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 (2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA, a novel antiepileptic drug, has been shown to bind to a specific binding site located in the brain (Eur. J. Pharmacol. 286 (1995) 137). To identify the protein constituent of the levetiracetam binding site in situ, we synthesized the photoaffinity label [3H]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide), a levetiracetam analog with higher affinity for the levetiracetam binding site. This radioligand was used to map the levetiracetam binding site within the brain and to study its cellular and subcellular distribution. Autoradiography experiments using [3H]ucb 30889 in rat brain revealed a unique distribution profile that did not match that of classical receptors known to be involved in the generation of epileptic seizures. There was a high level of binding in the dentate gyrus, the superior colliculus, several thalamic nuclei, the molecular layer of the cerebellum and to a lesser extent in the cerebral cortex, the striatum and the hypothalamus. The levetiracetam binding site was restricted to neuronal cell types, undifferentiated PC12 cells and was highly enriched in synaptic vesicles. [3H]ucb 30889 was also used in photoaffinity labelling studies and shown to bind covalently to a membrane protein with a molecular weight of approximately 90 kDa.
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PMID:Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines. 1455 79

A large number of new antiepileptic drugs (AEDs) have become available over the last 10 years. Results from placebo-controlled clinical trials and community-based practice have demonstrated that levetiracetam has a broad spectrum of activity in suppressing seizures as add-on treatment and monotherapy and that it is safe and well-tolerated. Levetiracetam also has a favourable pharmacokinetic profile characterised by rapid and nearly complete absorption, very low potential for drug interactions and a prolonged pharmacodynamic effect that permits twice-daily dosing. Although, the mechanism of action of levetiracetam is not completely understood, preclinical studies suggest that it may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression.
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PMID:Levetiracetam: treatment in epilepsy. 1459 61

Levetiracetam, an antiepileptic drug, is used worldwide as an adjunctive treatment for partial-onset seizures. The availability of a new oral solution formulation would provide an additional treatment option for patients who have difficulty swallowing tablets. A phase I single-center, randomized, open-label, two-way crossover, single-dose study was conducted to confirm that a 10% oral solution of levetiracetam was bioequivalent to the 750-mg oral tablet and to characterize its pharmacokinetics. Each of 24 healthy subjects received a single oral 750-mg dose of the randomized levetiracetam formulation (7.5 mL of 10% solution or 750-mg tablet) on day 1 and a single oral dose of the alternate formulation on day 8. Serial blood samples were collected from 0 to 36 hours after each dose administration for determination of plasma levetiracetam concentrations. Pharmacokinetic parameters were calculated, and bioequivalence of the two formulations was evaluated. The mean levetiracetam plasma concentration-time curves and pharmacokinetic parameters essentially were identical for the oral 10% solution and tablet and consistent with previously reported levetiracetam pharmacokinetics. The 90% confidence limits of the geometric mean ratio of the two formulations for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to last measurable time point, and maximum plasma concentration were within the 80% to 125% range, demonstrating bioequivalence of the two formulations. Both levetiracetam formulations were well tolerated. The levetiracetam 10% oral solution is a bioequivalent, well-tolerated alternative to the tablet formulation in patients who have difficulty swallowing.
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PMID:Levetiracetam: relative bioavailability and bioequivalence of a 10% oral solution (750 mg) and 750-mg tablets. 1461 73

Levetiracetam (LEV) is effective for treating localisation-related epilepsy, but it is uncertain whether it is effective for treating idiopathic generalised epilepsy. We compared 12-week baseline and LEV treatment periods for patients with generalised seizure types-myoclonic, tonic-clonic and absence seizures--who had failed other anticonvulsants. The majority of 55 patients (76%) had >50% seizure reduction with LEV therapy, 40% became seizure-free; 15% discontinued LEV due to adverse events, mostly sedation. This is preliminary evidence that LEV is effective for treating idiopathic generalised epilepsy.
Seizure 2003 Dec
PMID:Levetiracetam treatment of idiopathic generalised epilepsy. 1463 May 6

We investigated the Levetiracetam (LVT) ability to protect the brain against kainic acid (KA) induced neurotoxicity. Brain injury was induced by intraperitoneal administration of KA (10 mg/kg). Sham brain injury rats were used as controls. Animals were randomized to receive either LVT (50 mg/kg) or its vehicle (1 ml/kg) 30 min. before KA administration. Animals were sacrificed 6 hours after KA injection to measure brain malonildialdehyde (MDA), glutathione levels (GSH) and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of LVT decreased significantly MDA in the cortex (KA + vehicle = 0.25 +/- 0.03 nmol/mg protein; KA + LVT = 0.13 +/- 0.01 nmol/mg protein; P < 0.005), and in the diencephalons (KA + vehicle = 1,01 +/- 0.2 nmol/mg protein; KA + LVT = 0,33 +/- 0,08 nmol/mg protein; P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 5 +/- 1 micromol/g protein; KA + LVT = 15 +/- 2 micromol/g protein; P < 0.005) and diencephalons (KA + vehicle = 9 +/- 0.8 micromol/g protein; KA + LVT = 13 +/- 0.3 micromol/g protein; P < 0.05), reduced brain IL-1beta mRNA and markedly controlled seizures. Histological analysis showed a reduction of cell damage in LVT treated samples. The present data indicate that LVT displays neuro-protective effects against KA induced brain toxicity and suggest that these effects are mediated, at least in part, by inhibition of lipid peroxidation.
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PMID:Levetiracetam protects against kainic acid-induced toxicity. 1469 8

