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)

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study is a continuing phase IV open-label evaluation of the antiepileptic drug levetiracetam (Keppra) as an adjunctive therapy in adult patients with uncontrolled partial seizures. The study, which began in April 2000, is scheduled to include 1400 patients from 300 centres in 16 countries. An interim analysis of the first 731 patients from 117 centres in nine countries treated over a 16-week period showed that seizure frequency was reduced by half or more in 49% of patients across all seizure types. A substantial 17.2% of patients achieved complete freedom from seizures. Levetiracetam was well tolerated overall. Adverse events were predominantly mild to moderate and rarely led to discontinuation. The most commonly reported symptoms were asthenia, somnolence, headache and dizziness.
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PMID:The SKATE study: interim analysis. 1291 96

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

(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.
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PMID:Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. 1473 35

The primary goals of antiepileptic treatment are complete cessation of seizure without any adverse reaction. In adult refractory focal epilepsies, a rational approach is based on adequate syndromic categorization and accurate knowledge of the pharmacological properties of antiepileptic drugs, whose number has significantly increased in recent years. Since 1991 nine new antiepileptic medications have been marketed in France, i. e. by order of appearance, vigabatrin (Sabril), felbamate (Taloxa), gabapentin (Neurontin), lamotrigine (Lamictal), tiagabine (Gabitril), fosphenytoin (a water-soluble phenytoin prodrug, Prodilantin), topiramate (Epitomax), oxcarbazepine (Trileptal) and levetiracetam (Keppra). Efficacy of these new compounds in focal epilepsies is proven, and in some patients with middle-severity focal epilepsy, clinical benefit is significant. Improvement is especially significant in terms of tolerability, ease of use and reduced interaction potential. However, some of these drugs (tiagabine, topiramate) may have an unfavorable short-term tolerance profile, while others (felbamate, lamotrigine) expose patients to a potential risk of severe acute idiosyncratic reactions. Increased availability of new drugs and the fact that drug monitoring has been claimed to be of little or no value in newly-marketed drugs have paradoxically strongly complicated therapeutic options. Moreover, only a few patients with truly refractory focal epilepsy can be made seizure-free by these new compounds, and the search for more effective anticonvulsants should continue in addition with alternative therapies or surgery.
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PMID:[Treatment protocol for long-term anti-epilepsy drugs in adults with refractory partial epilepsy]. 1533 73

We identified 46 patients with a history of partial seizures, with and without secondarily generalization, who received levetiracetam (LEV) (Keppra) monotherapy. Patients began LEV either as first line therapy (n=11) or were converted to LEV monotherapy (n=35) after failing prior antiepileptic medications (AEDs). Patients were followed up to 12 months after LEV started. The majority of these patients were able to continue on LEV and a small number of patients discontinued LEV secondary to lack of efficacy. One third of the non-seizure free group at 6 months of follow-up had worse seizure control at 12 months and two thirds had the same or better seizure control. Our 1-year follow-up data of LEV as monotherapy suggests that LEV can be effective and well tolerated in adults with either new or difficult to control epilepsy. A prospective, large, long-term double-blind study is needed to confirm this finding.
Seizure 2005 Mar
PMID:Clinical experience of levetiracetam monotherapy for adults with epilepsy: 1-year follow-up study. 1569 69

Levetiracetam (Keppra) is a novel antiepileptic drug approved as adjunctive treatment for adults with partial onset seizures. Although the drug is generally well tolerated, behavioral side effects have been reported in variable frequency. Most behavioral problems are mild in nature (agitation, hostility, anxiety, emotional lability, apathy, depression) and quickly resolve with discontinuation of medication. However, serious psychiatric adverse events may also occur with rare cases of psychosis and suicidal behavior. We report here the case of a 43-year-old woman who developed symptoms compatible with catatonia after being exposed to levetiracetam for the treatment of epilepsy. To our knowledge, it is the first reported case of catatonia induced by levetiracetam. We review the difficulties that may be encountered in the differential diagnosis of medical catatonia.
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PMID:Catatonia induced by levetiracetam. 1624 24

Keppra (levetiracetam) was used as a part of the complex therapy in 87 patients with partial epilepsy and in 17 patients with adult idiopathic generalized epilepsy. Most of the cases were pharmacoresistant. Remission was observed in 25.3% of patients for the period over 12 months. Therapeutic efficacy by a decrease of seizures frequency by 75% and more has been reached in 12.6% of cases; by 50% and more--in 43.7%. The absence of drug effect and insufficient efficacy were detected only in 18.4% of cases. The therapeutic effect was stable and did not decrease after 12 and 24 months. The drug was well tolerated and was withdrawn in 5 cases (4.8%) because of side effects. The results obtained hold promise for using keppra in epileptology, in particular in treatment of pharmacoresistant epilepsy.
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PMID:[The results of the two-year experience of using keppra in therapy of adult patients with epilepsy]. 1692 15

