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)

Levetiracetam ((S)-alpha-2-oxo-pyrrolidine acetamide, ucb L059) is a novel anticonvulsant drug presently in clinical development. Its mechanism of action is unknown although a recently novel specific binding site for [3H]levetiracetam, unique to brain, may be involved. This binding site has yet been characterized, but some evidence suggested a possibly indirect interaction with the GABA system. We therefore examined levetiracetam's effects on GABA metabolism and turnover in several rat brain regions after systemic administration of anticonvulsant doses. Furthermore, in order to study functional effects of levetiracetam on a well defined system of GABAergic neurons in a brain region that has been critically involved in anticonvulsant drug action, we examined levetiracetam's action on spontaneous firing of substantia nigra pars reticulata (SNR) neurons in anesthetized rats. Although levetiracetam did not alter the activity of the GABA synthesizing and degrading enzymes glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T) in vitro, systemic administration induced significant alterations in these enzymes in several brain regions, indicating that these enzyme alterations were no direct drug effects but a consequence of postsynaptic changes in either GABAergic or other neurotransmitter-related systems. In the striatum, levetriacetam, 170 mg/kg i.p., induced a significant increase in GABA-T activity while GAD activity markedly decreased. When GABA turnover was estimated after inhibition of GABA-T by aminooxyacetic acid (AOAA), treatment with levetiracetam (given 15 min prior to injection of AOAA) significantly reduced GABA turnover in the striatum. Since the substantia nigra pars reticulata (SNR) receives a strong GABAergic input from the striatum, we examined if the alterations in GABA metabolism and turnover in the striatum led to functional alterations in neuronal activity in the SNR by recording single unit activity of SNR neurons after i.p. injection of levetiracetam. While injection of vehicle did not affect SNR neuronal activity, a significant decrease in spontaneous neuronal firing was recorded after levetiracetam. Since a substantial body of evidence suggests that the SNR is a critical site at which decrease of neuronal firing results in protection against various seizure types, the suppressive effect of levetiracetam on SNR activity may contribute to the anticonvulsant action of this drug.
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PMID:The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. 891 59

The anticonvulsant effects of levetiracetam were assessed in two genetic rat models. In the audiogenic-seizure prone rat, levetiracetam, 5.4 to 96 mg/kg i.p. dose-dependently inhibited both wild running and tonic-clonic convulsions. In the GAERS model of petit mal epilepsy, levetiracetam markedly suppressed spontaneous spike-and-wave discharge (SWD) but left the underlying EEG trace normal. The effects were already marked at 5.4 mg/kg and did not increase significantly up to 170 mg/kg although more animals were completely protected. Levetiracetam produced no observable effects on behaviour apart from slight reversible sedation at 170 mg/kg. In contrast, piracetam, a structural analogue of levetiracetam, significantly and consistently suppressed SWD in GAERS rats only at the high dose of 1000 mg/kg with some slight effects at lower doses. The effect of piracetam appeared to be due to increased sleeping rather than to a direct antiepileptic effect. The results with levetiracetam argue for a clinical application in both petit mal, absence epilepsy and in treating generalised tonic-clonic and partial seizures.
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PMID:Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. 899 87

Levetiracetam is a novel antiepileptic agent with a wide spectrum of activity against experimental and clinical seizures. The mechanism of its anticonvulsant action remains to be determined. We have investigated the effects of levetiracetam on several gamma-aminobutyric acid (GABA)-related neurochemical parameters in mouse brain. Adult male mice were randomised into two groups and administered levetiracetam (0-300 mg/kg) intraperitoneally either as a single dose or twice daily for 5 days. Four hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of GABA, glutamate and glutamine and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single dose and repeated levetiracetam treatments were without effect on all of the parameters investigated. The anticonvulsant action of levetiracetam is unlikely to be mediated via an action on the GABAergic system.
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PMID:Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. 915 36

