Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba-pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox-carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

左乙拉西坦和托吡酯对癫(疒间)大鼠脑P-糖蛋白表达的影响

目的研究左乙拉西坦(LEV)和托吡酯(TPM)对癫大鼠脑P-糖蛋白(P-gp)表达的影响。方法将海人酸1.5μg(3μl)注射至SD大鼠海马制作癫模型(癫组),对照组大鼠海马注射3μl生理盐水(NS)。将癫组(18只)和对照组(15只)大鼠分别随机分为LEV、TPM和NS亚组(每亚组6只、5只),各亚组大鼠予相应药物(LEV50mg/kg、TPM40mg/kg、等体积NS)灌胃,每天1次,共30d。采用免疫组化EnVi-sion染色法检测大鼠颞叶、海马P-gp表达水平,采用LeicaQwin图像分析系统中平均整合灰度(MIB)值对P-gp表达水平进行半定量分析。结果癫各亚组大鼠颞叶和海马P-gp表达水平(MIB值)均显著高于其相应对照亚组(P<0.05～0.001);对照亚组中,LEV和TPM组与NS亚组间P-gp表达水平比较,差异无统计学意义;在癫组中,TPM亚组P-gp表达水平显著高于NS亚组(1550.3±371.9vs1049.7±282.8,P=0.004);而LEV亚组与NS亚组差异无统计学意义(1285.1±340.3vs1049.7±282.8,P=0.172)。结论癫发作可诱导...     

Antiepileptic Drugs, Cognitive Function, and Behavior in Children: Evidence from Recent Studies

Summary: The effects of antiepileptic drugs (AEDs) on cognitive function and behavior in children are reviewed on the basis of published studies. Individual AEDs have been shown to differ–the deleterious effects of phenytoin generally contrasting with the relatively minimal effects of valproate and carbamazepine. Some of the differences between results may be attributed to the psychological tests used and to age differences. However, there appears to be a dissociation between AEDs that affect higher cognitive function, e.g., phenytoin, and those mainly affecting motor function, e.g., carbamazepine, which appears to increase speed of performance. AEDs should be prescribed with care in children with epilepsy, taking account of their differing effects on cognitive function and behavior.     

左乙拉西坦治疗癫（癎）伴认知功能障碍患儿疗效观察

目的 分析左乙拉西坦治疗癫（癎）伴认知功能障碍患儿的临床疗效.方法 选择在本院接受治疗的癫（癎）伴认知功能障碍患儿作为研究对象,分别给予常规治疗及左乙拉西坦治疗,比较2组患儿的认知功能、脑电活动情况及生活质量评分等差异.结果 观察组总有效率（66.67%）、MMES评分（25.47±4.83）、无认知功能障碍（83.33%）、躯体功能（76.87±7.16）、心理功能（59.32±5.34）、社会功能（58.76±2.16）、总体生活质量（82.34±8.21）评分均明显高于对照组（P〈0.05）;癫（癎）样放电（15%）、α波（18.21±3.36）、β波（10.32±2.25）、δ（12.36±2.25）、θ波（20.32±3.24）数目均明显少于对照组（P＜0.05）.结论 左乙拉西坦可有效改善癫（癎）伴认知功能障碍患儿的认知功能,减少异常脑电活动,提高生活质量.     

Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up

The present study was conducted to evaluate the long-term effects of low-dose topiramate (TPM) monotherapy on the cognitive function of epilepsy patients. Forty-seven epilepsy patients received TPM, with target doses of 50, 75, and 100 mg/day. Cognitive tests were performed twice, at baseline and 1 year after starting medication. Thirty-six patients completed the follow-up neuropsychological tests. After a year of treatment, 16 patients (44%) complained of cognitive problems. Although it improved seizure frequency and EEG abnormalities, TPM had significantly negative effects on the digit span and verbal fluency tests. These cognitive effects were dose-related and significantly improved after withdrawal from TPM and substitution with older antiepileptic drugs. In conclusion, even at a low dose, TPM has long-term, negative effects on working memory and verbal fluency.     

