Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A significant proportion of women with epilepsy have an increase in their seizure frequency during pregnancy. Multiple factors may be involved in this phenomenon, but changes in antiepileptic drug (AED) concentration appear to be the most significant. AED concentration declines as pregnancy progresses, due primarily to dynamic changes in plasma protein binding. Total concentrations of all first-line AEDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) fall significantly during pregnancy, compared to baseline. Free or unbound drug concentrations, however, fall significantly only for phenobarbital. Valproate free concentrations actually increase by 25% by delivery. Women taking carbamazepine, phenytoin, or valproate may be relatively protected by adequate free concentrations of these compounds. When managing pregnant women with epilepsy, measurement of free AED concentrations and appropriate dose adjustment to maintain therapeutic ranges will permit more effective clinical management than using total concentration values.
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PMID:Antiepileptic drug disposition during pregnancy. 157 66

High concentrations of valproate (VPA; greater than 20 mM) depolarized identified neuronal individuals in the buccal ganglia of Helix pomatia and transiently induced paroxysmal depolarization shifts (PDS). Threshold concentration of VPA for the induction of PDS was decreased (a) by increased seizure susceptibility, (b) by increased concentrations of derivatives of VPA, and (c) by increased H+ concentrations. Intrasomatic injection of VPA did not induce PDS. The epileptogenic action of VPA is believed to be exerted from the extracellular side of the cell membrane.
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PMID:Effects of valproate in a model nervous system (buccal ganglia of Helix pomatia): II. Epileptogenic actions. 162 94

The abolition of seizures using a single antiepileptic agent can be expected in more than 80% of patients, although not necessarily with the first drug tried. The remainder often receive polypharmacy, and current evidence suggests that perhaps only around 10% of these benefit significantly in terms of improved seizure control. Many more experience complicated drug interactions. Carbamazepine, phenytoin, phenobarbital, and primidone (metabolized in part to phenobarbital) all induce the synthesis of hepatic monooxygenase and conjugating enzymes. This will result in an acceleration in the metabolism of other lipid-soluble drugs with likely attenuation of their pharmacological effects. Valproate, on the other hand, is a minor enzyme inhibitor. Pharmacokinetic interactions are almost invariable when more than one antiepileptic drug is coprescribed. The extent and direction of interactions with combinations of these drugs are varied and unpredictable. Discontinuation of an enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s). Pharmacodynamic interactions also cause problems in epileptic patients. A number of commonly prescribed psychoactive drugs, such as tricyclic antidepressants and neuroleptics, can worsen seizure control by reducing the convulsion threshold. In addition, there seems little doubt that ethanol abuse and withdrawal can precipitate seizures in susceptible patients. Antiepileptic polypharmacy is more likely to impair cognitive function than the same drugs used singly. In addition, the more antiepileptic drugs received by a patient in the first trimester of pregnancy, the higher the risk of teratogenesis in the exposed infant. Drug interactions prolong and complicate the process of new drug assessment, particularly when introduced in treated patients with refractory epilepsy. The candidate antiepileptic drug may alter the concentration of concomitant therapy, or its own breakdown may be influenced by coprescribed enzyme inducers or inhibitors. Even if the new drug is excreted unchanged by the kidney, unexpected interactions can be uncovered. Pharmacodynamic interactions need not always be detrimental. Currently, there is no rational approach to the treatment of intractable epilepsy. As more new drugs with single mechanisms of action become available, the potential exists for combining these synergistically. This approach may revolutionize the pharmacological management of the epileptic patient in the 21st century.
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PMID:Drug interactions in epilepsy. 164 52

Neonatal Long-Evans hooded rats were treated with AY-9944, a cholesterol biosynthesis inhibitor, every 6 days for 7 weeks to induce a permanent absence-like epileptic condition. AY-9944-treated rats averaged 50 +/- 15 generalized non-motor seizures per hour of 2-15 s duration as monitored by electrocorticography. Clinically effective anti-absence drugs were observed to reduce seizure occurrence in a dose-dependent manner. Paradoxically, GABA agonists increased seizure occurrence while GABA antagonists decreased seizure occurrence. Evaluation of the benzodiazepines, diazepam and clonazepam, in this model revealed inhibition of seizure activity by GABA-independent mechanisms. Valproic acid produced a biphasic effect suggesting a GABA-independent, antiabsence action at low doses and GABAergic augmentation of seizure occurrence at higher doses. The results of this study support the hypothesis that increased GABAergic stimulation may induce inhibitory seizures in absence epilepsy.
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PMID:Paradoxical role of GABA in a chronic model of petit mal (absence)-like epilepsy in the rat. 169 Jan 39

We report on 79 pregnancies in 66 female outpatients with epilepsy. An increase of seizure frequency was significantly more frequent in complex partial seizures than in grand mal seizures and in absences. The reason for these disparities are not clear. In most patients a raised frequency of seizures during pregnancy decreased again after delivery. Carbamazepine was the antiepileptic drug prescribed most frequently followed by valproic acid. The course of the blood levels of carbamazepine and valproic acid was nonuniform during pregnancy. Total concentrations of carbamazepine in cord blood were on average 84.5% of those in maternal blood (n = 22). Valproic acid blood levels were on average 183% of those in maternal blood (n = 15). It is still unclear whether these differences are clinically relevant. During the last weeks of pregnancy we found an increase of the free fraction of carbamazepine and valproic acid. Simultaneously the total protein concentration decreased. Until now these findings are without clinical relevance. The course of labor did not differ from normal population concerning the ratios of spontaneous labor, cesarean section and delivery by forceps. Miscarriage and perinatal mortality were 2.7% each and outnumbered the risk in the general population. In 42.8% of the neonates one to three perinatal complications were observed. The ratio of perinatal complications is not different between patients with monotherapy and combined therapy respectively. There was a tendency to lower values of length, weight and head circumference in the male neonates but not in the female neonates. The risk of minor malformations was 26%, the risk of major malformations was 14% (including one case of suspected malformation) without a discernible correlation with a specific antiepileptic drug.
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PMID:[The course of pregnancy and teratogenicity of antiepileptic agents in 66 patients with epilepsy]. 172 Dec 36