Levetiracetam (Keppra) was evaluated in a subset of patients aged >/=65 years (n=78) enrolled in a large (n=1030) open-label, phase IV trial (the KEEPER trial). A 4-week dose adjustment was followed by a 12-week evaluation period. An overall median reduction in partial seizures of 80.1% (n=65) was observed. Overall, 76.9% of patients were >/=50% responders, 56.9% were >/=75% responders, and 40.0% were 100% responders. Levetiracetam was well tolerated, with 42.3% of patients reporting one or more adverse events. A total of 15 patients (19.2%) experienced an adverse event that led to discontinuation. Somnolence (n=13,16.7%) and dizziness (n=7,9.0%) were the most commonly reported adverse events. Despite the limitations of the open-label study design, these data provide information regarding the use of levetiracetam as add-on therapy for the treatment of partial-onset seizures in patients >/=65 years of age, including those requiring concomitant medications.
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PMID:Use of levetiracetam in a population of patients aged 65 years and older: a subset analysis of the KEEPER trial. 1469 4

Levetiracetam is a new anti-epileptic drug that is currently not licensed for use in children. Studies in adults suggest that it may be a useful adjunctive treatment both in partial onset and generalised epilepsy. A retrospective case notes review of 26 children age 10 years and under with refractory epilepsy was undertaken to evaluate the efficacy and safety of the drug. The drug appeared to be most effective in children with partial onset seizures and least effective in those with myoclonic seizures. Sixty-one percent of patients showed a good response to levetiracetam with at least a 50% reduction in seizure frequency with two of these 26 children with previously refractory epilepsy becoming seizure-free. Levetiracetam was also found to be well-tolerated with very few reported side-effects.
Seizure 2004 Apr
PMID:Efficacy and tolerability of levetiracetam in children aged 10 years and younger: a clinical experience. 1501 50

The amygdala-kindling model has been proposed as a model of sensitization processes with relevance to epilepsy as well as affective disorders. Levetiracetam is a novel anticonvulsant drug that delays the process of kindling, i.e., possesses antiepileptogenic properties. Preliminary reports also suggest a mood-stabilizing potential for levetiracetam. Brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) are central modulators of seizure activity, which undergo plastic changes during kindling epileptogenesis. Consequently, we investigated the regulation of BDNF and NPY mRNA and Y1-, Y2-, and Y5-like receptor binding in the hippocampus of vehicle-pretreated, partially and fully amygdala-kindled rats and corresponding levetiracetam-pretreated rats (40 mg/kg i.p.). The present data indicate that the process of kindling is associated with an upregulation of hippocampal BDNF and NPY mRNA levels and downregulation of Y1- and particularly Y5-like receptors. Pretreatment with levetiracetam markedly delays the progression of kindling and, in addition, exhibits a clear anticonvulsant effect. These effects are associated with abolition of the kindling-induced rise in BDNF and NPY mRNA and increasing levels of Y1- and particularly Y5-like receptors in all hippocampal subfields. Lastly, the present study reveals that an identical dose of levetiracetam reduced immobility in the rat forced swim test, the first experimental evidence indicative of an antidepressant and/or mood stabilizer-like profile of this drug. Considering that animal depression models display impairments in hippocampal NPY systems that become normalized following mood-stabilizing treatment, and that exogenous NPY exerts anticonvulsant as well as antidepressive-like activity in rodents, it is a heuristic possibility that increased hippocampal excitability and affective symptomatology may converge on an impaired hippocampal NPY function. Speculatively, the ability of levetiracetam to increase hippocampal Y1- and Y5-like receptor levels may have implications for the antiepileptic properties of levetiracetam, as well as its purported mood-stabilizing properties.
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PMID:Levetiracetam prevents changes in levels of brain-derived neurotrophic factor and neuropeptide Y mRNA and of Y1- and Y5-like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood-stabilizing properties. 1512 22

Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.
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PMID:Clinical pharmacokinetics of levetiracetam. 1530 75

Levetiracetam is highly effective as add-on treatment in refractory partial-onset seizures but there are only limited data supporting its benefit in generalised epilepsies. We have reviewed the clinical records of 25 consecutive adult patients with generalised epilepsies (84% females; mean age 34 (range 16-75) years) prescribed levetiracetam for at least six months. The epilepsy was considered idiopathic in 22 patients (88%)--including 13 with juvenile myoclonic epilepsy--and symptomatic in three. Most patients (68%) reported some improvement in seizure frequency on levetiracetam including 16% who became seizure free. Levetiracetam was generally well tolerated although 11/25 (44%) of patients reported some tiredness, weight change or rash. Levetiracetam was stopped in five patients, four because of side effects and one though lack of efficacy. In four cases, pre-existing antiepileptic medication was withdrawn, leaving levetiracetam as monotherapy. We conclude that levetiracetam is a useful add-on treatment for patients with refractory generalised epilepsies.
Seizure 2004 Oct
PMID:Levetiracetam as add-on therapy in generalised epilepsies. 1532 24


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