Comparison of Antiepileptic Drugs on Cognitive Function in Newly Diagnosed Epileptic Children: A Psychometric and Neurophysiological Study

Summary: Using a randomized parallel group study design, we compared the cognitive effects of carbamazepine (CBZ), phenobarbital (PB), and valproate (VPA) in children with epilepsy. Seventy-three children with newly diagnosed epilepsy were tested with the Wechsler Intelligence Scale for Children-Revised (WISC-R), Bender-Gestalt test, and auditory event-related potentials (P₃₀₀) before and 6 and 12 months after antiepileptic drug (AED) treatment. There were no significant differences in WISC-R IQs and Bender-Gestalt scores for children in any group at any of the three sessions. P₃₀₀ latencies were increased in the children receiving PB but not in children receiving CBZ and VPA. P₃₀₀ amplitudes were significantly reduced in treated children in all three groups, but amplitudes were not significantly different among the three groups. These findings suggest that PB may affect cognitive function of epileptic children and that the P₃₀₀ may be a sensitive additional procedure that can be used to assess the cognitive effect of AEDs.     

左乙拉西坦添加治疗学龄期难治性癫痫患儿认知功能与生活质量的影响

目的观察并探讨左乙拉西坦(levetiracetam,LEV)添加治疗对学龄期难治性癫痫(refractory epilepsy,RE)患儿认知功能与生活质量的影响。方法入选2013年6月至2015年12月收治的55例RE儿童为研究对象,所有患儿在继续原有治疗方案基础上行LEV添加治疗16周,起始剂量8~10 mg/(kg·d),逐步加量至50 mg/(kg·d),达标后维持剂量30 mg/(kg·d),期间记录药物不良反应,治疗结束后判定临床疗效,采用韦氏儿童智力量表评价患儿认知功能,采用儿童癫痫生活质量量表评价生活质量改变。结果患儿治疗后癫痫平均发作次数(3.8±1.3 vs.6.6±2.3)次/月较入组前明显下降(P0.05)。治疗后临床控制率、显效率、有效率、无效率分别为9.1%、36.4%、43.6%、10.9%,总体有效率为89.1%。患儿治疗后WISC-CR智力评价中算术(10.9±2.6 vs.9.2±2.1)、填图评分(15.1±3.9 vs.13.8±3.3)较治疗前显著提高(P0.05)。患儿治疗后QOLCE评价中生活质量总分(65.7±5.7vs.62.8±4.9)及认知功能(60.0±5.7 vs.57.4±6.2)、社会功能(65.0±6.3 vs.62.5±5.5)评分显著高于治疗前(P0.05)。服药期间,患儿头晕、乏力、嗜睡、易激惹、欣快感、一过性转氨酶升高发生率分别为12.7%、9.1%、20.0%、5.5%、3.6%、3.6%;16周服药保留率96.4%。结论 LEV添加治疗能显著减少RE患儿癫痫发作次数,并有助于改善患儿认知功能与生活质量,但应注意LEV对精神行为的影响。     

The Effect of Age on Pharmacokinetics of Antiepileptic Drugs

Summary: Management of epilepsy in the elderly requires understanding of the unique biochemical and pharmacologic characteristics of this patient population. Accurate assessment of seizures and identification of epilepsy syndromes, thorough neurologic assessment to define etiology, and comprehensive evaluation of the patient's health and living situation are necessary for informed management decisions. Challenges to treatment include concomitant diseases, polypharmacy with accompanying drug interactions, and changes in physiology, such as changes in renal clearance and hepatic function that alter drug absorption, protein binding, metabolism, and elimination. Elderly patients with declining intellectual function, motor impairment, or altered sensory function may be especially susceptible to dose-related CNS side effects of antiepileptic drugs (AEDs). Drugs pre-scribed for concomitant illnesses such as hypertension, cardiovascular disease, infections, behavioral problems, and gastrointestinal disturbances may alter absorption, distribution, and metabolism of AEDs, with an adverse impact on efficacy and increased occurrence of adverse effects. The AEDs may induce metabolism of other drugs, resulting in decline in target response. Addition of an AED to an elderly patient's medical regimen requires careful review of all prescribed drugs. Optimal care of elderly patients with epilepsy includes use of free drug levels to monitor AED concentrations, careful dose selection, and sensitivity to the social problems that may occur in this population.     

