Newer antiepileptic drugs]

Ten newer antiepileptic drugs have been developed since 1990s. These drugs have wider therapeutic spectra, fewer side-effects, and lesser drug-to-drug interactions compared with the older typical antiepileptic drugs. Among them, zonisamide was developed in Japan and has been used from 1989. Gabapentin was at length approved in 2006. The other newer antiepileptic drugs are not approved yet in Japan. Felbamate can not be used in Europe because it may induce lethal hepatic toxicity and aplastic anemia. Vigabatrin is not approved in USA because it may induce permanent visual field deficit. The USA guideline for epilepsy treatment recommends that patients with newly diagnosed epilepsy can be treated with gabapentin, lamotrigine, topiramate, and oxcarbazepine. In contrast, based on epilepsy treatment guideline in England, newer antiepileptic drugs are considered only when patients with newly diagnosed epilepsy are unable to use the older antiepileptic drugs for some reasons. All newer antiepileptic drugs are used for intractable partial epilepsies, and lamotrigine and topiramate can also be used for idiopathic generalized epilepsies. The response rate (seizure reduction rate with 50% or more) and drop-out rate are overlapping among all newer antiepileptic drugs. Gabapentin, levetiracetam, and pregabalin are eliminated from kidney, and they had no drug-to-drug interactions and can be titrated rapidly. The serum concentration of lamotrigine is decreased with co-administration of hepatic enzyme inducing drugs and is increased with co-administration of valproic acid. Hypersensitivity reactions are rare with gavapentin, levetiracetam, topiramate, and tiagabin. Psychoses are reported to be induced with zonisamide, however, they can be induced with the other newer drugs (topiramate, levetiracetam, etc.). Drug-induced psychiatric symptoms, especially depression, may be often underdiagnosed. Many of these newer drugs (gabapentine, lamotrigine, levetiracetam, oxycarbazepine, etc.) have effects on chronic neuropathic pain. Some newer drugs show mood stabilizing effects (lamotrigine, oxycarbazepine, etc.), or antianxiety effect (gabapentin, topiramate, levetiracetam, pregavalin, etc.). Wide range of action to central nervous system of these newer antiepileptic drugs may serve not only for clinical seizure suppression, but also for neuroprotection.     

Hypnotic effects of a benzodiazepine derivative: a clinical observation

A double-blind study was conducted on triazolam, using nitrazepam and placebo as control compounds; statistically significant differences were demonstrated in favor of triazolam compared with placebo and with nitrazepam in many aspects of efficacy, but there was no significant difference between triazolam and nitrazepam in the incidence of concomitant symptoms and side effects. The fact that a certain quantity of triazolam is equivalent in strength to ten times that quantity of nitrazepam suggests the high potency of the former. These data indicate that triazolam is a valuable sleep inducer, with highly-rated efficacy and safety.     

The treatment of anxiety with a polyfluorinated benzodiazepine derivative.

Following 4 weeks of treatment with ORF-8063 a polyfluorinated benzodiazepine derivative, 8 hospitalized patients manifesting a primary pathology of anxiety showed marked general improvement. 2 other persons were treated, but for shorter periods: 9 and 14 days. Both are included in the pre-post analysis. Mean optimal dosage was 66.5 mg. The five instruments used to measure therapeutic effect showed pre- to posttreatment change with high level of statistical significance in serveral of the pathological factors. When measures of change are considered, patients showed more improvement related to psychic than somatic components of anxiety. Change data also indicates more patients improvement in anxiety than depression. Side effects reported more were dizziness, faintness and insomnia; these were reported in 8 patients. 6 patients noted drowsiness, and 4 noted excitement. 5 persons tolerated optimum dosages with no extreme reactions; 5 others (including the 2 subjects who terminated treatment early) were unable to maintain optimum dosages because of side effects.     

Psychosocial outcomes of antiepileptic drug discontinuation. The Medical Research Council Antiepileptic Drug Withdrawal Study Group.

The MRC Antiepileptic Drug Withdrawal Study compared seizure control and the risk of relapse resulting from policies of slow discontinuation and routine maintenance of antiepileptic drug (AED) treatment in patients seizure-free for > or = 2 years. Because the decision to discontinue AEDs can have important psychosocial as well as medical consequences, we also sought to examine the psychosocial outcomes of the alternative policies Questionnaires were sent to eligible adults 2 years after their randomization. The response rate was 85%. There was little evidence of substantial effects of treatment policy on psychosocial outcomes, but seizure recurrence since randomization was associated with increased distress on several measures. However, receiving AEDs to control seizures was also associated with increased distress. Among patients for whom the risk of relapse after discontinuation appears low, the psychosocial benefits of discontinuation may be considerable.     

Antioxidant activity of topiramate: an antiepileptic agent

A number of experimental and clinical reports suggest the involvement of oxidative stress in pathophysiology of epilepsy. Topiramate, a new antiepileptic drug, induces antioxidant effect in epileptic animals. However, to date, no further studies appear to be carried out in order to demonstrate the ability of topiramate to act as antioxidant. Therefore, the objective of this work was to evaluate the in vitro superoxide (O ₂ ^·? ), hydroxyl radical (OH·), hypochlorous acid (HOCl), hydrogen peroxide (H₂O₂), singlet oxygen (¹O₂) and peroxynitrite (ONOO^?) scavenging capacity of topiramate in comparison with reference compounds. In addition, we investigated the possible antitumour activity of this compound in some cancer cell lines. Topiramate displays a scavenging capacity compared to the reference compound, with the exception of ONOO^?, although it was less efficient than nordihydroguaiaretic acid, dimethylthiourea, ascorbic acid, sodium pyruvate and glutathione for O ₂ ^·? , OH·, HOCl, H₂O₂ and ¹O₂ (P < 0.0001), respectively, and not induced significant growth inhibition in cancer cell lines. The direct antioxidant properties of topiramate could explain the neuroprotective effects attributed to this compound and suggest its use as chemopreventive agent in a future.     

