started having seizures again. Six (11.8%) had <50% reduction, twenty-four (47%) had no change, and eight (15.7%) had increasing seizures. Twenty-five (43.9%) patients reported unwanted effects although this contributed to the withdrawal of zonisamide in only ten (17.6%) patients. Conclusions Zonisamide appeared to be a reasonably effective and generally well-tolerated antiepileptic drug in a heterogeneous group of 57 children with poorly controlled epilepsy and provides another treatment option for children with refractory seizures.

Evaluation of Potential role for Valproic Acid in IL-3-Mediated Megakaryopoiesis and Erythropoiesis in Serum-Free and Serum-Containing Cultures.

Abstract 2746Poster Board II-722Although attention has been paid to the antitumor activity of histone deacetylase (HDAC) inhibitors in hematologic disease, a role for HDAC in normal hematopoiesis has not been clearly defined. Previous study have shown that the potent HDAC inhibitor FK228 (romidepsin, depsipeptide) stimulates IL-3-mediated erythropoiesis in serum-free cultures. Here, we precisely examined the effects of well-tolerated antiepileptic drug valproic acid (VPA) on IL-3-mediated megakaryopoiesis and erythropoiesis in serum-free and serum-containing cultures. After incubation of CD34+ cells in serum-free medium containing IL-3+SCF, CD61+GPA− megakaryocytic, a CD61+GPA+ mixture of megakaryocytic and erythroid, and CD61−GPA+ erythroid precursors were generated. Pharmacological concentration of VPA (100 μg/ml) and FK228 (0.45 ng/ml) remarkably increased the number of CD61+GPA+ cells by 7-fold and 9-fold, respectively. Other populations were also increased by FK228 and VPA. VPA and FK228 enhanced the generation of megakaryocytic and erythroid precursors from more mature CD34+ cell-derived CD36+ erythroid and megakaryocytic precursors. Thus, VPA was found to be as potent as FK228 in stimulating the IL-3-mediated megakaryopoiesis and erythropoiesis. In the presence of GM-CSF+SCF, CD61−GPA+ erythroid precursors were mostly developed. Addition of VPA to the cultures mainly promoted the generation of CD61−GPA+ erythroid precursors, while the generation of megakaryocytic precursors was also moderately enhanced. In serum-containing cultures, there were only low numbers of CD61+ or GPA+ cells detected even in the presence of IL-3+SCF. Nevertheless, addition of VPA to the cultures containing IL-3+SCF increased the numbers of CD61+GPA−, CD61+GPA+, and CD61−GPA+ cells by 3-fold, 18-fold, and 4-fold, respectively from three independent experiments. In megakaryopoiesis and erythropoiesis, GATA-1 and GATA-2 are shown to play important roles in the proliferation and differentiation process, respectively. By quantitative RT-PCR analysis, after incubation of CD34+ cells with IL-3+SCF, GATA-2 m-RNA expression was increased at day1 but returned to initial levels at day3. VPA increased the expression level of GATA-2 gene by 1.6-fold and 1.7-fold at day1 and day3, respectively. While GATA-1 gene expression was remarkably elevated at day1 and day3, its expression was not affected by VPA. Our data reveal a potential for VPA to promote the ability of IL-3 to stimulate megakaryopoiesis and erythropoiesis in serum-free and serum-containing cultures and thus implicate a novel therapeutic approach of epigenetic therapy for treatment of hematologic disease such as myelodysplastic syndrome. Disclosures:No relevant conflicts of interest to declare.

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide and lenalidomide. VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.

Valproic Acid-induced Agranulocytosis

Valproic acid is considered to be the most well-tolerated antiepileptic drug. However, few cases of neutropenia or leukopenia caused by valproic acid have been reported. We present a patient who took valproic acid to treat a complication of brain surgery and in whom severe agranulocytosis occurred after 2.5 months. Valproic acid was stopped immediately, and granulocyte colony-stimulating factor was administered for 2 days. The patient's white blood cell count returned to normal within 2 weeks. The result of bone marrow aspiration was compatible with drug-induced agranulocytosis. This case illustrates that patients who take valproic acid may need regular checking of complete blood cell count.