Discontinuation of Antiepileptic Drugs in Children Who Have Outgrown Epilepsy: Effects on Cognitive Function

Summary: Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls.     

The Aspects and Mechanisms of Cognitive Alterations in Epilepsy: The Role of Antiepileptic Medications

Epilepsy is a major health problem. Several studies suggest a significant influence of epilepsy and its treatment on dynamic and functional properties of brain activity. Epilepsy can adversely affect mental development, cognition, and behavior. Epileptic patients may experience reduced intelligence, attention, and problems in memory, language, and frontal executive functions. Neuropsychological, functional, and quantitative neuroimaging studies revealed that epilepsy affect the brain as a whole. Mechanisms of epilepsy‐related cognitive dysfunction are poorly delineated. Cognitive deficits with epilepsy may be transient, persistent, or progressive. Transient disruption of cognitive encoding processes may occur with paroxysmal focal or generalized epileptic discharges, whereas epileptogenesis‐related neuronal plasticity, reorganization, sprouting, and impairment of cellular metabolism are fundamental determinants for progressive cognitive deterioration. Also antiepileptic drugs (AEDs) have differential, reversible, and sometimes cumulative cognitive adverse consequences. AEDs not only reduce neuronal irritability but also may impair neuronal excitability, neurotransmitter release, enzymes, and factors critical for information processing and memory. The present article serves as an overview of recent studies in adult and childhood epilepsy literatures present in PubMed that highlighted cognitive evaluation in epilepsy field (publications till 2008 were checked). We also checked the reference lists of the retrieved studies for additional reports of relevant studies, in addition to our experience in this field. Our search revealed that although the aspects of cognitive dysfunction, risk factors, and consequences have been explored in many studies; however, the mechanisms of contribution of epilepsy‐related variables, including AEDs, to patients' cognition are largely unexplored. In this review, we discussed the differential effect of AEDs in mature and immature brains and the known mechanisms underlying epilepsy and AEDs adverse effects on cognition. The nature, timing, course, and mechanisms of cognitive alteration with epilepsy and its medications are of considerable clinical and research implications.     

Antiepileptic Drugs and the Regulation of Mood and Quality of Life (QOL): The Evidence from Epilepsy

Summary:  We review the literature on the influence of antiepileptic drugs (AEDs) on mood and quality of life in patients with epilepsy. Although many anecdotal reports cover a spectrum of AEDs, most of the controlled data have come from studies of carbamazepine and lamotrigine. Both of these compounds appear to have positive effects on mood, and these data parallel the effects noted in nonepilepsy populations. AEDs that are γ-aminobutyric acid (GABA)ergic tend to have negative effects on mood, and an affective disorder is often noted as a treatment-emergent effect. It is speculated that the amygdala is an important anatomic structure in the cerebral circuits that regulate mood in affective disorders but also in epilepsy, and an effect of AEDs on such circuits aids mood stability in both populations of patients.     