A young woman with acute intermittent porphyria (AIP) and juvenile myoclonic epilepsy began to have generalized tonic-clonic seizures (GTCs) at age 13. Subsequently, she had myoclonic seizures, which were often precipitated by visual stimulation, tended to occur in the morning, and sometimes evolved into GTCs. Valproate (VPA) resulted in a worsening of latent AIP, and treatment with a combination of phenytoin (PHT), carbamazepine (CBZ), and clonazepam (CZP) led to severe neuropathy of AIP and an electrolyte imbalance. These conditions were improved by water restriction, infusion of high doses of carbohydrates, and discontinuation of all antiepileptic drugs (AEDs) except for CZP. CZP appeared to be effective both in improving GTCs and myoclonic seizures and did not induce any symptoms of AIP. CZP may be porphyrogenic but can be used safely at a low dose for treatment of epilepsy in patients with AIP.
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PMID:Acute intermittent porphyria and epilepsy: safety of clonazepam. 173 41

The anticonvulsant potency of the trans isomer of 2-en-valproate (trans-2-en-VPA) was determined in standardized models for different seizure types in rodents and dogs. In mice and rats, adverse effects were quantified by the rotarod and chimney tests. Clinically established antiepileptic drugs (valproate, ethosuximide, phenobarbital, carbamazepine, phenytoin, diazepam) were used for comparison. Based on time course studies, drug potencies were determined and compared at the individual time of peak anticonvulsant effect. Potency comparisons were based on administered dosages and, in the case of trans-2-en-VPA and valproate, also on plasma levels determined after administration of anticonvulsant doses. The data show that trans-2-en-VPA exerts anticonvulsant effects against different seizure types, i.e., myoclonic, clonic, and tonic seizures in rodents and (myo)clonic seizures in dogs. In most seizure models, trans-2-en-VPA was more potent than valproate, when both compounds were compared at their individual times of peak effect. Time course and pharmacokinetic studies showed that duration of action and pharmacokinetic characteristics of trans-2-en-VPA and valproate are similar. In the rotarod and chimney tests in mice and rats, trans-2-en-VPA was more potent than valproate. However, because of the higher anticonvulsant potency of trans-2-en-VPA, protective indices calculated from rodent models were similar to those of valproate. Similarly, in dogs trans-2-en-VPA exerted anticonvulsant effects at doses below those which induced sedation and ataxia. In view of the previously reported advantages of trans-2-en-VPA compared to valproate with respect to teratogenic and hepatotoxic effects, the present data substantiate that trans-2-en-VPA might be a valuable alternative to valproate in antiepileptic therapy.
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PMID:Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs. 174 83

MK-801 (a potent non-competitive antagonist of N-methyl-D-aspartic acid-mediated events) in subcutaneous doses of 0.1 and 0.2 mg/kg increased the threshold for electroconvulsions and in doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against maximal electroshock-induced convulsions in mice. Valproate-induced side-effects (evaluated by means of dark-avoidance acquisition and retention testing and the chimney test) at its ED50 against maximal electroshock (i.e. 268 mg/kg) were pronounced whereas they were absent in the case of a combined treatment with MK-801 (0.0125 mg/kg) and valproate (91 mg/kg). This treatment provided 50% protection against maximal electroshock-induced seizures. Moreover, MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, reducing phenobarbital-induced motor impairment totally at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg. The N-methyl-D-aspartic acid antagonist did not affect the total plasma levels of either valproate or phenobarbital (as measured by immunofluorescence), so a pharmacokinetic interaction, in terms of total plasma levels at least, is unlikely to be involved in the observed effects. The finding that the combined treatment of MK-801 with valproate or phenobarbital, apart from the distinct potentiation of their anticonvulsant activities, is devoid of side-effects should be carefully considered.
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PMID:Influence of MK-801 on the anticonvulsant activity of antiepileptics. 178 90

Eating epilepsy is a rare type of reflex epilepsy. A 24 years-old male with eating reflex complex partial seizures was submitted to clinical, neurological, neuroradiological and EEG studies. Neurologic and CT examinations were normal. EEG recordings including video-EEG monitoring during meals disclosed focal abnormalities related to both temporal lobes prevailing at the left side and secondary bilateral synchrony mainly in more anterior regions. Ictal findings were similar to the interictal secondary bilateral synchrony except for its longer duration. PB, VPA and DPH monotherapies were ineffective. High dose CBZ monotherapy yielded good but incomplete seizure control. Since a big number of precipitants could be involved, no specific physiopathological basis could be established.
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PMID:Eating epilepsy. 180 34

We report three cases of reflex epilepsy with myoclonic jerks of the right arm and fingers precipitated by calculation using a Soroban. An EEG spike-wave complex with left central prevalence was induced. Various types of stimulation were used to induce epileptic discharges, and a simultaneous mental task requiring a high degree of concentration and complicated and delicate finger movements was necessary to induce the epileptic discharges. Comparison of our cases with previously reported reflex epilepsy induced by higher mental activity led to the assumption that the neural mechanism inducing seizures in our cases is similar to that of writing epilepsy. Valproate was effective in reducing epileptic discharges, and all patients became seizure-free.
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PMID:Reflex epilepsy induced by calculation using a "Soroban," a Japanese traditional calculator. 189 20


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