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)

SV2A, a synaptic vesicle protein, has been recently identified as a binding target for levetiracetam (Keppra). The specific mechanism by which SV2A binding leads to seizure protection has not yet been fully elucidated. However, a functional correlation between SV2A binding affinity and anticonvulsant potency has been observed in the mouse audiogenic seizure model. The present study was undertaken to test whether similar correlations exist in rodent models of partial and generalized epilepsies. As expected, there was a high degree of correlation between anticonvulsant potency and SV2A binding affinity in the mouse audiogenic seizure model (r(2)=0.77; p<0.001). A similar correlation was also observed in the mouse corneal kindling (r(2)=0.80; p<0.01) and in the rat model of generalized absence epilepsy (GAERS) (r(2)=0.72; p<0.01). Moreover, there were no significant differences between the slopes and intercepts of regression lines in these models. Interestingly, the protective potencies in these three epilepsy models were also well correlated with each other. As such, protective doses of a given SV2A ligand in one model could be easily predicted based on the data obtained in another model. Taken together, these results support the concept that SV2A protein is an important target for both partial and generalized epilepsies and thereby relevant for the generation of new antiepileptic drugs with potential broad-spectrum efficacy.
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PMID:SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. 1820 4

There is accumulating evidence that epileptic activity is accompanied by inflammatory processes. In the present study, we evaluated the effect of levetiracetam (Keppra), an anticonvulsant drug with decisive antiepileptic features, with regard to its putative antiinflammatory potential. We previously established an in vitro cell culture model to mimic inflammatory conditions: Primary astrocytic cultures of newborn rats were cocultured with 30% (M30) microglial cells. Alternatively, cocultures containing 5% microglia (M5) were incubated with the proinflammatory mediator, the cytokine interleukin-1beta (IL-1beta), and lipopolysaccharide (LPS), a potent bacterial activator of the immune system. For the M30 cocultures, we observed reduced expression of connexin 43 (Cx43), the predominant gap junction protein. Impaired functional dye coupling and depolarized membrane resting potential (MRP) were monitored in M30 cocultures as well as in M5 cocultures treated with IL-1beta and LPS. We could show that the Cx43 expression, the coupling property, and the membrane resting potential on which we focused our inflammatory coculture model were normalized to noninflammatory level under treatment with levetiracetam (Keppra). Cumulatively, our results provide evidence for antiinflammatory properties of levetiracetam in seizure treatment.
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PMID:Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. 1833 43

A comparative analysis of treatment with keppra and topamax of various types of epilepsy has been carried out in 37 patients aged from 1 to 35 years. Symptomatic temporal-frontal-lobe epilepsy was diagnosed in 22 patients, symptomatic temporal lobe epilepsy in 15 including "urgent aid" cases with previous antiepileptic therapy being ineffective. Effect of the drugs on the cerebral blood flow was studied with the single proton emission CT. Keppra treatment was assigned to 20 patients in dosages varying from 500 to 2,500 mg (30-50 mg/kg/daily) for single intake. Then the patients received the drug two times daily under the clinical and EEG control. The drug was tested for using in the "urgent care mode". The clinical effect by 43% decreasing (p<0,001) of seizures was observed in the first 12 h. The "stability state" was 80% after 8 months of the treatment. Topamax was administered to 17 patients in two dosages depending on patient's age and weight starting with 25-50 mg (from 3 to 12,5 mg/kg/daily) with the dose adjustment during 2 days. The latter was depended on the dynamics of clinical data and EEG. For the first 2 days, patients revealed changes in seizures quality: the seizure structure became less complex, without generalized seizures, and period of a seizure was shorter. Reduction of seizures frequency was observed on the 7-10th day and made up on average 73,9% (p<0,01). Comparing to keppra, topamax did not cause signs of autonomic and psychological discomfort. Generalized seizures became less frequent by the 3rd day.
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PMID:[Dynamics of clinical, neurophysiological and radiological indices as a criterion for evaluation of treatment quality of symptomatic epilepsy with keppra and topamax]. 1837 76

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.
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PMID:Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam. 1862 16

Efficacy of keppra was studied in 52 patients, aged 10-55 years, after the surgical treatment of gliomas of the brain hemispheres. The medication was used (in combination with other anticonvulsant drugs and hormones) during the radiotherapy. In 30 (57,8%) of cases epileptic seizures were before the surgery. In 22 (42,2%) of patients they developed during the radiotherapy. Keppra was used in the regiment of "urgent aid" in relation to the appearance of seizures and increase of their frequency during the radiotherapy. Doses of keppra varied from 500 to 2500 mg (30-50 mg/kg/day) in a single dose. Then patients received the drug 2 times daily under the control of clinical and EEG presentations. A clinical effect, including the decrease of seizures frequency by 48,3% (p<0,001), positive changes of quality of seizures (more simple structure, reduced time of seizures), was observed for the first 24 h and in future the state of patients was stable. All patients have completed the course of radiotherapy. The choice of dose was depended on age, body mass and dynamics of clinical and EEG data.
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PMID:[Use of keppra during the radiotherapy in patients with brain tumors and epileptic seizures after surgical treatment]. 1900 49