We have previously shown that the novel anticonvulsant levetiracetam exerts potent anticonvulsant activity against both focal and secondarily generalized seizures in fully amygdala-kindled rats, i.e. , a model of temporal lobe epilepsy. We examined whether levetiracetam also exhibits antiepileptogenic activity, i.e., prevents or retards acquisition or development of amygdala-kindling in rats. Before the experiments with chronic administration of levetiracetam at different doses, we determined the pharmacokinetics of the drug after i.p. injection. Levetiracetam had a relatively short half-life (about 2-3 hr) in rats, so that any lasting effects of the drug after chronic administration were certainly not due to drug accumulation. When rats were treated with levetiracetam during kindling acquisition at daily i.p. doses of 13, 27 or 54 mg/kg, the drug dose-dependently suppressed the increase in seizure severity and duration induced by repeated amygdala stimulation. After termination of daily treatment with 54 mg/kg, duration of behavioral seizures and of afterdischarges recorded from the amygdala remained to be significantly shorter compared to vehicle controls, although amygdala stimulations were continued in the absence of drug. These data thus indicate that levetiracetam not simply masked the expression of kindled seizures through an anticonvulsant action, but exerted a true antiepileptogenic effect. Adverse effects were not observed at any dose of levetiracetam tested in kindled rats. The powerful antiepileptogenic activity of levetiracetam in the kindling model indicates that levetiracetam is not only an interesting novel drug for symptomatic treatment of epilepsy but might be suited for pharmacological prevention of this disease in patients with a high prospective risk of the development of epilepsy.
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PMID:Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. 945 87

The protective and adverse effect potentials of levetiracetam ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) in rodent models of seizures and epilepsy were compared with the profile of several currently prescribed and newly developed antiepileptic drugs. Levetiracetam was devoid of anticonvulsant activity in the acute maximal electroshock seizure test and in the maximal pentylenetetrazol seizure test in mice (up to 540 mg/kg, i.p.) but exhibited potent protection against generalised epileptic seizures in electrically and pentylenetetrazol-kindled mice (ED50 values = 7 and 36 mg/kg, respectively, i.p.). This differs markedly from established and most new antiepileptic drugs which induce significant protection in both the acute seizure tests and the kindling models. Furthermore, levetiracetam was devoid of anticonvulsant activity in several maximal chemoconvulsive seizure tests although an interesting exception was the potent protection observed against secondarily generalised activity from focal seizures induced by pilocarpine in mice (ED50 value = 7 mg/kg, i.p.), pilocarpine and kainic acid in rats (minimum active dose = 17 and 54 mg/kg, respectively, i.p.). The protection afforded by levetiracetam on the threshold for methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)-induced seizures persisted after chronic administration (17-170 mg/kg, i.p., twice daily/14 days) and levetiracetam did not lower the seizure threshold for the proconvulsant action of the inverse benzodiazepine receptor agonist, N-methyl-beta-carboline-3-carboxamide (FG 7142). The main metabolite of levetiracetam (ucb L057; (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid) was found to be inactive in sound-sensitive mice after acute administration of doses up to 548 mg/kg, i.p. Levetiracetam induced only minor behavioural alterations in both normal and amygdala-kindled rats (54-1700 mg/kg, i.p.) resulting in an unusually high safety margin between rotarod impairment and seizure suppression of 148 in corneally kindled mice and 235 in Genetic Absence Epilepsy Rats from Strasbourg. In comparison, existing antiepileptic drugs have ratios between 2 and 17 in the corneally kindled mouse model. These studies reveal a unique profile of levetiracetam in rodent models. Characteristics are a general lack of anticonvulsant activity against maximal, acute seizures and selective protection with a very high safety margin in genetic and kindled animals and against chemoconvulsants producing partial epileptic seizures. This activity differs markedly from that of the established and newly introduced antiepileptic drugs and appears to derive from the parent compound since its major metabolite was inactive in all models studied. Together these results therefore suggest that levetiracetam may offer an effective, broad-spectrum treatment of epileptic seizures in patients, with a minimum of adverse effects.
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PMID:Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. 972 49

Levetiracetam is a novel orally active antiepileptic drug with a unique preclinical profile. It has a high therapeutic index and potential antiepileptogenic effects. Results of clinical trials indicate activity in partial-onset and generalized seizures. The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an antiepileptic drug, with good bioavailability, rapid achievement of steady-state concentrations, linear and time-invariant kinetics, minimal protein binding, and minimal metabolism. The major metabolic pathway of levetiracetam is not dependent on the hepatic cytochrome P450 system, and levetiracetam does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. Sixty-six percent of an administered levetiracetam dose is eliminated unchanged in urine; 24% is metabolized to an inactive metabolite that is detectable in blood and is also excreted in urine. Total body clearance of levetiracetam is decreased in patients with renal impairment, and doses should be modified according to creatinine clearance values. Levetiracetam is not appreciably protein-bound, nor does it affect the protein binding of other drugs. Thus, because of its minimal protein binding and lack of hepatic metabolism, the risk of drug interactions is very low. Levetiracetam has a wide margin of safety and patient-friendly pharmacokinetics that distinguish it from other currently available antiepileptic drugs. This profile may facilitate the clinical management of patients with epilepsy by providing a safer and less-complicated therapeutic strategy.
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PMID:Pharmacokinetic profile of levetiracetam: toward ideal characteristics. 1072 21