Antiepileptic drug therapy for adult patients with intractable seizures]

Epileptic syndrome, antiepileptic drug (AED) therapy and mental disorder were studied in 223 patients with intractable epilepsy, who were admitted to our epilepsy center between 1992 and 2000. Symptomatic localization-related epilepsy was diagnosed in 86.1% of patients, symptomatic or cryptogenic generalized epilepsy in 7.6%, idiopathic generalized epilepsy in 1.8%, unclassifiable epilepsy in 3.1% and non-epilepsy in 1.3% on discharge. Only 6.3% had diagnoses on discharge that were incongruent with their diagnoses on admission. AED therapy during admission improved markedly in 50% of patients and moderately in 20%, however, 60% had seizures more frequently than 4 a month on discharge. Generalized tonic and clonic seizures were suppressed completely in 82.5% of patients. The number of AEDs used were 2 AEDs in 28.6%, 3 in 39.1% and 4 in 22.3%. Only 6.4% of patients were on monotherapy on discharge. Mental retardation was in 58.7%, schizophrenia-like psychosis in 8.5%, delusional disorder in 1.8%, mood disorder in 3.6%, AED-related disorder in 14.3% and psychogenic disorders in 21.5%. AED therapy is effective for intractable seizures, but it is limited in its effect. Mental disorders also coexisted in most of patients. Therefore comprehensive therapy of epilepsy is necessary for patients with intractable seizures.     

Antiepileptic activity of melatonin in guinea pigs with pentylenetetrazol-induced seizures

Abstract

Background: Antiepileptic and neuroprotective effects of melatonin (N-acetyl-5-methoxytryptamine) have been shown at higher doses (50–160 mg/kg). We aimed to investigate the antiepileptic effects of low-dose melatonin (10 mg/kg) on pentylenetetrazol (PTZ)-induced experimental epilepsy model.

Materials and Methods: Twelve male albino guinea pigs weighing 500–800 g were used in our work. Initially, latent period, seizure intensity and mortality parameters were evaluated during the epileptic seizure induced by PTZ. After a recovery period of 7 days, effects of the neuroprotective agent, melatonin (which is dissolved in 2.5% ethanol–saline solution), on epileptic seizures induced by PTZ were evaluated. Effects of 2.5% ethanol, which is an anticonvulsant agent when administered acutely in high concentrations, on PTZ-induced seizures were also evaluated.

Results: Data obtained from the study groups (PTZ, PTZ + melatonin and PTZ + ethanol) were evaluated by paired t-test, and p<0.005 was considered statistically significant. The differences of latent periods between the PTZ and PTZ + melatonin groups were found to be statistically significant (p<0.001).

Conclusion: Although melatonin does not have a primary anticonvulsant effect at low doses (10 mg/kg), it lowers the mortality rates and attenuates seizure severity while increasing the latent period.     

The activity of antiepileptic drugs as histone deacetylase inhibitors

PURPOSE: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors. METHODS: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate. RESULTS: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent Ki values of 2.22 +/- 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinone-n-butyric acid (PBA), inhibited HDACs with Ki values of 2.25 +/- 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively. CONCLUSIONS: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.     

Subchronic treatment with antiepileptic drugs modifies pentylenetetrazol-induced seizures in mice: Its correlation with benzodiazepine receptor binding

Experiments using male CD1 mice were carried out to investigate the effects of subchronic (daily administration for 8 days) pretreatments with drugs enhancing GABAergic transmission (diazepam, 10 mg/kg, ip; gabapentin, 100 mg/kg, po; or vigabatrin, 500 mg/kg, po) on pentylenetetrazol (PTZ)-induced seizures, 24 h after the last injection. Subchronic administration of diazepam reduced latencies to clonus, tonic extension and death induced by PTZ. Subchronic vigabatrin produced enhanced latency to the first clonus but faster occurrence of tonic extension and death induced by PTZ. Subchronic gabapentin did not modify PTZ-induced seizures. Autoradiography experiments revealed reduced benzodiazepine receptor binding in several brain areas after subchronic treatment with diazepam or gabapentin, whereas subchronic vigabatrin did not induce significant receptor changes. The present results indicate differential effects induced by the subchronic administration of diazepam, vigabatrin, and gabapentin on the susceptibility to PTZ-induced seizures, benzodiazepine receptor binding, or both.     

N-acetyl-beta-glucosaminidase and beta-galactosidase activity in children receiving antiepileptic drugs

To evaluate renal tubular function in children receiving antiepileptic drugs the urinary activity of two lysosomal enzymes, N-acetyl-beta-glucosaminidase and beta-galactosidase, were measured. The enzyme levels were determined before the administration of antiepileptic drugs and 8 months after. Fourteen epileptic children received valproate, and 17 received carbamazepine. The urinary activity of these enzymes in 25 healthy control patients also was examined. Increased N-acetyl-beta-glucosaminidase activity was found in 50% of patients taking valproate and in 17.6% of patients taking carbamazepine. Increased beta-galactosidase activity was found in 28.5% of patients taking valproate and 11.7% of patients taking carbamazepine compared with the results before treatment. On the basis of these results, it is suggested that patients taking antiepileptic drugs, especially valproate, may demonstrate minor signs of tubular dysfunction. In those patients who use these drugs at increased dosage levels or for long periods, the possibility of tubular dysfunction may be increased, and these dysfunctions may manifest in clinical symptoms.