A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures

PURPOSE: This study compares the cognitive effects of topiramate (TPM) with those of valproate (VPA) using efficacious doses of each drug when used as adjunctive therapy to carbamazepine (CBZ). A key question of the study is to what extent a more gradual introduction of TPM improves tolerability and prevents cognitive impairment. METHODS: The study is a multicenter, randomized, observer-blinded, parallel-group clinical trial with VPA or TPM given as first-line add-on therapy to steady-state treatment with CBZ. TPM is introduced at 25 mg and increased with weekly 25mg/d increments to a minimum dosage of 200 mg/d. The target dosage ranges from 200 to 400 mg/d for TPM and is 1800 mg/d for VPA. The study evaluates cognitive function changes from baseline to end point (after 20 weeks of treatment) and during titration (after 8 weeks of treatment). The primary outcome measure is the difference between the treatments (TPM versus VPA) in change from baseline to end point and change from baseline to titration, using a 95% confidence interval approach. RESULTS: For the 10 baseline-to-end point comparisons, one test measuring short-term verbal memory (Rey Auditory Verbal Learning Test) yields a statistically significant difference between the treatments (p = 0.02), showing worsening for TPM and improvement of scores for VPA. The 10 baseline-to-titration comparisons also show one statistically significant difference, again for a test measuring short-term memory (Recognition of Words; p = 0.04), showing a larger change in the negative direction for TPM. None of the mood tests or the test for subjective complaints shows statistically significant differences between the treatments, although more scores are in the negative direction for TPM during titration. CONCLUSION: Although the pattern of changes in the negative direction seems consistent with clinical information, the differences found between the treatments are small. An important finding of our study is that, when the results are compared with those of other studies, it is clear that gradual introduction of TPM can reduce the extent of cognitive impairment (with a maximum of about 0.6 SD).     

The effects of levetiracetam on cognition: a non-interventional surveillance study

Objective and subjective cognitive measures were evaluated in 401 patients before and 3 and 6 months after introducing levetiracetam (LEV). Initially, cognitive impairment was indicated in 37–44% of the patients, and subjective impairments in 32–67%. With LEV, 87% of untreated patients changed to monotherapy, and 94% changed from mono- to polytherapy. The rate of retention of LEV was 97%; adverse events were reported by 7%. Under LEV, 36% achieved early seizure control, 25% achieved late seizure control, 33% continued to have seizures, and 7% had a relapse. Very good tolerance was reported by 68%, and cognitive improvement by 58%. Objective improvement was significant in 23–29% of the patients; 5–6% deteriorated. Better baseline scores, later-onset epilepsies, fewer initial antiepileptic drugs, and seizure control were predictive of a better cognitive outcome. Considering the uncontrolled study design and the increase in total drug load, LEV appeared safe and efficacious, and a general subjective and objective cognitive improvement could be noted. However, a controlled study design would be required to attribute these improvements to a specific drug action.     

Side-effects of antiepileptic drugs: The economic burden

PurposeAntiepileptic drugs are a potentially effective treatment for epilepsy. Side-effects are, however, common and the negative consequences necessitate treatment ranging from minor interventions to very expensive hospitalization. This analysis has been conducted to provide insight into the costs of side-effects due to antiepileptic drugs in The Netherlands from a societal perspective.MethodResources allocated to care (grouped according to health, patient and family and other) for five different categories of side-effect were measured using a questionnaire. Standard cost prices were derived from the Dutch costing manual. Chronic epilepsy patients were invited to complete the questionnaire if they had experienced side-effects during the previous 12 months.ResultsBased on data from 203 patients, the total societal costs of common side-effects in 2012 are estimated to be €20,751 CI:15,049–27,196 (US$26,675 CI:19,345–34,960) per patient per year. These consist of: health care costs (mean €4458; US$5731), patient and family costs (i.e. informal care, mean €10,526; US$13,531) and other costs (i.e. productivity losses, mean €5761; US$7406). Examining the different categories of side-effects separately, ranging from the most to the least expensive category, the cost estimates per patient per year were as follows: other (mean €13,228; US$17,005), behavioral (mean €9689; US$12,455), general health (mean €7454; US$9582), cognitive (mean €7285; US$9365) and cosmetic side-effects (mean €2845; US$3657). Subgroup analyses showed significant differences in costs between patients using monotherapy and those using polytherapy when looking at cognitive and cosmetic side-effects.ConclusionThese estimates should be considered in the overall assessment of the economic impact of a pharmacotherapy.