The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase. Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05] and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily. Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose.
Seizure 2000 Mar
PMID:A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. 1084 30

Levetiracetam has recently been approved as an adjunctive medication for partial seizures and frequently will be added to phenytoin. The objective of this study was to determine the presence or absence of a pharmacokinetic drug interaction of levetiracetam with phenytoin. A stable isotope tracer technique using deuterium-labeled (D10) phenytoin and high-performance liquid chromatography with ultraviolet detection (rather than mass spectrometric detection) was employed. Tracer doses of D10-phenytoin were administered i.v. before and 12 weeks after adding levetiracetam to the regimen of 6 subjects on phenytoin monotherapy for epilepsy. Blood was collected for 96 hours after each infusion. The following pharmacokinetic parameters were determined for phenytoin: Cmax, Cmin, Cavo, AUC, CL, t 1/2, VD, and free (nonprotein bound) fraction. The ratio and the 90% confidence interval of the ratio of log-transformed mean values for phenytoin pharmacokinetic parameters before (denominator) and after (numerator) adding levetiracetam all fell within the range of 0.85 to 1.17 (two one-sided test). The authors conclude that the addition of levetiracetam did not bring about clinically important changes in phenytoin pharmacokinetic parameters and that it is not necessary to change the phenytoin dosing rate when levetiracetam is added to phenytoin.
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PMID:Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique. 1086 9

Field potentials were recorded from rat hippocampal slices in order to compare the electrophysiological action of the new antiepileptic drug (AED), levetiracetam (LEV), with that of the classical AEDs, valproate, clonazepam and carbamazepine, on epileptiform responses induced by a 'high K(+)-low Ca(2+)' perfusion fluid. Increasing [K(+)] from 3 to 7.5 mM and decreasing [Ca(2+)] from 2.4 to 0.5 mM, in the bathing fluid, produced population spikes (PSs) of increasing amplitudes in the CA3 area of the slices, repetitive PSs evoked by single stimuli, and spontaneous bursts. Clinically relevant concentrations of LEV, 32 and 100 micro M, consistently reduced the second (PS(2)) and third (PS(3)) population spikes, and the number (N) of repetitive PSs per evoked response. Levetiracetam 32 micro M also opposed the increase in amplitude of the first PS (Delta PS(1)). Neither valproate 1 mM, nor clonazepam 1 micro M, nor carbamazepine 50 micro M, produced any decrease in Delta PS(1)and in PS(2), but all decreased N. These results show that LEV contrasts to reference AEDs by its ability to antagonize neuronal (hyper)synchronization, in the highly seizure-prone CA3 area of rat hippocampal slices.
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PMID:Inhibition of neuronal hypersynchrony in vitro differentiates levetiracetam from classical antiepileptic drugs. 1098 84

A brief review of epilepsy as a disease, anti-epileptic drugs (AEDs) and methods of evaluation of AEDs are presented as a background for the assessment of levetiracetam which has been approved by the FDA as add-on therapy for the treatment of partial seizures with or without secondary generalisation in adults. The exact mechanism of action of levetiracetam is not known but its action differs from that of other anti-epileptic drugs. A specific binding site for levetiracetam has been identified and is possibly related to anticonvulsant activity. Levetiracetam offers an effective and broad spectrum treatment of epileptic seizures, partial as well as generalised epilepsy. Levetiracetam has been shown to be effective in genetic and kindled animal models of epilepsy and against chemoconvulsant-induced partial epileptic seizures. Levetiracetam has a near perfect pharmacokinetic profile, with rapid absorption following oral administration, excellent bioavailability, quick attainment of steady-state concentrations, linear kinetics and minimal plasma protein binding. Levetiracetam does not interact with commonly used drugs and other AEDs. In recent Phase III clinical trials, the responder rate was 39.4 - 42.1% on 3000 mg dose, compared with placebo rates of 10.9 - 16.7%. Levetiracetam has a favourable safety profile and the most frequently reported adverse events were somnolence, asthenia and dizziness. Overall, levetiracetam is considered to have several advantages over current AEDs.
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PMID:An assessment of levetiracetam as an anti-epileptic drug. 1106 Jul 65


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