Neuroprotective properties of valproate

Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.     

Open, Double-Blind and Long-Term Study of Vigabatrin in Chronic Epilepsy

We performed an open, double-blind, and long-term study of vigabatrin (gamma-vinyl-GABA, GVG) in patients with treatment-resistant epilepsy who were receiving only one or at most two standard antiepileptic drugs (AEDs). The novel design included a parallel, double-blind, placebo-controlled phase that minimized the number of patients receiving placebo and allowed determination of the optimum dose of GVG for each patient before initiation of the double-blind phase. The study was divided into four phases. The first phase was a 6-week period of baseline observation. In the second phase, GVG was added openly to previous AEDs for 8 weeks. During the first 2 weeks of this phase, the dose of GVG was increased weekly and then, in the absence of adverse effects, was held constant for the next 6 weeks. At the end of this open phase, seizure frequency during the 6 weeks of constant treatment was compared with the baseline seizure frequency for each patient. Patients who experienced reduction greater than 50% in the frequency of any seizure type during the open phase were defined as responders. These responders were then entered into the third and double-blind phase, in which they were randomly allocated wither to continue active GVG treatment or placebo for 8 weeks. Thirty-three patients entered the study; 31 of 33 patients completed the initial open phase. Twenty patients achieved a reduction greater than or equal to 50% in the frequency of one or more seizure types and were eligible for the double-blind phase; 10 were randomized to continue GVG and 10 were randomized to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Overview of the Clinical Efficacy of Lamotrigine

Summary: Testing the efficacy of lamotrigine (LTG) in epileptic patients has been approached in several ways. The first pilot study examined the effect of a single dose of LTG in patients with frequent interictal spikes, and a reduction in spike frequency was observed. Subsequently, single doses reduced photosensitivity in appropriate patients. Single-blind administration of LTG for 1 week in addition to the patients' regular antiepileptic drugs (AEDs), in patients with refractory seizures, reduced seizures despite the short duration of therapy. This regimen was continued using a placebo-controlled crossover study with 1-week duration of treatment. Efficacy in partial and tonic-clonic seizures was subsequently confirmed in four double-blind crossover studies; a meta-analysis of these four studies showed a 30% reduction in partial seizures despite the intractable nature of the seizures in the patients included. Current studies aim at evaluating the drug as monotherapy and in different seizure types.     

Lack of Major Effects on Mouse Brain Adenosine A1 Receptors of Oral Carbamazepine and Calcium Antagonists

Interaction with adenosine A1 receptors is a possible contributory mechanism to the anticonvulsant effects of carbamazepine (CBZ) and the dihydropyridine calcium antagonists. We measured the binding of [3H]cyclohexyladenosine to adenosine A1 receptors in mouse brain stem, cerebellum, and cortex after oral administration of nifedipine, nimodipine (NMD), and CBZ for 7 days and compared the results with binding in control mice. Equilibrium dissociation constant (Kd) and receptor numbers (Bmax) were calculated using Scatchard and saturation isotherm analyses. Mean Kds (SEM) in control brain stem, cerebellum, and cortex were 2.09 (0.31), 2.39 (0.2), and 3.12 (0.28) nM, respectively. Results of Bmax for the same areas were 188 (26), 280 (24), and 449 (54) fmol/mg protein. Nifedipine (p less than 0.005) and NMD (p less than 0.02) raised the Kd of A1 receptors only in the cerebellum, and CBZ increased cerebellar Bmax (p less than 0.05). These minor effects on A1 receptors in CF1 mice, when given in doses previously shown to have anticonvulsant properties in these animals, do not suggest that alteration in A1 receptor activity is an important mechanism for the anticonvulsant effects of these drugs.     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

Juvenile Myoclonic Epilepsy: Factors of Error Involved in the Diagnosis and Treatment

Juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, has a distinct clinical and electroencephalographic profile. Often JME is not recognized, with serious consequences on the sufferers. We examined factors contributing to the missed diagnosis even in an epilepsy clinic. Of 70 JME patients, 66 (91.4%) were not diagnosed on referral and 22 (33%) were not initially recognized in the epilepsy clinic. The correct diagnosis was established after a mean of 8.3 +/- 5.5 years from disease onset and an interval of 17.7 +/- 10.4 months from first evaluation in the epilepsy clinic. Myoclonic jerks, the hallmark of the disease, were not usually reported by patients. Similarly, relevant questioning may not be included in the history. Absence seizures antedating jerks by many years, myoclonic jerks reported as unilateral, generalized tonic-clonic seizures occurring during sleep and focal EEG abnormalities are other factors contributing to not recognizing JME. Our study reemphasizes the need to have not only a correct seizure diagnosis but also a correct epilepsy-disease diagnosis.     