In this paper we review the current information regarding the use of new antiepileptic drugs (AEDs) used as monotherapy in children. We specifically include the following AEDs: lamotrigine (Lamictal), topiramate (Topamax), zonisamide (Zonegran), levetiracetam (Keppra), and oxcarbazepine (Trileptal). All of these AEDs have a broad spectrum of action in the treatment of partial and generalized seizures, except Oxcarbazepine, which is effective only in partial seizures. It is unclear whether or not monotherapy with the new AEDs offers higher efficacy and/or lower side effects compared to classic AEDs (phenobarbital, phenytoin, carbamazepine, or valproate) thereby significantly improving the quality of life in children with epilepsy. More studies are needed to answer these questions.
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PMID:[Role of monotherapy with new antiepileptic drugs in the treatment of childhood epilepsy]. 1924 7

Seletracetam is a pyrrolidone derivative with a one-log-unit higher affinity for the synaptic vesicle protein 2A (SV2A) than levetiracetam (Keppra). This study explored its anticonvulsant properties in animal models of epilepsy. Seletracetam reduced both the amplitude and repetitive firing of population spikes induced by a high K(+)/low Ca(2+) concentration fluid (HKLCF) in rat hippocampal slices. The reduction of HKLCF-induced increases in population spike amplitude was particularly pronounced, and occurred at approximately 10 times lower seletracetam concentrations than previously observed for levetiracetam. These invitro data suggest that desynchronisation of epileptiform activity may contribute significantly to the antiepileptic properties of seletracetam. Seletracetam also showed a potent anti-seizure activity in animal models mimicking partial-onset (kindled animals) and generalized epilepsy (audiogenic seizure susceptible mice and genetic absence epilepsy rats from Strasbourg (GAERS)). In amygdala-kindled rats, seletracetam increased the generalized seizure threshold current and decreased the duration of the after-discharge and the seizure severity observed at the after-discharge threshold current, and generally had a much more potent effect than previously observed for levetiracetam. Seletracetam showed no psychomimetic effects and a very high central nervous system (CNS) tolerability in both kindled and GAERS rats, markedly superior to that of levetiracetam and other antiepileptic drugs. These results suggest that seletracetam may represent an effective and very well tolerated broad-spectrum agent for the symptomatic treatment of epilepsy.
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PMID:Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy. 1938 93

Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR(); UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam's mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug-drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.
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PMID:Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. 1977 68

Poorly-controlled epilepsy can have a significant negative impact on quality of life, clinically important changes are seen in patients emotional well-being, cognitive functioning, social functioning and energy/fatigue levels. Poorly-controlled epilepsy places an undue economic burden on the patient and community. Increased costs are seen in both direct and indirect healthcare costs (e.g., inpatient care and loss of earnings associated with time lost from work). Therefore, long-term efficacy and tolerability are key considerations when designing the patient's treatment regimen. Therapy can be individualized using both classical drugs and newer antiepileptics such as levetiracetam (Keppra, UCB Pharma Inc.), which is currently recommended as add-on therapy for partial-onset seizures. Studies have revealed characteristics that suggest levetiracetam is the first of a new class of antiepileptic drugs, differentiated by its innovative mechanism of action. Its efficacy and tolerability have enabled many patients who were refractory to treatment with other antiepileptic drugs to achieve long-term seizure freedom. Levetiracetam has a high long-term retention rate, a powerful measure of adverse events and efficacy over time. Another equally important benefit is ease of use, levetiracetam is administered twice-daily and has a simple titration regimen. Pharmacoeconomic data show that the incremental cost of treating patients with levetiracetam is low when compared with the benefits of seizure freedom. Ongoing studies suggest that this antiepileptic drug has potential as first-line treatment for many types of epilepsy and in many different patient populations.
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PMID:Levetiracetam: an innovative and cost-effective add-on drug for refractory partial epilepsy. 1980 17

Breakthrough seizure activity has been reported with conversion from brand name to generic anticonvulsants. This has prompted several organizations to support physician notification of generic substitution and patient consent. Recently, a generic formulation of levetiracetam has become available. Risk of seizures with generic levetiracetam has yet to be reported. Literature was reviewed regarding risk of generic substitution. Four cases of seizure activity in primary brain tumor patients after conversion from Keppra to generic levetiracetam are reported. In all cases, there was no evidence of tumor growth or concurrent illness that would increase the risk of seizures. In three cases, the patients have remained seizure free with conversion back to Keppra. The final patient required an increased dose of levetiracetam. As has been described with generic substitution of other anticonvulsants, patients switched to generic levetiracetam may be at risk for breakthrough seizure activity.
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PMID:Seizure risk in brain tumor patients with conversion to generic levetiracetam. 1993 24


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