Brivaracetam (UCB 34714) is chemically related to levetiracetam (LEV, Keppra). It possesses a binding affinity for the synaptic vesicle protein 2A (SV2A) ten-fold above that of LEV and also shows an ability to inhibit Na+ channels. This correlates with a higher potency in suppressing epileptiform responses in vitro and a more potent and complete suppression of different seizure types in animals with an acquired or genetic epilepsy. Brivaracetam has been tested in a comprehensive safety pharmacology, toxicology, developmental toxicology, and genotoxicity program. It is of low acute toxicity, target organ for toxic effects is the hepatobiliary tract. Carcinogenicity studies are ongoing. Human pharmacology studies have shown that brivaracetam has a half-life of 8 h and nearly complete bioavailability. Brivaracetam is primarily metabolized via hydrolysis of the acetamide group and CYP2C8-mediated hydroxylation. Its metabolites are not pharmacologically active. Excretion of over 95% of the dose, including metabolites, occurs renally within 72 h. Healthy volunteer studies demonstrated a favorable tolerability profile. Treatment emergent adverse events were mild to moderate, mostly of CNS origin, and resolved within 24 hrs, with decreasing incidence after repeated intake. Drug-drug interaction studies with high dose of brivaracetam (400 mg/d) showed a dose-dependent increase of carbamazepine-epoxide levels. No significant interaction with low doses of phenytoin was observed at the same high dose levels of brivaracetam, and only a moderate pharmacokinetic interaction with an oral contraceptive, without impact on hormonal levels or ovulation, was observed. The pharmacokinetic profile of brivaracetam is unaltered in elderly subjects or those with impaired renal function. Clearance of brivaracetam is reduced in patients with hepatic insufficiency. In the photoparoxysmal response model in patients with photosensitive epilepsy brivaracetam was effective at all tested doses (10 - 80 mg) in reducing or abolishing EEG discharges evoked by a photic stimulus. Phase 2 studies in patients with refractory partial onset seizures have recently been completed.
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PMID:Brivaracetam (UCB 34714). 1719 19

Better pharmacotherapies for epilepsy are needed for patients who are refractory to or have tolerability difficulties with current treatments. Seletracetam, a new drug in epilepsy development, is a pyrrolidone derivative structurally related to levetiracetam (trade name Keppra). It was discovered because of its high binding affinity to the synaptic vesicle 2A (SV2A) protein, which is now known to be the binding site for this family of compounds. Seletracetam shows very potent seizure suppression in models of acquired or genetic epilepsy, as well as high CNS tolerability in various animal models. Pharmacokinetic studies in animals suggest that seletracetam is rapidly and highly absorbed, with linear and time-independent pharmacokinetics. Seletracetam appears neither to inhibit nor to induce the major human drug metabolizing enzymes, and it demonstrates low plasma protein binding (<10%), which suggests a low potential for drug-drug interactions. Initial studies in humans demonstrated first-order monocompartmental kinetics with a half-life of 8 h and an oral bioavailability of >90%. Studies in healthy volunteers showed that the treatment emergent adverse events were of mild to moderate severity, were mostly of CNS origin and were resolved within 24 h. Altogether, these results suggest that seletracetam represents a promising new antiepileptic drug candidate, one that demonstrates a potent, broad spectrum of seizure protection and a high CNS tolerability in animal models, with initial clinical findings suggestive of straightforward pharmacokinetics and good tolerability.
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PMID:Seletracetam (UCB 44212). 1719 25

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study aimed to evaluate the safety and efficacy of levetiracetam (Keppra, LEV) as add-on therapy for refractory partial seizures in clinical practice. This Phase IV, 16-week, open-label study recruited patients > or =16-year old with treatment-resistant partial seizures. LEV (1000 mg/day) was added to a stable concomitant antiepileptic drug regimen. LEV dosage was adjusted based on seizure control and tolerability to a maximum of 3000 mg/day. 1541 patients (intent-to-treat population) were recruited including 1346 (87.3%) who completed the study and 77.0% who declared further continuing on LEV after the trial. Overall, 50.5% of patients reported at least one adverse event that was considered related to LEV treatment. The most frequently reported drug-related adverse events were mild-to-moderate somnolence, fatigue, dizziness and headache. Serious adverse events considered related to LEV occurred in 1.0% of patients. 7.5% of patients reported adverse events as the most important reason for study drug discontinuation. The median reduction from baseline in the frequency of all seizures was 50.2%; 15.8% of patients were seizure free; 50.1% had seizure frequency reduction of > or =50%. At the end of the study, 60.4% of patients were considered by the investigator to show marked or moderate improvement. There was a significant improvement in health-related quality of life as assessed with the QOLIE-10-P (total score increasing from 55.6 to 61.6; p<0.001). This community-based study suggests that LEV is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of LEV demonstrated in the pivotal Phase III placebo-controlled studies.
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PMID:The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. 1768 53


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