Neuropharmacology and Drug Interactions in Clinical Practice

Summary: Absorption, distribution, and clearance are key pharmacokinetic principles. These parameters can be highly variable among patients and among compounds, and are factors that must be considered in the wide variability in response to medications. Current antiepileptic drugs (AEDs) present many challenges in their administration. However, understanding and utilizing pharmacokinetic principles can assist the clinician in the appropriate optimization of AEds.     

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.     

Ictal and Interictal Electrographic Seizure Durations in Preterm and Term Neonates

Summary: The effect of gestational age on neonatal ictal and interictal durations has not been investigated. Sixty-eight neonates with 644 electrographic seizures were identified retrospectively. Thirty-five full-term (FT) neonates were compared with 33 preterm (PT) neonates. Eighteen older preterm infants (OPT) [>31 weeks estimated gestational age (EGA)] were also compared with 15 young preterm infants (YPT) of ≤31 weeks EGA. Ictal/ interictal durations were calculated for the total cohort with and without status epilepticus (SE). Statistical analyses were two-tailed t tests, chi-square calculations, and one-way analysis of variance (ANOVA) with Duncan's multiple-range test. Eleven of 35 (33%) FT had SE as compared with 3 of 33 (9%) PT (chi-square = 7.8, p < 0.05). The mean ictal duration was 14.2 min for FT infants as compared with 3.1 min for PT infants (p < 0.01); only borderline differences were noted after those with SE were excluded. Interictal durations were longer for OPT than YPT (p < 0.05). By ANOVA and Duncan's multiple-range tests, group differences included longer mean ictal durations for FT infants as compared with OPT infants (p = 0.06, ANOVA; p < 0.05, Duncan's), and longer mean interictal durations for FT infants versus OPT and OPT versus YPT (p = 0.02, ANOVA; p < 0.05, Duncan's). More developed neuronal networks result in longer ictal durations in FT than in PT neonates, including FT infants with SE. Inhibitory networks responsible for longer interictal periods are more dominant in OPT infants than in YPT infants, reflecting maturational changes that suppress seizure activity during the latter part of the third trimester before the infant reaches an FT corrected age.     

治疗血浓度下抗癫(癎)药对未成熟脑发育影响的实验研究

目的 探讨抗癫(癎)药物(AEDs)在治疗血浓度下对未成熟脑发育的影响.方法 以AEDs血浓度达到临床治疗稳态血浓度为实验剂量,设立健康幼鼠及成年SD大鼠氯硝西泮(CNP)、苯巴比妥(PB)、丙戊酸(VPA)、托吡酯(TPM)实验组及正常对照组(各18只).AEDs灌胃5周,于停药后次日、2周及1个月末,行Morris水迷宫及穿梭箱测试.停药当天记录体重、脑重,海马及额叶组织行苏木素-伊红(HE)、尼氏染色及电镜观察.结果 (1)停药后次日及2周的穿梭箱实验,幼鼠CNP和PB组逃避潜伏期明显长于对照组.即使停药后1个月,幼鼠CNP[(6.05±2.04)s]及PB组[(5.81±1.75)s]与对照组的差异仍有统计学意义[(4.75±2.43)s,P＜0.01].而停药后2周,成年鼠各AEDs组与对照组已无差异;(2)Morris水迷宫实验,分别于停药后次日、2周及1个月,幼鼠CNP和PB组登平台潜伏期均长于对照组.而成年鼠各组登平台潜伏期于停药后2周已无差异;(3)幼鼠CNP组脑重(1.67±0.04)g,PB组脑重(1.66±0.04)g,较对照[(1.75±0.06)g]轻;(4)神经元广泛变性坏死,神经细胞数[CNP组为(76.87±18.60)个/200倍视野,PB组(72.60±17.26)个/200倍视野]较对照少[(109.13±33.73)个/200倍视野,P＜0.01];(5)停药1个月后,PB组幼鼠神经元超微结构仍异常.结论 长期服用PB、CNP可引起未成熟脑学习记忆功能及脑组织病理学持续异常,PB对未成熟脑的损伤存在可能是不易恢复的.